Fatty acid metabolism, energy expenditure and insulin resistance in muscle

in Journal of Endocrinology

Fatty acids (FAs) are essential elements of all cells and have significant roles as energy substrates, components of cellular structure and signalling molecules. The storage of excess energy intake as fat in adipose tissue is an evolutionary advantage aimed at protecting against starvation, but in much of today's world, humans are faced with an unlimited availability of food, and the excessive accumulation of fat is now a major risk for human health, especially the development of type 2 diabetes (T2D). Since the first recognition of the association between fat accumulation, reduced insulin action and increased risk of T2D, several mechanisms have been proposed to link excess FA availability to reduced insulin action, with some of them being competing or contradictory. This review summarises the evidence for these mechanisms in the context of excess dietary FAs generating insulin resistance in muscle, the major tissue involved in insulin-stimulated disposal of blood glucose. It also outlines potential problems with models and measurements that may hinder as well as help improve our understanding of the links between FAs and insulin action.

Abstract

Fatty acids (FAs) are essential elements of all cells and have significant roles as energy substrates, components of cellular structure and signalling molecules. The storage of excess energy intake as fat in adipose tissue is an evolutionary advantage aimed at protecting against starvation, but in much of today's world, humans are faced with an unlimited availability of food, and the excessive accumulation of fat is now a major risk for human health, especially the development of type 2 diabetes (T2D). Since the first recognition of the association between fat accumulation, reduced insulin action and increased risk of T2D, several mechanisms have been proposed to link excess FA availability to reduced insulin action, with some of them being competing or contradictory. This review summarises the evidence for these mechanisms in the context of excess dietary FAs generating insulin resistance in muscle, the major tissue involved in insulin-stimulated disposal of blood glucose. It also outlines potential problems with models and measurements that may hinder as well as help improve our understanding of the links between FAs and insulin action.

Overview

Fatty acids (FAs) are organic acids largely defined by the length and saturation of the aliphatic side chain attached to a carboxylic acid. In animals, these side chains normally contain an even number of carbon atoms and FAs are grouped into short chain (2–6 carbon atoms), medium chain (8–12 carbon atoms), long chain (14–18 carbon atoms) and very long chain (20–26 carbon atoms). The major types of FAs in the circulation and in the tissues of mammals are the long-chain and very-long-chain FAs with varying degrees of saturation. These include palmitic acid (C16:0), palmitoleic acid (C16:1), stearic acid (C:18:0), oleic acid (C18:1n-9), linoleic acid (C18:2n-6) and, particularly in smaller mammals, arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3). These FAs are the major components of storage triglycerides and cellular membranes, and although C16–C18 FAs are also components of some of the FA-derived signalling molecules (diacylglycerols (DAGs) and ceramides), many of the major lipid signalling molecules (prostaglandins and leukotrienes) are synthesised from very-long-chain, unsaturated FAs (e.g. arachidonic and docosahexaenoic acids) ( Kruger et al. 2010).

In the context of the links between excessive lipid storage (obesity) and reduced insulin action (insulin resistance) in muscle, this article will deal with FAs as an alternative energy substrate to glucose, the relevance of this substrate competition to overall energy expenditure and an assessment of the various mechanisms by which excess FA availability is thought to reduce insulin action in muscle and predispose to metabolic diseases.

Fuel for energy production

All three of the major types of macromolecules that make up organic material (carbohydrates, proteins and fats) can be broken down and oxidised to provide energy for the maintenance, growth and reproduction of biological systems. In animals, all proteins have a cellular function (e.g. as enzymes, or with structural or carrier function), and there is no identifiable depot of proteins specifically manufactured and stored solely for future use in energy production. On the other hand, carbohydrates and fats in various forms have specific and important functional roles in cells, but are also present in animal tissues as energy storage depots of glucose polymers (glycogen) and lipid droplets (triglycerides). Although glycogen and triglyceride stores can be found in nearly all tissues, glycogen stored in the liver is critical for the maintenance of blood glucose levels when glucose is not being absorbed from the gut and triglycerides stored in adipose tissue act as an alternative, more reduced and higher energy-yielding substrate (in terms of energy per gram) for energy production in tissues with a capacity for fat oxidation. Although excess protein intake can be converted to glucose and FAs for energy storage and glucose can also be converted to fat for energy storage or amino acids for protein synthesis, it is one of the maxims of energy metabolism that fat cannot be quantitatively converted to carbohydrate or protein. Essentially, this means that FAs stored in adipose tissue can only be used as an energy source to support cellular functions or to provide specific precursors that are needed to replace or expand the structure or signalling functions of FAs.

The contribution of different tissues to fuel oxidation and energy expenditure

Some tissues have an obligatory need for glucose (brain, red blood cells and retinal cells), while most tissues have the capacity to switch between glucose and FAs. The contribution of different fuels to energy production in specific tissues and the contribution of different tissues to the overall energy production and utilisation in the whole body vary quite markedly. Because of its relative size in man and most animals, muscle is considered to be a major tissue for the disposal of both glucose (James et al. 1985, Shulman et al. 1990) and FAs (Furler et al. 2000). Because of the ability of muscle to substantially increase energy expenditure during exercise (Bangsbo 2000), this tissue is also very flexible in its capacity to act as a sink for energy substrates. Other tissues such as the heart have a similar capacity to increase both the amount and type of substrate oxidation depending on demand, but because of the relative size of heart to muscle in the body, the overall contribution of the heart to whole-body substrate oxidation is only 5–10% (Rolfe & Brown 1997). The liver has a significant role in the disposal of glucose after a meal and in the provision of glucose to the circulation to maintain blood glucose levels when nutrients are not being absorbed from the gut. The liver also has the ability to take up FAs, oxidise them or package them in lipoproteins for export and storage in other tissues and is therefore central to lipid and glucose homoeostasis (Postic et al. 2004, Moore et al. 2012). Adipose tissue can, particularly in obese individuals, be the tissue contributing most to whole-body mass, but per unit mass it does not have a major impact on whole-body glucose disposal (Kraegen et al. 1985, Ng et al. 2012). White adipose tissue also has little impact on the whole-body oxidation of FAs, although there is significant current research interest in investigating whether white adipocytes can acquire a more oxidative brown adipocyte phenotype with a greater contribution to whole-body substrate oxidation and energy expenditure (Wu et al. 2013).

The effect of fibre composition and exercise on substrate utilisation by muscle

Although the musculature as a whole is a major contributor to total body glucose and FA metabolism (Ng et al. 2012), individual muscles may contribute differently depending on their fibre composition. Type 1 red muscle fibres are considered more insulin sensitive, with a greater oxidative capacity for glucose and FAs, while type II white muscle fibres contain less mitochondria, are considered less insulin sensitive and contribute less to FA oxidation (Nyholm et al. 1997, Pearen et al. 2012). Therefore, a higher composition of type 1 red fibres in muscle has been reported to be associated with increased insulin responsiveness (Stuart et al. 2013). This view has been challenged by some recent studies where genetically manipulated mice (Izumiya et al. 2008, Meng et al. 2013) and pharmacological approaches (Akpan et al. 2009) suggest that altering the fibre composition of muscles towards glycolytic type II fibres improves glucose homoeostasis and insulin action in the whole animal. It does seem important to consider that the contribution of the skeletal musculature to whole-body energy metabolism and substrate oxidation should not be based on the assessment of these parameters in a single muscle type. Acute exercise and exercise training also have a significant impact on substrate preference and utilisation at a whole-body and muscle level (Spriet & Watt 2003, Kiens 2006). Some of these effects correlate with observed shifts in muscle size and fibre type that occur with training (Shaw et al. 2012, Stuart et al. 2013), but other adaptations in muscle metabolism and body organs could also contribute to changes in energy metabolism and substrate utilisation associated with exercise (Laughlin & Roseguini 2008).

Linking substrate oxidation to energy conservation and energy expenditure

The pathways by which different fuels are oxidised to support tissue and cellular energy demands in animals are thoroughly dealt with in major textbooks and summarised in Fig. 1. Through the glycolytic pathway, pyruvate dehydrogenase (PDH) and the tricarboxylic acid (TCA) cycle, glucose can be completely oxidised to CO2 and the energy released (as reducing equivalents) harnessed in the form of NADH+H+ and FADH2. NADH+H+ and FADH2 are reoxidised by the electron transport chain (ETC) and the reducing equivalents used to reduce atomic oxygen to water. The electrochemical (proton) gradient generated by the ETC then drives ATP synthesis via ATP synthase (Fig. 1). The oxidation of FAs by the mitochondrial β-oxidation pathway also produces NADH+H+ and FADH2 for the ETC and acetyl CoA that can also be completely oxidised in the TCA cycle. Because FAs are chemically more reduced molecules than carbohydrates, FAs are theoretically able to produce more energy when completely oxidised than an equivalent carbohydrate molecule. In other words, the complete oxidation of six-carbon glucose consumes six oxygen molecules and produces six carbon dioxide molecules accompanied by the synthesis of 36 ATP molecules. On the other hand, the complete oxidation of six-carbon hexanoic acid consumes eight oxygen molecules and produces six carbon dioxide molecules for 44 ATP molecules. Such calculations are based on a fixed stoichiometry between NADH+H+ and FADH2 oxidation and ATP synthesis and can lead to the conclusion that the oxidation of FAs produces ATP at a cost of greater oxygen consumption or lower efficiency. Therefore, a switch to the oxidation of FAs as the major energy substrate should result in less efficient ATP production and an increase in whole-body energy expenditure that could lead to a loss of fat mass if energy intake remains constant (Clapham 2004a,b, Leverve et al. 2007).

Figure 1
Figure 1

Pathways of substrate metabolism in muscle. Oxidation pathways of glucose, FAs and amino acids converge at the level of acetyl CoA. The energy of oxidation is conserved as NADH+H+ and FADH2, which are used by the electron transport chain to produce a chemiosmotic gradient across the inner mitochondrial membrane. This proton motive force is dissipated by ATP synthesis and by proton leak via the adenine nucleotide transporter (ANT) and activated uncoupling proteins (UCPx). Demand for ATP and proton leak are greater determinants of oxygen consumption and heat production than the substrate being oxidised.

Citation: Journal of Endocrinology 220, 2; 10.1530/JOE-13-0397

Indirect calorimetry is often used in human and animal studies to determine total energy expenditure (indirectly by the measurement of oxygen consumption and carbon dioxide production), and the measurement of oxygen consumption and carbon dioxide production can also be used to calculate the relative use of glucose and FAs to support that energy expenditure (respiratory exchange ratio, RER), assuming that any contribution of protein oxidation is relatively small and constant (Ferrannini 1988, Arch et al. 2006). Based on the assumption that there is a direct stoichiometry between NADH+H+ and FADH2 oxidation, proton translocation and ATP synthesis, calculations have been made suggesting that a complete switch from glucose to FAs as a source of energy would increase oxygen consumption by 7%. However, in practice, it is unlikely that such theoretical calculations can be applied to the regulation of energy balance with any certainty. For instance, rarely does the measured RER shift from complete glucose oxidation (1.0) to complete FA oxidation (0.7), even with prolonged exercise (Gimenez et al. 2013) and starvation (Hoeks et al. 2010) or without some change in protein oxidation. More importantly, although there is a direct stoichiometry between the oxidation of a substrate molecule and the production of NADH+H+ and FADH2, NADH+H+ can be reoxidised in reactions other than Complex I of the ETC and the proton motive force generated by the ETC can be dissipated by processes other than ATP synthesis (e.g. counter-ion transport and uncoupling protein activity) (Mazat et al. 2013). The concepts of efficiency and plasticity in the coupling of substrate oxidation to energy conservation (ATP synthesis) have been expanded on in several authoritative review articles (Harper et al. 2008, Mazat et al. 2013). These review articles have highlighted the presence of a significant and variable basal proton leak in mitochondria (20–25%) of most tissues and reported that in perfused rat muscle systems futile proton cycling may contribute as much as 50% to the respiration rate (Rolfe & Brand 1996), although other methodologies have suggested that this could be as little as 10% (Marcinek et al. 2004, Conley et al. 2007).

Irrespective of the exact mechanisms of proton leak and mitochondrial coupling of substrate oxidation to ATP production and oxygen consumption, it seems clear that using strict stoichiometric relationships (three ATPs per NADH+H+ and two ATPs per FADH2) to calculate whole-body oxygen consumption and energy expenditure from the measurements of relative substrate oxidation is unlikely to reflect the actual measurements of energy expenditure. In reality, coupling efficiency can vary significantly depending on changes in proton leak or ATP demand, but in cell systems at least, changes in substrate oxidation do not appear to influence the relationship between oxygen consumption and ATP synthesis (Brand et al. 1993).

Can switching substrate alter energy expenditure?

The above discussion clearly leads to the conclusion that the cost of generating mitochondrial ATP in terms of ETC activity and oxygen consumption can vary significantly and is not affected to any large extent by the substrate being oxidised to provide the reducing equivalents for electron transport. Despite this, it is not uncommon to read about studies in whole animal systems (particularly genetically modified mice) where differences in fat mass are often mechanistically related to changes in the mRNA levels of FA metabolism genes in a variety of tissues without appropriate consideration of the contribution of these tissues to whole-body energy expenditure (Abu-Elheiga et al. 2001, 2003, Lee et al. 2009, Hu et al. 2012, Ronis et al. 2013). In the context of investigations of energy balance in lean and obese mice, there are excellent recent reviews pointing out potential problems with assessing differences in food intake and energy expenditure using indirect calorimetry systems and extrapolating any differences to explain gain or loss of fat mass (Butler & Kozak 2010, Tschop et al. 2012). For example, expression of oxygen consumption or heat production on a kilogram body weight basis can be misleading if animals have significantly different amounts of fat tissue, because the metabolic rate of fat per gram is much lower in tissues such as muscle and liver (Frayn et al. 1995). Similarly, the difference in daily food intake needed to contribute to a significant gain of body fat over several weeks in mice can be so small as to be undetectable unless large numbers of mice (200–300) are used for the comparison (Tschop et al. 2012). Changes in the body weight and body fat of groups of adult mice with different genotypes on different diets should reflect cumulative differences in energy intake and energy expenditure. However, any differences might not be easily detected if animals are assessed for food intake and energy expenditure individually in indirect calorimetry systems, away from their home cage and communal environment for only a 24–48-h period of the several weeks over which body weight and fat mass have been monitored.

AMPK activation, FA oxidation and energy expenditure

AMP-activated protein kinase (AMPK) is recognised as a master regulator of energy metabolism, particularly in times of energy stress such as exercise, hypoxia and starvation (Hardie et al. 2012). The activation of AMPK has been shown to acutely increase FA and glucose uptake and metabolism in a variety of experimental situations including in vitro and in vivo experiments in muscle (Iglesias et al. 2004, Smith et al. 2005). The long-term effects of AMPK activation in muscle lead to the activation of gene transcription pathways that increase mitochondrial biogenesis and proteins of oxidative metabolism (Winder et al. 2000, Hardie et al. 2012). The acute regulation of FA oxidation by AMPK is largely through the phosphorylation and inactivation of the enzyme acetyl CoA carboxylase 2 (ACC2). ACC2 produces malonyl CoA, an allosteric inhibitor of the key enzyme carnitine palmitoyltransferase 1 (CPT1), which controls the entry of FAs into the mitochondria for oxidation (Hardie & Pan 2002).

The pharmacological activation of AMPK has been shown to produce changes in muscle metabolic pathway capacity similar to those produced by exercise training (O'Neill et al. 2013); however, there is considerable controversy as to whether AMPK activation can drive energy expenditure in the absence of exercise. A series of studies employing genetic deletion of Acc2 (Acacb) have reported reduced fat depots in association with increased FA oxidation in isolated muscle (Abu-Elheiga et al. 2001, 2003) and have subsequently reported increased energy expenditure (although not increased FA oxidation) in Acc2-knockout mice with less fat and less lean mass (Choi et al. 2007). These results suggest that the inhibition of ACC2 by the activation of AMPK or development of ACC2 inhibitors might promote FA oxidation and produce fat loss. Subsequent studies using independently generated Acc2-knockout mice did not reproduce these effects, reporting that although these mice exhibited increased FA oxidation at the whole-body and isolated muscle level, there was no measurable difference in energy expenditure, fat mass or food intake (Hoehn et al. 2010). However, there was an increased glycogen content in muscle, an effect of AMPK activation noted previously (Winder et al. 2000, Buhl et al. 2001), which is consistent with AMPK activation and ACC2 inhibition promoting FA oxidation and channelling glucose taken up by muscle into storage as glycogen (Vitzel et al. 2013). Another study using independently generated genetically manipulated mice has reported no difference in body weight, food intake or fat mass in global or muscle-specific Acc2 gene-deleted mice (Olson et al. 2010), adding to the conclusion that altering FA oxidation in the absence of any change in energy expenditure or energy intake is insufficient to have a significant impact on whole-body fat mass.

Therefore, it would appear that apart from theoretical calculations suggesting that increasing fat oxidation will drive increased energy expenditure, there is little experimental evidence to support the idea that energy expenditure can be increased simply by increasing substrate availability or by switching to oxidise FAs.

Insulin regulation of energy metabolism

From an energy metabolism point of view, the flow of different substrates to tissues for oxidation or storage is largely under the control of the circulating hormone insulin. After a meal, direct stimulation of the β-cells of the islets of Langerhans of the pancreas by nutrients (glucose, FAs and amino acids) increases insulin release into the circulation. Certain gut hormones (GLP1 and G-1-P) can also augment insulin secretion, as can neural signals from the brain (Thorens 2011). Insulin has many stimulatory and inhibitory actions in different tissues mediated by a complex intracellular signalling pathway, but for the purpose of this discussion, the actions of insulin to stimulate glucose uptake and metabolism in muscle and regulate FA metabolism will be a major focus. The failure of insulin to appropriately regulate glucose and FA metabolism is termed insulin resistance, and this condition is most frequently observed in the muscle and liver of overweight or obese individuals (Eckardt et al. 2011). Insulin resistance is considered a significant predisposing factor for the development of type 2 diabetes (T2D) and therefore there is considerable research effort put into determining the mechanistic relationship between excess lipid accumulation (obesity) and insulin resistance, particularly in muscle. Studies from over 20 years ago first showed that triglyceride accumulation in the muscle of high-fat diet-fed rats coincided with insulin resistance (Storlien et al. 1987, Kraegen et al. 1991), thereby establishing the hypothesis that insulin resistance is causally related to triglyceride accumulation in muscle. Since then, the relationship between muscle lipid accumulation and insulin resistance has also been established in humans, and many mechanisms have been put forward to explain how lipid accumulation could generate insulin resistance (Bosma et al. 2012, Samuel & Shulman 2012). Over the last decade, the major challenge has been determining whether these proposed mechanisms are universal or specific to the model of lipid-induced insulin resistance being studied. It is also possible that different mechanisms are important at different times during the development of insulin resistance and that some proposed mechanisms depend on the experimental methods used to assess insulin action.

Methods for assessing insulin action in muscle

All discussions of the relationship between increased fat metabolism and insulin action are dependent on the methodology used to assess insulin resistance and the assumptions associated with different methodologies. As has been mentioned previously, nearly all investigations of lipid-induced insulin resistance in rodent models utilise high-fat diet feeding to increase adiposity, but the methods of assessing insulin action can be quite varied and rely on glucose tolerance tests or insulin tolerance tests and less frequently (because of the technical difficulty) on hyperinsulinaemic–euglycaemic clamps. Various technical considerations of glucose and insulin tolerance tests must be considered when discussing the metabolic implications of these tests for muscle insulin action. The timing and route of administration of glucose and duration of fast before glucose administration influence the results of glucose tolerance tests (Andrikopoulos et al. 2008, McGuinness et al. 2009), and our recent studies suggest that changes in glucose tolerance may reflect changes in lipid content and insulin action in the liver more than insulin action in muscle, especially in the initial stages of fat accumulation after starting a high-fat diet (Montgomery et al. 2013, Turner et al. 2013). Insulin tolerance tests were devised largely to assess the effectiveness of counter-regulatory mechanisms in response to insulin-induced hypoglycaemia and therefore the utility of these tests to assess peripheral insulin action is debatable. This is particularly the case when conclusions about insulin effectiveness are related to glucose measurements in the later half of the test (30–90 min) when the injected insulin has largely been cleared or when there is a difference in basal glycaemia and results are expressed as % basal (McGuinness et al. 2009). Neither glucose tolerance nor insulin tolerance tests give specific data regarding insulin effectiveness in muscle, although several methodological variations have used concurrent injection of radioactive tracers to assess glucose clearance into muscle during a glucose tolerance or insulin tolerance test (Crosson et al. 2003, Cooney et al. 2004).

The hyperinsulinaemic–euglycaemic clamp with glucose tracer administration gives the most reproducible assessment of muscle glucose clearance in response to constant insulin stimulation and constant glucose availability (Ayala et al. 2006, Wasserman et al. 2011). This technique relies on plasma insulin levels (not insulin infusion rates) during the comparison of the clamp being matched between the groups. In many studies, plasma insulin levels during the clamp are not reported, making the assessment of muscle insulin action difficult (Chapman et al. 2010, Laskewitz et al. 2010, Parlevliet et al. 2010). In vitro assessment of insulin effectiveness in isolated soleus or extensor digitorum longus muscle is also often used to demonstrate the effects of FA exposure (Thompson et al. 2000, Alkhateeb et al. 2007), and although this methodology provides reproducible comparisons between control and treatment muscle, it is subject to all the assumptions of comparing the in vitro situation with the in vivo situation (e.g. reliance on diffusion and not on perfusion). While all the above methods can give useful information about the effects of muscle lipid accumulation on insulin action, this information can be specific for the test employed. Even the data obtained from hyperinsulinaemic–euglycaemic clamp studies describe fluxes measured after at least an hour of exposure to constant insulin stimulation and constant glucose availability, a situation that is unlikely to ever exist in the normal 24-h feeding–fasting cycle. Therefore, it would seem important to consider the method used to demonstrate a difference in insulin action with lipid accumulation, when assessing the relevance of various mechanisms to reduced glucose metabolism in muscle when no restrictive experimental conditions (e.g. in vitro assessment, constant infusion and i.p. delivery) have been applied to the ‘free-living’ system.

Linking intramyocellular triglyceride content and insulin action

As has been mentioned above, the association between intramyocellular triglyceride (IMTG) content and insulin resistance is now well established in animals and obese humans, and most studies investigating the mechanisms of insulin resistance in muscle use high-fat diet rodent models. It has also become standard practice in assessing the phenotype of genetically manipulated mice to place them on high-fat diets to investigate whether there is any impact (favourable or detrimental) of gene manipulation on glucose and energy homoeostasis. There is a reasonable assumption that, independent of genetic background in animals or humans, overconsumption of energy-dense diets plays a major role in the accumulation of fats and development of metabolic derangements in muscle. In humans, overconsumption of energy-dense diets for a few weeks is enough to increase fat mass and have detrimental effects on whole-body insulin action (Samocha-Bonet et al. 2010). In mice, high-fat feeding for as little as a few days can impair glucose tolerance (Turner et al. 2013) and 2–3 weeks of exposure to a high-fat diet is enough to observe significant insulin resistance in muscle using in vitro (Thompson et al. 2000) or in vivo (Turner et al. 2013) assessment. Apart from the well-documented ‘athlete's paradox’ where increased IMTG content is associated with improved insulin action (Coen & Goodpaster 2012), most interventions that change insulin action are associated with reciprocal changes in IMTG content. Studies that improved insulin sensitivity by low-calorie diets in patients with T2D were accompanied by a reduction in IMTG content (Jazet et al. 2008, Lara-Castro et al. 2008). Insulin resistance associated with ageing (Nakagawa et al. 2007), growth hormone administration (Krag et al. 2007) and post-burn trauma (Cree & Wolfe 2008) has been reported to be associated with increased IMTG content. Current opinion is reasonably clear on the fact that IMTG is a useful marker of the level of cytosolic lipid accumulation, but it is more likely that active lipid metabolites such as LCACoAs, DAGs and ceramides or intermediates of FA oxidation pathways interfere with insulin action via a variety of potential mechanisms (Fig. 2). These mechanisms are largely based on the idea that insulin resistance in muscle is the result of reduced transduction of the insulin signal through the phosphorylation cascade leading to the translocation of the glucose transporter GLUT4 to the sarcolemmal membrane (Stockli et al. 2011). A significant body of work in the 1990s using nuclear magnetic resonance has identified glucose transport/phosphorylation and glycogen synthesis as major defects in FA-induced insulin resistance in humans (Shulman et al. 1990, Roden et al. 1996). Since that time, research into the molecular mechanism of FA-induced insulin resistance in muscle has mainly focused on linking excess FAs to defects in the insulin signalling pathways that regulate glucose uptake. However, there are some established and some more speculative mechanisms that also link increased FA metabolism with reduced insulin action, and these are discussed in the subsequent sections.

Figure 2
Figure 2

Proposed mechanisms for the build-up of bioactive lipid species and how they interfere with insulin action in muscle to produce insulin resistance. DAG can activate lipid-sensitive kinases to serine phosphorylate and reduce tyrosine phosphorylation of IRS1. Ceramide can inhibit Akt phosphorylation and reduce transduction through the insulin signalling pathway. Circulating cytokines or FAs themselves are reported to activate inflammatory pathway serine kinases that interfere with insulin signalling. Reduced or dysregulated FA oxidation in mitochondria could create a build-up of bioactive lipids and generate reactive oxygen species (ROS) that also activate kinases that interfere with insulin signalling.

Citation: Journal of Endocrinology 220, 2; 10.1530/JOE-13-0397

Lipid intermediates, inflammation and insulin resistance

IMTGs are considered to be relatively benign with regard to insulin resistance (Goodpaster et al. 2001), largely because they are packaged into discrete lipid droplets that are located within the cytoplasm and are thus unlikely to directly interfere with proximal insulin signalling (Fujimoto & Parton 2011). However, despite the general consensus that IMTGs are metabolically inert, it is possible that the expanded IMTG pool generates intermediates of lipid metabolism that are more likely to play a mechanistic role in the development of muscle insulin resistance. In this respect, the bioactive lipid metabolites DAG and ceramide are leading candidates. The levels of both DAG (Turinsky et al. 1990, Turpin et al. 2009) and ceramide (Holland et al. 2007, Bruce et al. 2013) are elevated in the muscle of obese insulin-resistant rodents, and the earliest detectable defect in muscle insulin sensitivity in high-fat diet-fed mice is associated with the accumulation of these lipids (Turner et al. 2013). While less is known about the role of these lipids in humans, it has been reported that acute lipid-induced insulin resistance is associated with muscle DAG accumulation (Itani et al. 2002) and that ceramide levels are elevated in the muscle of obese insulin-resistant individuals (Amati et al. 2011). Furthermore, interventions that enhance insulin action, such as exercise training, cause reductions in muscle DAG and ceramide content (Bruce et al. 2006).

Mechanistically, DAG and ceramide are potent signalling molecules that may cause insulin resistance by activating a cascade of serine/threonine kinases that ultimately impinges upon insulin signalling (Summers et al. 1998, Ruvolo 2003, Li et al. 2004). Specifically, DAG accumulation is thought to impair insulin action via the activation of novel protein kinase C (PKC) isoforms, which subsequently inhibits insulin signal transduction to glucose transport via serine phosphorylation of insulin receptor substrate 1 (IRS1; Yu et al. 2002, Li et al. 2004). Ceramide has been reported to cause insulin resistance by impairing insulin signalling at the level of Akt (Schmitz-Peiffer et al. 1999, Bruce et al. 2006, Holland et al. 2007). In addition, ceramide is a potent activator of inflammatory molecules, including c-Jun N-terminal kinase (JNK; Westwick et al. 1995) and nuclear factor κB/inducer of κ kinase (IKK) (Wang et al. 1999), which have been reported to be associated with the development of muscle insulin resistance (Itani et al. 2002, Sriwijitkamol et al. 2006, Henstridge et al. 2012). However, while inflammation has been proposed as a critical factor causing insulin resistance, studies carried out by our group and other groups suggest that inflammation is not involved in the initiation of lipid-induced insulin resistance, but may be more important in the exacerbation and maintenance of insulin resistance once obesity is established (Lee et al. 2011, Turner et al. 2013).

Although there is mounting evidence supporting a role for DAG and ceramide in the regulation of insulin sensitivity, it is important to highlight that the accumulation of these lipids is not always associated with insulin resistance. In fact, a recent study has found that total DAG content is actually elevated in the muscle of highly insulin-sensitive endurance-trained athletes compared with the skeletal muscle of obese individuals (Amati et al. 2011). Furthermore, a positive correlation between total muscle ceramide content and insulin sensitivity has been reported (Skovbro et al. 2008). These data suggest a more complex role for DAG and ceramide in the regulation of insulin action (Amati et al. 2011) and emphasise the importance of not only determining the total content of these lipids but also examining specific molecular species as well as their subcellular localisation, as these are likely to be critical factors that influence the relationship between lipids, insulin signalling and muscle insulin sensitivity (Bergman et al. 2012).

While the bioactive lipid hypothesis has gained strong support, an alternative concept linking the accumulation of intermediates of mitochondrial FA oxidation with muscle insulin resistance has gained attention (Koves et al. 2008). This model proposes that lipid oversupply drives an increase in mitochondrial β-oxidation that exceeds the capacity of the Krebs cycle, leading to the accumulation of by-products of FA oxidation (Koves et al. 2008). This is supported by studies demonstrating an increase in incomplete FA oxidation and an accompanying increase in intramuscular acylcarnitine levels in obese rodents (Koves et al. 2008). While data in humans are currently limited, there is evidence that acylcarnitine does accumulate in the muscle of humans in response to a high-fat diet (Putman et al. 2003). However, it is not clear whether acylcarnitine plays a direct role in the modulation of skeletal muscle insulin sensitivity by disrupting signalling processes or whether it simply reflects a state of mitochondrial stress. Unravelling the role of acylcarnitine in muscle insulin sensitivity will no doubt be a focus of future research.

Mitochondrial dysfunction, reactive oxygen species and insulin resistance

Another prominent theory on the aetiology of insulin resistance implicates abnormalities in mitochondrial function as a major causative factor leading to reductions in insulin sensitivity. More specifically, defects in mitochondrial metabolism have been suggested to lead to inadequate substrate oxidation, precipitating a build-up of intracellular lipid metabolites, impaired insulin signalling and the subsequent development of insulin resistance (Lowell and Shulman 2005, Kim et al. 2008, Turner & Heilbronn 2008, Samuel & Shulman 2012).

The initial studies that set the platform for this theory in the late 1990s showed that there was reduced mitochondrial enzyme activity and decreased fat oxidation in the skeletal muscle of obese, insulin-resistant subjects and in individuals with T2D (Kelley et al. 1999, Simoneau et al. 1999, Kelley & Mandarino 2000, Kim et al. 2000). Kelley et al. (2002) also reported that mitochondrial size, as assessed by electron microscopy, was decreased in the muscle of obese subjects with insulin resistance and/or T2D. In the following year, two prominent microarray studies were published, describing a coordinated down-regulation of genes involved in mitochondrial biogenesis and oxidative phosphorylation in subjects with T2D and, importantly, also in non-diabetic individuals with a family history of T2D (Mootha et al. 2003, Patti et al. 2003).

In the ensuing decade since the publication of these landmark studies, many groups have reported defects in different mitochondrial parameters in the skeletal muscle of a range of different insulin-resistant populations (obese, T2D and PCOS). These include decreased mRNA and/or protein expression of mitochondrial genes/proteins (Morino et al. 2005, Heilbronn et al. 2007, Skov et al. 2007, Hwang et al. 2010), reductions in mitochondrial DNA (mtDNA) levels (Ritov et al. 2005, Boushel et al. 2007), lower oxidative enzyme activity (Ritov et al. 2005, 2010, Heilbronn et al. 2007) and a reduction in mitochondrial content measured by electron microscopy (Kelley et al. 2002, Morino et al. 2005, Ritov et al. 2005). Functional studies in muscle biopsy samples or in vivo using magnetic resonance spectroscopy have also reported decreases in mitochondrial oxidative capacity in insulin-resistant individuals (Petersen et al. 2003, 2004, Befroy et al. 2007, Mogensen et al. 2007, Phielix et al. 2008). Collectively, all these studies suggest that at some level, mitochondria in insulin-resistant individuals are not as effective at burning fuel substrates in muscle and this compromises insulin action.

Despite the large body of evidence described above, this area is controversial, as many studies report a dissociation between insulin resistance and mitochondrial dysfunction. For example, providing rodents with excess fat in their diet leads to an enhancement of mitochondrial oxidative capacity in muscle while at the same time inducing insulin resistance (Turner et al. 2007, Hancock et al. 2008, Stephenson et al. 2012). Several lines of mice with genetic manipulations that cause compromised mitochondrial function in muscle do not exhibit insulin resistance (Vianna et al. 2006, Wredenberg et al. 2006, Handschin et al. 2007, Pospisilik et al. 2007). Conversely, two separate lines of muscle-specific Pgc1α (Ppargc1a) transgenic mice displayed a significant enhancement in the markers of mitochondrial content and yet were insulin resistant due to excessive FA delivery and reduced GLUT4 (SLC2A4) expression in muscle (Miura et al. 2003, Choi et al. 2008). A growing number of studies in humans have also reported intact mitochondrial function in various insulin-resistant populations (De Feyter et al. 2008, Trenell et al. 2008, Lefort et al. 2010, van Tienen et al. 2012, Fisher-Wellman et al. 2013). Collectively, these studies suggest that mitochondrial dysfunction in muscle is not an obligatory factor required for the accumulation of intramuscular lipids and the development of insulin resistance. Furthermore, it has also been argued that as muscle has such a high amount of ‘spare’ capacity to elevate substrate oxidation over basal levels (Bangsbo 2000), it is questionable whether mitochondrial deficiencies of the magnitude reported in some insulin-resistant subjects would have any impact on the rate of FA oxidation (and lipid accumulation) when energy requirements are relatively low (e.g. normal free-living conditions) (Hancock et al. 2008).

In addition to their role as major sites for energy transduction, mitochondria are also known to be a major source of reactive oxygen species (ROS), which are produced as a by-product of normal metabolic reactions (Andreyev et al. 2005). ROS have the capacity to damage macromolecules, and when the production of these reactive species is in excess of the antioxidant defences, a state of oxidative stress results. FA catabolism is known to promote mitochondrial ROS production (St-Pierre et al. 2002, Anderson et al. 2009, Seifert et al. 2010), and studies carried out by several groups have shown that in cultured cell models, genetic or diet-induced obese rodents, and in human subjects fed a high-fat diet, there is increased mitochondrial ROS production in muscle in association with insulin resistance (Houstis et al. 2006, Anderson et al. 2009, Hoehn et al. 2009, Hey-Mogensen et al. 2012, Fisher-Wellman et al. 2013). Importantly, many studies have shown that insulin action is improved when mitochondrial ROS production is attenuated (Houstis et al. 2006, Anderson et al. 2009, Hoehn et al. 2009, Boden et al. 2012), indicating a potentially important role for reactive species generation in this organelle in insulin resistance. While the exact mechanism linking mitochondrial ROS with insulin resistance is not resolved, it has been proposed that insulin resistance may be caused by ROS-dependent changes in stress-sensitive Ser/Thr kinases, leading to perturbed insulin signalling, although this requires verification (Fisher-Wellman & Neufer 2012).

Substrate competition and reduced insulin action

Before the elucidation of the insulin signalling pathway and recognition of the complex processes involved in the translocation of GLUT4 from intracellular vesicles to sarcolemmal membrane, there was a large amount of experimental data pointing to significant FA regulation of glucose metabolism at the level of PDH (Randle et al. 1963, Randle 1998). If humans, animals or in vitro preparations of muscle are exposed to an increased availability of FAs in the presence of glucose, the oxidation of FAs increases and the oxidation and uptake of glucose decrease (Boden et al. 1994, Vaag et al. 1994). On the other hand, reduction of the availability of FAs by inhibiting lipolysis (Vaag et al. 1991, Lim et al. 2011) and blocking FA entry into the mitochondria reduces FA oxidation and increases glucose uptake and oxidation (Oakes et al. 1997, Timmers et al. 2012, Keung et al. 2013), although there are some reports that prolonged inhibition of FA oxidation can lead to reduced glucose uptake (Dobbins et al. 2001). Although the initial observations of Randle and colleagues on the reciprocal relationship between glucose and FA metabolism were made 50 years ago, the idea that increasing or reducing FA availability will reciprocally affect glucose utilisation is no less valid today. Therefore, in the context FA-induced insulin resistance, a role for substrate competition and regulation at the level of PDH should not be overlooked.

Reassessment of the role of insulin signalling in FA-induced insulin resistance

As outlined in other sections of this review, the current dogma suggests that the major mechanisms for FA-induced insulin resistance in muscle involve active lipid species interfering with insulin signalling via the activation of various serine kinases (Fig. 2). The canonical insulin signalling cascade comprises scaffolding proteins (e.g. IRS1) and enzymes (e.g. PI3 kinase, Akt and GSK3), and the activity of these proteins is modulated by tyrosine and/or serine phosphorylation. DAG via the activation of PKC and inflammatory factors via the activation of the serine kinases JNK and IKK are thought to serine phosphorylate and reduce the insulin receptor-mediated tyrosine phosphorylation of IRS1 (Samuel & Shulman 2012). Mitochondrial insufficiency and ROS are also thought to feedback and impinge on the efficiency of insulin signalling via the activation of regulatory kinases. While there are many studies showing clear differences in the phosphorylation status of various insulin signalling proteins after insulin stimulation in control and FA-exposed or obese or high-fat diet-fed muscle, these changes are not always consistent. For example, a change in Akt phosphorylation is not always accompanied by a detectable change in downstream GSK3 or AS160 phosphorylation or upstream changes in IRS1 phosphorylation (Frangioudakis & Cooney 2008, Hoehn et al. 2008, Tonks et al. 2013). There are a number of studies reporting that insulin-stimulated Akt activation is in fact not impaired in the muscle of obese individuals with insulin resistance, of glucose-intolerant first-degree relatives of patients with T2D and of patients with T2D (Kim et al. 1999, Storgaard et al. 2004). Furthermore, in rats made insulin resistant by 5 h of hyperlipidemia/hyperinsulinaemia (Hoy et al. 2009) or in isolated soleus muscle made insulin resistant by palmitate incubation (Alkhateeb et al. 2007), no defect in insulin-stimulated Akt phosphorylation was reported. Finally, reduction of IRS1 levels in muscle by 60% by direct in vivo genetic manipulation did not result in impaired insulin action (Cleasby et al. 2007).

This dissociation between measured changes in insulin-stimulated glucose flux and insulin effects on signalling proteins has a number of implications. First, it might highlight the technical difficulties of obtaining reliable, quantitative data on protein modification using the essentially non-quantitative technique of immunoblotting. The ability to detect differences with this methodology can also depend on the affinity of individual antibodies, and the amount of phosphorylation does not necessarily correlate linearly with the activity of the signalling protein. A good example of this is provided by two studies showing that in adipocytes maximal insulin-stimulated glucose transport and GLUT4 translocation are achieved when only 10–20% of the total IRS1 and Akt is phosphorylated (Whitehead et al. 2001, Hoehn et al. 2008). If a similar situation exists in muscle, the physiological importance of statistically significant differences of 10–20% in the phosphorylation of signalling intermediates could be difficult to assess. The introduction of mass spectrometry techniques to analyse changes in global protein phosphorylation in response to insulin, as has been applied in adipocytes (Humphrey et al. 2013), could be helpful in this regard. Another possibility is that phosphorylation is not the only post-translational modification of proteins involved in the generation of lipid-induced insulin resistance. Recently, the emergence of nitrosative modifications (White et al. 2010), reversible acetylation, malonylation and succinylation of proteins in central metabolic pathways has revealed new possibilities by which increased FA metabolism could influence metabolic fluxes (Newman et al. 2012, Park et al. 2013). Similarly, reversible modification of proteins by O-linked N-acetylglucosamine has been proposed to have a significant impact on metabolism in response to nutrient levels (Bond & Hanover 2013, Ruan et al. 2013).

Circadian metabolism and insulin resistance

Another area of research that is increasingly realised to have a significant impact on metabolic disease is circadian biology. Daily patterns of activity and rest are historically aligned with feeding and fasting and changes in energy metabolism are intrinsically linked to the light/dark cycle (Bass 2012). The suprachiasmatic nucleus in the brain is considered to be the master regulator of circadian behaviour because of its ability to coordinate inputs from the environment (light, food, exercise and temperature), but it is now clear that every tissue has the molecular components that comprise the clock, raising the possibility that circadian processes in tissues could be regulated directly by some inputs. Some mouse models with genetic manipulations of core clock genes have altered circadian rhythms and are more prone to developing obesity (Turek et al. 2005, Kennaway et al. 2007, Paschos et al. 2012), and manipulation of feeding schedules in mice and rats has been shown to have significant effects on adiposity, energy expenditure and glucose homoeostasis (Bray et al. 2013, Coomans et al. 2013, Reznick et al. 2013). If there is an underlying rhythm to metabolism in muscle driven by the molecular clock (Lefta et al. 2011), the timing of experiments over the normal 24-h period might be critical to a proper understanding of how repeated daily exposure to a high-fat diet leads to lipid accumulation and insulin resistance in muscle. In fact, a recent report has suggested that the time of day can have a significant effect on the data obtained from euglycaemic-hyperinsulinaemic clamps in mice (Shi et al. 2013), and as rodents have an phase opposite to that of humans with regard to activity and sleep and feeding and fasting, the relevance of daylight experiments in nocturnal animals to human physiology requires renewed debate.

Summary and perspective

The correlation between increased FA availability and reduced insulin-stimulated glucose metabolism is well established. Despite this clear relationship, to date, there has been no unifying mechanism that explains lipid-induced reductions in insulin action under all circumstances. The most described mechanisms are that toxic lipid intermediates and/or activation of inflammatory and stress signalling pathways act to decrease the phosphorylation and function of proteins in the insulin signalling pathway, and this explains the decreased insulin-stimulated glucose uptake observed with lipid accumulation. However, there are an increasing number of experimental situations where reduced effects of insulin in muscle have been observed without significant changes in the phosphorylation of signalling proteins or where differences in phosphorylation are only observed with stimulation by supraphysiological insulin concentrations. This suggests that other control mechanisms or other forms of protein modification may predominate depending on the exact experimental conditions used to examine insulin resistance (e.g. bolus insulin injections, hyperinsulinaemic clamps and glucose or lipid infusion).

Figure 3 summarises some of the key control points other than insulin signalling for GLUT4 translocation that could alter the balance between glucose and FA metabolism and affect insulin-stimulated glucose disposal. For example, utilisation of glucose and FAs is dependent on their availability in the circulation and delivery to the muscle tissue, and changes in microvasculature occur with obesity and contribute to muscle insulin resistance (St-Pierre et al. 2010, Premilovac et al. 2013). Other work (Furler et al. 1991, Wasserman 2009) has established that glucose transport into muscle is not rate limiting for glucose metabolism under all conditions. The phosphorylation of glucose by hexokinase and the pathway for conversion of glucose-6-phosphate to glycogen are subject to regulation by glucose-6-phosphate and glycogen respectively, and decreased glucose phosphorylation and glycogen synthesis will affect glucose uptake (Fueger et al. 2007, Bouskila et al. 2010). Another well-documented node regulating the metabolism of glucose is centred on the activity of PDH. The activity of this enzyme complex is inhibited by phosphorylation via PDH kinase 4 (PDK4). Interestingly, the amount of PDK4 in muscle is significantly increased in high-fat diet-fed, insulin-resistant animals and PDK4 is activated by acetyl CoA, providing evidence that this regulatory node could significantly affect glucose metabolism in muscle as hypothesised by Newsholme and Randle many years ago (Randle et al. 1963) and many others since (Holness & Sugden 2003, Hue & Taegtmeyer 2009).

Figure 3
Figure 3

Nodes of control of glucose metabolism other than insulin-stimulated translocation of GLUT4 that could be influenced by the excess availability of FAs. Utilisation of glucose and FAs is dependent on their availability in the circulation and delivery to the muscle tissue. The phosphorylation of glucose and conversion to glycogen are regulated by substrate availability and G-6-P concentration. PDH is a critical regulator balancing glucose use and FA oxidation to support energy requirements. The regulation of FA sequestration in, or release from, muscle fat droplets can control the level of bioactive lipid species. The regulation of FA metabolism at the AMPK–ACC2–malonyl CoA–CPT1 axis also has a significant impact on the balance between FA and glucose metabolism. There are a number of newly recognised post-translational modifications that can occur on key metabolic or signalling proteins and would be expected to be influenced by changes in the availability and metabolism of FAs.

Citation: Journal of Endocrinology 220, 2; 10.1530/JOE-13-0397

FA metabolism in muscle can also be regulated at the membrane by transporter proteins (such as CD36), and at activation to acyl CoA by acyl CoA synthase (Glatz et al. 2010). The partitioning of FAs towards triglyceride storage or mitochondrial oxidation may depend on the activity of key enzymes such as glycerol phosphate acyltransferase and adipose triglyceride lipase (Greenberg et al. 2011, Watt & Hoy 2012). The entry of long-chain FAs into the mitochondria for oxidation is thought to be largely regulated by the activity of CPT1. The activity of CPT1 is modulated allosterically by malonyl CoA, and numerous studies, including our recently published papers using genetic and pharmacological interventions (Bruce et al. 2009, Hoehn et al. 2010), have manipulated CPT1B, AMPK and ACC activity to increase FA oxidation. Depending on the experimental design used, acutely increasing fatty oxidation in muscle can decrease glucose utilisation (Hoehn et al. 2010), while chronically increasing FA oxidation in muscle via CPT1 (CPT1B) overexpression can subsequently improve insulin-stimulated glucose uptake in fat-fed animals (Bruce et al. 2009). Interestingly, acute blockade of FA oxidation increases insulin-stimulated glucose uptake (Oakes et al. 1997), while chronic blockade of FA oxidation has been shown to be associated with decreased insulin sensitivity (Dobbins et al. 2001). These differences in acute and chronic responses when substrate metabolism is manipulated may be reconciled by considering the fact that energy metabolism is not constant in animals and humans, but has a substantial diurnal variation that is highly relevant to designing appropriate experiments to investigate lipid-induced insulin resistance.

In conclusion, it may be unrealistic to expect that a unifying mechanism may explain all situations where there is reduced glucose metabolism in muscle in response to insulin, as multiple factors may contribute to the establishment and long-term maintenance of insulin resistance in this tissue. With the emergence of powerful techniques for determining global changes in gene expression, protein modifications and metabolite profiles, it will hopefully become possible to gain a more comprehensive idea of the factors and pathways that may contribute to the aetiology of lipid-induced insulin resistance in muscle.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

The work carried out in the laboratories of the authors is supported by Program and Project grant funding from the National Health and Medical Research Council of Australia (NHMRC), the Australian Research Council (ARC) and the Diabetes Australia Research Trust. NT is supported by an ARC Future Fellowship. G J C and E W K hold research fellowships from the NHMRC and C R B has received a career development award from the NHMRC.

References

  • Abu-ElheigaLMatzukMMAbo-HashemaKAWakilSJ2001Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science29126132616. (doi:10.1126/science.1056843)

    • Search Google Scholar
    • Export Citation
  • Abu-ElheigaLOhWKordariPWakilSJ2003Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. PNAS1001020710212. (doi:10.1073/pnas.1733877100)

    • Search Google Scholar
    • Export Citation
  • AkpanIGoncalvesMDDhirRYinXPistilliEEBogdanovichSKhuranaTSUcranJLacheyJAhimaRS2009The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. International Journal of Obesity3312651273. (doi:10.1038/ijo.2009.162)

    • Search Google Scholar
    • Export Citation
  • AlkhateebHChabowskiAGlatzJFLuikenJFBonenA2007Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity. American Journal of Physiology. Endocrinology and Metabolism293E783E793. (doi:10.1152/ajpendo.00685.2006)

    • Search Google Scholar
    • Export Citation
  • AmatiFDubeJJAlvarez-CarneroEEdreiraMMChomentowskiPCoenPMSwitzerGEBickelPEStefanovic-RacicMToledoFG2011Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes?Diabetes6025882597. (doi:10.2337/db10-1221)

    • Search Google Scholar
    • Export Citation
  • AndersonEJLustigMEBoyleKEWoodliefTLKaneDALinCTPriceJWIIIKangLRabinovitchPSSzetoHH2009Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. Journal of Clinical Investigation119573581. (doi:10.1172/JCI37048)

    • Search Google Scholar
    • Export Citation
  • AndreyevAYKushnarevaYEStarkovAA2005Mitochondrial metabolism of reactive oxygen species. Biochemistry70200214.

  • AndrikopoulosSBlairARDelucaNFamBCProiettoJ2008Evaluating the glucose tolerance test in mice. American Journal of Physiology. Endocrinology and Metabolism295E1323E1332. (doi:10.1152/ajpendo.90617.2008)

    • Search Google Scholar
    • Export Citation
  • ArchJRHislopDWangSJSpeakmanJR2006Some mathematical and technical issues in the measurement and interpretation of open-circuit indirect calorimetry in small animals. International Journal of Obesity3013221331. (doi:10.1038/sj.ijo.0803280)

    • Search Google Scholar
    • Export Citation
  • AyalaJEBracyDPMcGuinnessOPWassermanDH2006Considerations in the design of hyperinsulinemic–euglycemic clamps in the conscious mouse. Diabetes55390397. (doi:10.2337/diabetes.55.02.06.db05-0686)

    • Search Google Scholar
    • Export Citation
  • BangsboJ2000Muscle oxygen uptake in humans at onset of and during intense exercise. Acta Physiologica Scandinavica168457464. (doi:10.1046/j.1365-201x.2000.00697.x)

    • Search Google Scholar
    • Export Citation
  • BassJ2012Circadian topology of metabolism. Nature491348356. (doi:10.1038/nature11704)

  • BefroyDEPetersenKFDufourSMasonGFde GraafRARothmanDLShulmanGI2007Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes5613761381. (doi:10.2337/db06-0783)

    • Search Google Scholar
    • Export Citation
  • BergmanBCHunerdosseDMKeregeAPlaydonMCPerreaultL2012Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia5511401150. (doi:10.1007/s00125-011-2419-7)

    • Search Google Scholar
    • Export Citation
  • BodenGChenXRuizJWhiteJVRossettiL1994Mechanisms of fatty acid-induced inhibition of glucose uptake. Journal of Clinical Investigation9324382446. (doi:10.1172/JCI117252)

    • Search Google Scholar
    • Export Citation
  • BodenMJBrandonAETid-AngJDPrestonEWilksDStuartECleasbyMETurnerNCooneyGJKraegenEW2012Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle. American Journal of Physiology. Endocrinology and Metabolism303E798E805. (doi:10.1152/ajpendo.00577.2011)

    • Search Google Scholar
    • Export Citation
  • BondMRHanoverJA2013O-GlcNAc cycling: a link between metabolism and chronic disease. Annual Review of Nutrition33205229. (doi:10.1146/annurev-nutr-071812-161240)

    • Search Google Scholar
    • Export Citation
  • BosmaMKerstenSHesselinkMKSchrauwenP2012Re-evaluating lipotoxic triggers in skeletal muscle: relating intramyocellular lipid metabolism to insulin sensitivity. Progress in Lipid Research513649. (doi:10.1016/j.plipres.2011.11.003)

    • Search Google Scholar
    • Export Citation
  • BoushelRGnaigerESchjerlingPSkovbroMKraunsoeRDelaF2007Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia50790796. (doi:10.1007/s00125-007-0594-3)

    • Search Google Scholar
    • Export Citation
  • BouskilaMHunterRWIbrahimAFDelattreLPeggieMvan DiepenJAVosholPJJensenJSakamotoK2010Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle. Cell Metabolism12456466. (doi:10.1016/j.cmet.2010.10.006)

    • Search Google Scholar
    • Export Citation
  • BrandMDHarperMETaylorHC1993Control of the effective P/O ratio of oxidative phosphorylation in liver mitochondria and hepatocytes. Biochemical Journal291739748.

    • Search Google Scholar
    • Export Citation
  • BrayMSRatcliffeWFGrenettMHBrewerRAGambleKLYoungME2013Quantitative analysis of light-phase restricted feeding reveals metabolic dyssynchrony in mice. International Journal of Obesity37843852. (doi:10.1038/ijo.2012.137)

    • Search Google Scholar
    • Export Citation
  • BruceCRHoyAJTurnerNWattMJAllenTLCarpenterKCooneyGJFebbraioMAKraegenEW2009Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes58550558. (doi:10.2337/db08-1078)

    • Search Google Scholar
    • Export Citation
  • BruceCRRisisSBabbJRYangCLee-YoungRSHenstridgeDCFebbraioMA2013The sphingosine-1-phosphate analog FTY720 reduces muscle ceramide content and improves glucose tolerance in high fat-fed male mice. Endocrinology1546576. (doi:10.1210/en.2012-1847)

    • Search Google Scholar
    • Export Citation
  • BruceCRThrushABMertzVABezaireVChabowskiAHeigenhauserGJDyckDJ2006Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. American Journal of Physiology. Endocrinology and Metabolism291E99E107. (doi:10.1152/ajpendo.00587.2005)

    • Search Google Scholar
    • Export Citation
  • BuhlESJessenNSchmitzOPedersenSBPedersenOHolmanGDLundS2001Chronic treatment with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes501217. (doi:10.2337/diabetes.50.1.12)

    • Search Google Scholar
    • Export Citation
  • ButlerAAKozakLP2010A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes59323329. (doi:10.2337/db09-1471)

    • Search Google Scholar
    • Export Citation
  • ChapmanJMilesPDOfrecioJMNeelsJGYuJGResnikJLWilkesJTalukdarSThaparDJohnsonK2010Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice. PLoS ONE5e13959. (doi:10.1371/journal.pone.0013959)

    • Search Google Scholar
    • Export Citation
  • ChoiCSBefroyDECodellaRKimSReznickRMHwangYJLiuZXLeeHYDistefanoASamuelVT2008Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. PNAS1051992619931. (doi:10.1073/pnas.0810339105)

    • Search Google Scholar
    • Export Citation
  • ChoiCSSavageDBAbu-ElheigaLLiuZXKimSKulkarniADistefanoAHwangYJReznickRMCodellaR2007Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. PNAS1041648016485. (doi:10.1073/pnas.0706794104)

    • Search Google Scholar
    • Export Citation
  • ClaphamJC2004aFat oxidation in obesity: druggable or risky enterprise?IDrugs: the Investigational Drugs Journal7238242.

  • ClaphamJC2004bTreating obesity: pharmacology of energy expenditure. Current Drug Targets5309323. (doi:10.2174/1389450043490451)

  • CleasbyMEReintenTACooneyGJJamesDEKraegenEW2007Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. Molecular Endocrinology21215228. (doi:10.1210/me.2006-0154)

    • Search Google Scholar
    • Export Citation
  • CoenPMGoodpasterBH2012Role of intramyocelluar lipids in human health. Trends in Endocrinology and Metabolism23391398. (doi:10.1016/j.tem.2012.05.009)

    • Search Google Scholar
    • Export Citation
  • ConleyKEAmaraCEJubriasSAMarcinekDJ2007Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo. Experimental Physiology92333339. (doi:10.1113/expphysiol.2006.034330)

    • Search Google Scholar
    • Export Citation
  • CoomansCPvan den BergSAHoubenTvan KlinkenJBvan den BergRPronkACHavekesLMRomijnJAvan DijkKWBiermaszNR2013Detrimental effects of constant light exposure and high-fat diet on circadian energy metabolism and insulin sensitivity. FASEB Journal2717211732. (doi:10.1096/fj.12-210898)

    • Search Google Scholar
    • Export Citation
  • CooneyGJLyonsRJCrewAJJensenTEMoleroJCMitchellCJBidenTJOrmandyCJJamesDEDalyRJ2004Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice. EMBO Journal23582593. (doi:10.1038/sj.emboj.7600082)

    • Search Google Scholar
    • Export Citation
  • CreeMGWolfeRR2008Postburn trauma insulin resistance and fat metabolism. American Journal of Physiology. Endocrinology and Metabolism294E1E9. (doi:10.1152/ajpendo.00562.2007)

    • Search Google Scholar
    • Export Citation
  • CrossonSMKhanAPrintenJPessinJESaltielAR2003PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance. Journal of Clinical Investigation11114231432. (doi:10.1172/JCI17975)

    • Search Google Scholar
    • Export Citation
  • De FeyterHMvan den BroekNMPraetSFNicolayKvan LoonLJPrompersJJ2008Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction. European Journal Endocrinology158643653. (doi:10.1530/EJE-07-0756)

    • Search Google Scholar
    • Export Citation
  • DobbinsRLSzczepaniakLSBentleyBEsserVMyhillJMcGarryJD2001Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes50123130. (doi:10.2337/diabetes.50.1.123)

    • Search Google Scholar
    • Export Citation
  • EckardtKTaubeAEckelJ2011Obesity-associated insulin resistance in skeletal muscle: role of lipid accumulation and physical inactivity. Reviews in Endocrine and Metabolic Disorders12163172. (doi:10.1007/s11154-011-9168-2)

    • Search Google Scholar
    • Export Citation
  • FerranniniE1988The theoretical bases of indirect calorimetry: a review. Metabolism37287301. (doi:10.1016/0026-0495(88)90110-2)

  • Fisher-WellmanKHNeuferPD2012Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends in Endocrinology and Metabolism23142153. (doi:10.1016/j.tem.2011.12.008)

    • Search Google Scholar
    • Export Citation
  • Fisher-WellmanKHWeberTMCatheyBLBrophyPMGilliamLAKaneCLMaplesJMGavinTPHoumardJANeuferPD2014Mitochondrial respiratory capacity and content are normal in young insulin-resistant obese humans. Diabetes63132141. (doi:10.2337/db13-0940)

    • Search Google Scholar
    • Export Citation
  • FrangioudakisGCooneyGJ2008Acute elevation of circulating fatty acids impairs downstream insulin signalling in rat skeletal muscle in vivo independent of effects on stress signalling. Journal of Endocrinology197277285. (doi:10.1677/JOE-07-0623)

    • Search Google Scholar
    • Export Citation
  • FraynKNHumphreysSMCoppackSW1995Fuel selection in white adipose tissue. Proceedings of the Nutrition Society54177189. (doi:10.1079/PNS19950047)

    • Search Google Scholar
    • Export Citation
  • FuegerPTLee-YoungRSShearerJBracyDPHeikkinenSLaaksoMRottmanJNWassermanDH2007Phosphorylation barriers to skeletal and cardiac muscle glucose uptakes in high-fat fed mice: studies in mice with a 50% reduction of hexokinase II. Diabetes5624762484. (doi:10.2337/db07-0532)

    • Search Google Scholar
    • Export Citation
  • FujimotoTPartonRG2011Not just fat: the structure and function of the lipid droplet. Cold Spring Harbor Perspectives in Biology3004838.1004838.17. (doi:10.1101/cshperspect.a004838)

    • Search Google Scholar
    • Export Citation
  • FurlerSMCooneyGJHegartyBDLim-FraserMYKraegenEWOakesND2000Local factors modulate tissue-specific NEFA utilization: assessment in rats using 3H-(R)-2-bromopalmitate. Diabetes4914271433. (doi:10.2337/diabetes.49.9.1427)

    • Search Google Scholar
    • Export Citation
  • FurlerSMJenkinsABStorlienLHKraegenEW1991In vivo location of the rate-limiting step of hexose uptake in muscle and brain tissue of rats. American Journal of Physiology261E337E347.

    • Search Google Scholar
    • Export Citation
  • GimenezPKerherveHMessonnierLAFeassonLMilletGY2013Changes in the energy cost of running during a 24-h treadmill exercise. Medicine and Science in Sports and Exercise4518071813. (doi:10.1249/MSS.0b013e318292c0ec)

    • Search Google Scholar
    • Export Citation
  • GlatzJFLuikenJJBonenA2010Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiological Reviews90367417. (doi:10.1152/physrev.00003.2009)

    • Search Google Scholar
    • Export Citation
  • GoodpasterBHHeJWatkinsSKelleyDE2001Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. Journal of Clinical Endocrinology and Metabolism8657555761. (doi:10.1210/jc.86.12.5755)

    • Search Google Scholar
    • Export Citation
  • GreenbergASColemanRAKraemerFBMcManamanJLObinMSPuriVYanQWMiyoshiHMashekDG2011The role of lipid droplets in metabolic disease in rodents and humans. Journal of Clinical Investigation12121022110. (doi:10.1172/JCI46069)

    • Search Google Scholar
    • Export Citation
  • HancockCRHanDHChenMTeradaSYasudaTWrightDCHolloszyJO2008High-fat diets cause insulin resistance despite an increase in muscle mitochondria. PNAS10578157820. (doi:10.1073/pnas.0802057105)

    • Search Google Scholar
    • Export Citation
  • HandschinCChoiCSChinSKimSKawamoriDKurpadAJNeubauerNHuJMoothaVKKimYB2007Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. Journal of Clinical Investigation11734633474. (doi:10.1172/JCI31785)

    • Search Google Scholar
    • Export Citation
  • HardieDGPanDA2002Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase. Biochemical Society Transactions3010641070. (doi:10.1172/JCI31785)

    • Search Google Scholar
    • Export Citation
  • HardieDGRossFAHawleySA2012AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Reviews. Molecular and Cellular Biology13251262. (doi:10.1038/nrm3311)

    • Search Google Scholar
    • Export Citation
  • HarperMEGreenKBrandMD2008The efficiency of cellular energy transduction and its implications for obesity. Annual Review of Nutrition281333. (doi:10.1146/annurev.nutr.28.061807.155357)

    • Search Google Scholar
    • Export Citation
  • HeilbronnLKGanSKTurnerNCampbellLVChisholmDJ2007Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. Journal of Clinical Endocrinology and Metabolism9214671473. (doi:10.1210/jc.2006-2210)

    • Search Google Scholar
    • Export Citation
  • HenstridgeDCBruceCRPangCPLancasterGIAllenTLEstevezEGardnerTWeirJMMeiklePJLamKS2012Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice. Diabetologia5527692778. (doi:10.1007/s00125-012-2652-8)

    • Search Google Scholar
    • Export Citation
  • Hey-MogensenMJeppesenJMadsenKKiensBFranchJ2012Obesity augments the age-induced increase in mitochondrial capacity for H2O2 release in Zucker fatty rats. Acta Physiologica204354361. (doi:10.1111/j.1748-1716.2011.02347.x)

    • Search Google Scholar
    • Export Citation
  • HoehnKLHohnen-BehrensCCederbergAWuLETurnerNYuasaTEbinaYJamesDE2008IRS1-independent defects define major nodes of insulin resistance. Cell Metabolism7421433. (doi:10.1016/j.cmet.2008.04.005)

    • Search Google Scholar
    • Export Citation
  • HoehnKLSalmonABHohnen-BehrensCTurnerNHoyAJMaghzalGJStockerRVan RemmenHKraegenEWCooneyGJ2009Insulin resistance is a cellular antioxidant defense mechanism. PNAS1061778717792. (doi:10.1073/pnas.0902380106)

    • Search Google Scholar
    • Export Citation
  • HoehnKLTurnerNSwarbrickMMWilksDPrestonEPhuaYJoshiHFurlerSMLaranceMHegartyBD2010Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metabolism117076. (doi:10.1016/j.cmet.2009.11.008)

    • Search Google Scholar
    • Export Citation
  • HoeksJvan HerpenNAMensinkMMoonen-KornipsEvan BeurdenDHesselinkMKSchrauwenP2010Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance. Diabetes5921172125. (doi:10.2337/db10-0519)

    • Search Google Scholar
    • Export Citation
  • HollandWLBrozinickJTWangLPHawkinsEDSargentKMLiuYNarraKHoehnKLKnottsTASieskyA2007Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metabolism5167179. (doi:10.1016/j.cmet.2007.01.002)

    • Search Google Scholar
    • Export Citation
  • HolnessMJSugdenMC2003Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochemical Society Transactions3111431151. (doi:10.1042/BST0311143)

    • Search Google Scholar
    • Export Citation
  • HoustisNRosenEDLanderES2006Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature440944948. (doi:10.1038/nature04634)

    • Search Google Scholar
    • Export Citation
  • HoyAJBrandonAETurnerNWattMJBruceCRCooneyGJKraegenEW2009Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation. American Journal of Physiology. Endocrinology and Metabolism297E67E75. (doi:10.1152/ajpendo.90945.2008)

    • Search Google Scholar
    • Export Citation
  • HuXLiYLiCFuYCaiFChenQLiD2012Combination of fucoxanthin and conjugated linoleic acid attenuates body weight gain and improves lipid metabolism in high-fat diet-induced obese rats. Archives of Biochemistry and Biophysics5195965. (doi:10.1016/j.abb.2012.01.011)

    • Search Google Scholar
    • Export Citation
  • HueLTaegtmeyerH2009The Randle cycle revisited: a new head for an old hat. American Journal of Physiology. Endocrinology and Metabolism297E578E591. (doi:10.1152/ajpendo.00093.2009)

    • Search Google Scholar
    • Export Citation
  • HumphreySJYangGYangPFazakerleyDJStockliJYangJYJamesDE2013Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metabolism1710091020. (doi:10.1016/j.cmet.2013.04.010)

    • Search Google Scholar
    • Export Citation
  • HwangHBowenBPLefortNFlynnCRDe FilippisEARobertsCSmokeCCMeyerCHojlundKYiZ2010Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes593342. (doi:10.2337/db09-0214)

    • Search Google Scholar
    • Export Citation
  • IglesiasMAFurlerSMCooneyGJKraegenEWYeJM2004AMP-activated protein kinase activation by AICAR increases both muscle fatty acid and glucose uptake in white muscle of insulin-resistant rats in vivo. Diabetes5316491654. (doi:10.2337/diabetes.53.7.1649)

    • Search Google Scholar
    • Export Citation
  • ItaniSIRudermanNBSchmiederFBodenG2002Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α. Diabetes5120052011. (doi:10.2337/diabetes.51.7.2005)

    • Search Google Scholar
    • Export Citation
  • IzumiyaYHopkinsTMorrisCSatoKZengLViereckJHamiltonJAOuchiNLeBrasseurNKWalshK2008Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metabolism7159172. (doi:10.1016/j.cmet.2007.11.003)

    • Search Google Scholar
    • Export Citation
  • JamesDEJenkinsABKraegenEW1985Heterogeneity of insulin action in individual muscles in vivo: euglycemic clamp studies in rats. American Journal of Physiology248E567E574.

    • Search Google Scholar
    • Export Citation
  • JazetIMSchaartGGastaldelliAFerranniniEHesselinkMKSchrauwenPRomijnJAMaassenJAPijlHOuwensDM2008Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients. Diabetologia51309319. (doi:10.1007/s00125-007-0862-2)

    • Search Google Scholar
    • Export Citation
  • KelleyDEGoodpasterBWingRRSimoneauJA1999Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. American Journal of Physiology277E1130E1141.

    • Search Google Scholar
    • Export Citation
  • KelleyDEHeJMenshikovaEVRitovVB2002Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes5129442950. (doi:10.2337/diabetes.51.10.2944)

    • Search Google Scholar
    • Export Citation
  • KelleyDEMandarinoLJ2000Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes49677683. (doi:10.2337/diabetes.49.5.677)

    • Search Google Scholar
    • Export Citation
  • KennawayDJOwensJAVoultsiosABodenMJVarcoeTJ2007Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues. American Journal of Physiology. Regulatory Integrative and Comparative Physiology293R1528R1537. (doi:10.1152/ajpregu.00018.2007)

    • Search Google Scholar
    • Export Citation
  • KeungWUssherJRJaswalJSRaubenheimerMLamVHWaggCSLopaschukGD2013Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice. Diabetes62711720. (doi:10.2337/db12-0259)

    • Search Google Scholar
    • Export Citation
  • KiensB2006Skeletal muscle lipid metabolism in exercise and insulin resistance. Physiological Reviews86205243. (doi:10.1152/physrev.00023.2004)

    • Search Google Scholar
    • Export Citation
  • KimJAWeiYSowersJR2008Role of mitochondrial dysfunction in insulin resistance. Circulation Research102401414. (doi:10.1161/CIRCRESAHA.107.165472)

    • Search Google Scholar
    • Export Citation
  • KimJYHicknerRCCortrightRLDohmGLHoumardJA2000Lipid oxidation is reduced in obese human skeletal muscle. American Journal of Physiology. Endocrinology and Metabolism279E1039E1044.

    • Search Google Scholar
    • Export Citation
  • KimYBNikoulinaSECiaraldiTPHenryRRKahnBB1999Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. Journal of Clinical Investigation104733741. (doi:10.1172/JCI6928)

    • Search Google Scholar
    • Export Citation
  • KovesTRUssherJRNolandRCSlentzDMosedaleMIlkayevaOBainJStevensRDyckJRNewgardCB2008Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metabolism74556. (doi:10.1016/j.cmet.2007.10.013)

    • Search Google Scholar
    • Export Citation
  • KraegenEWClarkPWJenkinsABDaleyEAChisholmDJStorlienLH1991Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes4013971403. (doi:10.2337/diab.40.11.1397)

    • Search Google Scholar
    • Export Citation
  • KraegenEWJamesDEJenkinsABChisholmDJ1985Dose–response curves for in vivo insulin sensitivity in individual tissues in rats. American Journal of Physiology248E353E362.

    • Search Google Scholar
    • Export Citation
  • KragMBGormsenLCGuoZChristiansenJSJensenMDNielsenSJorgensenJO2007Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL–triglyceride kinetics. American Journal of Physiology. Endocrinology and Metabolism292E920E927. (doi:10.1152/ajpendo.00374.2006)

    • Search Google Scholar
    • Export Citation
  • KrugerMCCoetzeeMHaagMWeilerH2010Long-chain polyunsaturated fatty acids: selected mechanisms of action on bone. Progress in Lipid Research49438449. (doi:10.1016/j.plipres.2010.06.002)

    • Search Google Scholar
    • Export Citation
  • Lara-CastroCNewcomerBRRowellJWallacePShaughnessySMMunozAJShiflettAMRigsbyDYLawrenceJCBohningDE2008Effects of short-term very low-calorie diet on intramyocellular lipid and insulin sensitivity in nondiabetic and type 2 diabetic subjects. Metabolism5718. (doi:10.1016/j.metabol.2007.05.008)

    • Search Google Scholar
    • Export Citation
  • LaskewitzAJvan DijkTHBloksVWReijngoudDJvan LieropMJDokterWHKuipersFGroenAKGrefhorstA2010Chronic prednisolone treatment reduces hepatic insulin sensitivity while perturbing the fed-to-fasting transition in mice. Endocrinology15121712178. (doi:10.1210/en.2009-1374)

    • Search Google Scholar
    • Export Citation
  • LaughlinMHRoseguiniB2008Mechanisms for exercise training-induced increases in skeletal muscle blood flow capacity: differences with interval sprint training versus aerobic endurance training. Journal of Physiology and Pharmacology59 (Suppl 7) 7188.

    • Search Google Scholar
    • Export Citation
  • LeeMSKimCTKimY2009Green tea (−)-epigallocatechin-3-gallate reduces body weight with regulation of multiple genes expression in adipose tissue of diet-induced obese mice. Annals of Nutrition and Metabolism54151157. (doi:10.1159/000214834)

    • Search Google Scholar
    • Export Citation
  • LeeYSLiPHuhJYHwangIJLuMKimJIHamMTalukdarSChenALuWJ2011Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes6024742483. (doi:10.2337/db11-0194)

    • Search Google Scholar
    • Export Citation
  • LefortNGlancyBBowenBWillisWTBailowitzZDe FilippisEABrophyCMeyerCHojlundKYiZ2010Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes5924442452. (doi:10.2337/db10-0174)

    • Search Google Scholar
    • Export Citation
  • LeftaMWolffGEsserKA2011Circadian rhythms, the molecular clock, and skeletal muscle. Current Topics in Developmental Biology96231271. (doi:10.1016/B978-0-12-385940-2.00009-7)

    • Search Google Scholar
    • Export Citation
  • LeverveXBatandierCFontaineE2007Choosing the right substrate. Novartis Foundation Symposium280108121.discussion 121-107 160-104

  • LiYSoosTJLiXWuJDegennaroMSunXLittmanDRBirnbaumMJPolakiewiczRD2004Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). Journal of Biological Chemistry2794530445307. (doi:10.1074/jbc.C400186200)

    • Search Google Scholar
    • Export Citation
  • LimELHollingsworthKGSmithFEThelwallPETaylorR2011Inhibition of lipolysis in type 2 diabetes normalizes glucose disposal without change in muscle glycogen synthesis rates. Clinical Science121169177. (doi:10.1042/CS20100611)

    • Search Google Scholar
    • Export Citation
  • LowellBBShulmanGI2005Mitochondrial dysfunction and type 2 diabetes. Science307384387. (doi:10.1126/science.1104343)

  • MarcinekDJSchenkmanKACiesielskiWAConleyKE2004Mitochondrial coupling in vivo in mouse skeletal muscle. American Journal of Physiology. Cell Physiology286C457C463. (doi:10.1152/ajpcell.00237.2003)

    • Search Google Scholar
    • Export Citation
  • MazatJPRansacSHeiskeMDevinARigouletM2013Mitochondrial energetic metabolism-some general principles. IUBMB Life65171179. (doi:10.1002/iub.1138)

    • Search Google Scholar
    • Export Citation
  • McGuinnessOPAyalaJELaughlinMRWassermanDH2009NIH experiment in centralized mouse phenotyping: the Vanderbilt experience and recommendations for evaluating glucose homeostasis in the mouse. American Journal of Physiology. Endocrinology and Metabolism297E849E855. (doi:10.1152/ajpendo.90996.2008)

    • Search Google Scholar
    • Export Citation
  • MengZXLiSWangLKoHJLeeYJungDYOkutsuMYanZKimJKLinJD2013Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation. Nature Medicine19640645. (doi:10.1038/nm.3144)

    • Search Google Scholar
    • Export Citation
  • MiuraSKaiYOnoMEzakiO2003Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1α down-regulates GLUT4 mRNA in skeletal muscles. Journal of Biological Chemistry2783138531390. (doi:10.1074/jbc.M304312200)

    • Search Google Scholar
    • Export Citation
  • MogensenMSahlinKFernstromMGlintborgDVindBFBeck-NielsenHHojlundK2007Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes5615921599. (doi:10.2337/db06-0981)

    • Search Google Scholar
    • Export Citation
  • MontgomeryMKHallahanNLBrownSHLiuMMitchellTWCooneyGJTurnerN2013Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia5611291139. (doi:10.1007/s00125-013-2846-8)

    • Search Google Scholar
    • Export Citation
  • MooreMCCoateKCWinnickJJAnZCherringtonAD2012Regulation of hepatic glucose uptake and storage in vivo. Advances in Nutrition3286294. (doi:10.3945/an.112.002089)

    • Search Google Scholar
    • Export Citation
  • MoothaVKLindgrenCMErikssonKFSubramanianASihagSLeharJPuigserverPCarlssonERidderstraleMLaurilaE2003PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics34267273. (doi:10.1038/ng1180)

    • Search Google Scholar
    • Export Citation
  • MorinoKPetersenKFDufourSBefroyDFrattiniJShatzkesNNeschenSWhiteMFBilzSSonoS2005Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. Journal of Clinical Investigation11535873593. (doi:10.1172/JCI25151)

    • Search Google Scholar
    • Export Citation
  • NakagawaYHattoriMHaradaKShiraseRBandoMOkanoG2007Age-related changes in intramyocellular lipid in humans by in vivo H-MR spectroscopy. Gerontology53218223. (doi:10.1159/000100869)

    • Search Google Scholar
    • Export Citation
  • NewmanJCHeWVerdinE2012Mitochondrial protein acylation and intermediary metabolism: regulation by sirtuins and implications for metabolic disease. Journal of Biological Chemistry2874243642443. (doi:10.1074/jbc.R112.404863)

    • Search Google Scholar
    • Export Citation
  • NgJMAzumaKKelleyCPencekRRadikovaZLaymonCPriceJGoodpasterBHKelleyDE2012PET imaging reveals distinctive roles for different regional adipose tissue depots in systemic glucose metabolism in nonobese humans. American Journal of Physiology. Endocrinology and Metabolism303E1134E1141. (doi:10.1152/ajpendo.00282.2012)

    • Search Google Scholar
    • Export Citation
  • NyholmBQuZKaalAPedersenSBGravholtCHAndersenJLSaltinBSchmitzO1997Evidence of an increased number of type IIb muscle fibers in insulin-resistant first-degree relatives of patients with NIDDM. Diabetes4618221828. (doi:10.2337/diab.46.11.1822)

    • Search Google Scholar
    • Export Citation
  • O'NeillHMHollowayGPSteinbergGR2013AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Molecular and Cellular Endocrinology366135151. (doi:10.1016/j.mce.2012.06.019)

    • Search Google Scholar
    • Export Citation
  • OakesNDCooneyGJCamilleriSChisholmDJKraegenEW1997Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes4617681774. (doi:10.2337/diab.46.11.1768)

    • Search Google Scholar
    • Export Citation
  • OlsonDPPulinilkunnilTClineGWShulmanGILowellBB2010Gene knockout of Acc2 has little effect on body weight, fat mass, or food intake. PNAS10775987603. (doi:10.1073/pnas.0913492107)

    • Search Google Scholar
    • Export Citation
  • ParkJChenYTishkoffDXPengCTanMDaiLXieZZhangYZwaansBMSkinnerME2013SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Molecular Cell50919930. (doi:10.1016/j.molcel.2013.06.001)

    • Search Google Scholar
    • Export Citation
  • ParlevlietETde Leeuw van WeenenJERomijnJAPijlH2010GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet. American Journal of Physiology. Endocrinology and Metabolism299E318E324. (doi:10.1152/ajpendo.00191.2010)

    • Search Google Scholar
    • Export Citation
  • PaschosGKIbrahimSSongWLKuniedaTGrantGReyesTMBradfieldCAVaughanCHEidenMMasoodiM2012Obesity in mice with adipocyte-specific deletion of clock component Arntl. Nature Medicine1817681777. (doi:10.1038/nm.2979)

    • Search Google Scholar
    • Export Citation
  • PattiMEButteAJCrunkhornSCusiKBerriaRKashyapSMiyazakiYKohaneICostelloMSacconeR2003Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. PNAS10084668471. (doi:10.1073/pnas.1032913100)

    • Search Google Scholar
    • Export Citation
  • PearenMAErikssonNAFitzsimmonsRLGoodeJMMartelNAndrikopoulosSMuscatGE2012The nuclear receptor, Nor-1, markedly increases type II oxidative muscle fibers and resistance to fatigue. Molecular Endocrinology26372384. (doi:10.1210/me.2011-1274)

    • Search Google Scholar
    • Export Citation
  • PetersenKFBefroyDDufourSDziuraJAriyanCRothmanDLDiPietroLClineGWShulmanGI2003Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science30011401142. (doi:10.1126/science.1082889)

    • Search Google Scholar
    • Export Citation
  • PetersenKFDufourSBefroyDGarciaRShulmanGI2004Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. New England Journal of Medicine350664671. (doi:10.1056/NEJMoa031314)

    • Search Google Scholar
    • Export Citation
  • PhielixESchrauwen-HinderlingVBMensinkMLenaersEMeexRHoeksJKooiMEMoonen-KornipsESelsJPHesselinkMK2008Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes5729432949. (doi:10.2337/db08-0391)

    • Search Google Scholar
    • Export Citation
  • PospisilikJAKnaufCJozaNBenitPOrthoferMCaniPDEbersbergerINakashimaTSaraoRNeelyG2007Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell131476491. (doi:10.1016/j.cell.2007.08.047)

    • Search Google Scholar
    • Export Citation
  • PosticCDentinRGirardJ2004Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes & Metabolism30398408. (doi:10.1016/S1262-3636(07)70133-7)

    • Search Google Scholar
    • Export Citation
  • PremilovacDBradleyEANgHLRichardsSMRattiganSKeskeMA2013Muscle insulin resistance resulting from impaired microvascular insulin sensitivity in Sprague Dawley rats. Cardiovascular Research982836. (doi:10.1093/cvr/cvt015)

    • Search Google Scholar
    • Export Citation
  • PutmanCTJonesNLHeigenhauserGJ2003Effects of short-term training on plasma acid-base balance during incremental exercise in man. Journal of Physiology550585603. (doi:10.1113/jphysiol.2003.039743)

    • Search Google Scholar
    • Export Citation
  • RandlePJ1998Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes/Metabolism Reviews14263283. (doi:10.1002/(SICI)1099-0895(199812)14:4%3C;263::AID-DMR233%3E;3.0.CO;2-C)

    • Search Google Scholar
    • Export Citation
  • RandlePJGarlandPBHalesCNNewsholmeEA1963The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet1785789. (doi:10.1016/S0140-6736(63)91500-9)

    • Search Google Scholar
    • Export Citation
  • ReznickJPrestonEWilksDLBealeSMTurnerNCooneyGJ2013Altered feeding differentially regulates circadian rhythms and energy metabolism in liver and muscle of rats. Biochimica et Biophysica Acta1832228238. (doi:10.1016/j.bbadis.2012.08.010)

    • Search Google Scholar
    • Export Citation
  • RitovVBMenshikovaEVAzumaKWoodRToledoFGGoodpasterBHRudermanNBKelleyDE2010Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. American Journal of Physiology. Endocrinology and Metabolism298E49E58. (doi:10.1152/ajpendo.00317.2009)

    • Search Google Scholar
    • Export Citation
  • RitovVBMenshikovaEVHeJFerrellREGoodpasterBHKelleyDE2005Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes54814. (doi:10.2337/diabetes.54.1.8)

    • Search Google Scholar
    • Export Citation
  • RodenMPriceTBPerseghinGPetersenKFRothmanDLClineGWShulmanGI1996Mechanism of free fatty acid-induced insulin resistance in humans. Journal of Clinical Investigation9728592865. (doi:10.1172/JCI118742)

    • Search Google Scholar
    • Export Citation
  • RolfeDFBrandMD1996Proton leak and control of oxidative phosphorylation in perfused, resting rat skeletal muscle. Biochimica et Biophysica Acta12764550. (doi:10.1016/0005-2728(96)00029-1)

    • Search Google Scholar
    • Export Citation
  • RolfeDFBrownGC1997Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiological Reviews77731758.

    • Search Google Scholar
    • Export Citation
  • RonisMJSharmaNVantreaseJBorengasserSJFergusonMMercerKEClevesMAGomez-AcevedoHBadgerTM2013Female mice lacking p47phox have altered adipose tissue gene expression and are protected against high fat-induced obesity. Physiological Genomics45351366. (doi:10.1152/physiolgenomics.00148.2012)

    • Search Google Scholar
    • Export Citation
  • RuanHBSinghJPLiMDWuJYangX2013Cracking the O-GlcNAc code in metabolism. Trends in Endocrinology and Metabolism24301309. (doi:10.1016/j.tem.2013.02.002)

    • Search Google Scholar
    • Export Citation
  • RuvoloPP2003Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacological Research47383392. (doi:10.1016/S1043-6618(03)00050-1)

    • Search Google Scholar
    • Export Citation
  • Samocha-BonetDCampbellLVViardotAFreundJTamCSGreenfieldJRHeilbronnLK2010A family history of type 2 diabetes increases risk factors associated with overfeeding. Diabetologia5317001708. (doi:10.1007/s00125-010-1768-y)

    • Search Google Scholar
    • Export Citation
  • SamuelVTShulmanGI2012Mechanisms for insulin resistance: common threads and missing links. Cell148852871. (doi:10.1016/j.cell.2012.02.017)

    • Search Google Scholar
    • Export Citation
  • Schmitz-PeifferCCraigDLBidenTJ1999Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. Journal of Biological Chemistry2742420224210. (doi:10.1074/jbc.274.34.24202)

    • Search Google Scholar
    • Export Citation
  • SeifertELEsteyCXuanJYHarperME2010Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation. Journal of Biological Chemistry28557485758. (doi:10.1074/jbc.M109.026203)

    • Search Google Scholar
    • Export Citation
  • ShawCSShepherdSOWagenmakersAJHansenDDendalePvan LoonLJ2012Prolonged exercise training increases intramuscular lipid content and perilipin 2 expression in type I muscle fibers of patients with type 2 diabetes. American Journal of Physiology. Endocrinology and Metabolism303E1158E1165. (doi:10.1152/ajpendo.00272.2012)

    • Search Google Scholar
    • Export Citation
  • ShiSQAnsariTSMcGuinnessOPWassermanDHJohnsonCH2013Circadian disruption leads to insulin resistance and obesity. Current Biology23372381. (doi:10.1016/j.cub.2013.01.048)

    • Search Google Scholar
    • Export Citation
  • ShulmanGIRothmanDLJueTSteinPDeFronzoRAShulmanRG1990Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. New England Journal of Medicine322223228. (doi:10.1056/NEJM199001253220403)

    • Search Google Scholar
    • Export Citation
  • SimoneauJAVeerkampJHTurcotteLPKelleyDE1999Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB Journal1320512060.

    • Search Google Scholar
    • Export Citation
  • SkovVGlintborgDKnudsenSJensenTKruseTATanQBrusgaardKBeck-NielsenHHojlundK2007Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. Diabetes5623492355. (doi:10.2337/db07-0275)

    • Search Google Scholar
    • Export Citation
  • SkovbroMBaranowskiMSkov-JensenCFlintADelaFGorskiJHelgeJW2008Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity. Diabetologia5112531260. (doi:10.1007/s00125-008-1014-z)

    • Search Google Scholar
    • Export Citation
  • SmithACBruceCRDyckDJ2005AMP kinase activation with AICAR simultaneously increases fatty acid and glucose oxidation in resting rat soleus muscle. Journal of Physiology565537546. (doi:10.1113/jphysiol.2004.081679)

    • Search Google Scholar
    • Export Citation
  • SprietLLWattMJ2003Regulatory mechanisms in the interaction between carbohydrate and lipid oxidation during exercise. Acta Physiologica Scandinavica178443452. (doi:10.1046/j.1365-201X.2003.01152.x)

    • Search Google Scholar
    • Export Citation
  • SriwijitkamolAChrist-RobertsCBerriaREaganPPratipanawatrTDeFronzoRAMandarinoLJMusiN2006Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. Diabetes55760767. (doi:10.2337/diabetes.55.03.06.db05-0677)

    • Search Google Scholar
    • Export Citation
  • St-PierreJBuckinghamJARoebuckSJBrandMD2002Topology of superoxide production from different sites in the mitochondrial electron transport chain. Journal of Biological Chemistry2774478444790. (doi:10.1074/jbc.M207217200)

    • Search Google Scholar
    • Export Citation
  • St-PierrePGendersAJKeskeMARichardsSMRattiganS2010Loss of insulin-mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance. Diabetes Obesity & Metabolism12798805. (doi:10.1111/j.1463-1326.2010.01235.x)

    • Search Google Scholar
    • Export Citation
  • StephensonEJCameraDMJenkinsTAKosariSLeeJSHawleyJASteptoNK2012Skeletal muscle respiratory capacity is enhanced in rats consuming an obesogenic Western diet. American Journal of Physiology. Endocrinology and Metabolism302E1541E1549. (doi:10.1152/ajpendo.00590.2011)

    • Search Google Scholar
    • Export Citation
  • StockliJFazakerleyDJJamesDE2011GLUT4 exocytosis. Journal of Cell Science12441474159. (doi:10.1242/jcs.097063)

  • StorgaardHJensenCBBjornholmMSongXMMadsbadSZierathJRVaagAA2004Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling in skeletal muscle in men at risk for type 2 diabetes. Journal of Clinical Endocrinology and Metabolism8913011311. (doi:10.1210/jc.2003-031243)

    • Search Google Scholar
    • Export Citation
  • StorlienLHKraegenEWChisholmDJFordGLBruceDGPascoeWS1987Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science237885888. (doi:10.1126/science.3303333)

    • Search Google Scholar
    • Export Citation
  • StuartCAMcCurryMPMarinoASouthMAHowellMELayneASRamseyMWStoneMH2013Slow-twitch fiber proportion in skeletal muscle correlates with insulin responsiveness. Journal of Clinical Endocrinology and Metabolism9820272036. (doi:10.1210/jc.2012-3876)

    • Search Google Scholar
    • Export Citation
  • SummersSAGarzaLAZhouHBirnbaumMJ1998Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Molecular and Cellular Biology1854575464.

    • Search Google Scholar
    • Export Citation
  • ThompsonALLim-FraserMYKraegenEWCooneyGJ2000Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro. American Journal of Physiology. Endocrinology and Metabolism279E577E584.

    • Search Google Scholar
    • Export Citation
  • ThorensB2011Brain glucose sensing and neural regulation of insulin and glucagon secretion. Diabetes Obesity & Metabolism13 (Suppl 1) 8288. (doi:10.1111/j.1463-1326.2011.01453.x)

    • Search Google Scholar
    • Export Citation
  • van TienenFHPraetSFde FeyterHMvan den BroekNMLindseyPJSchoonderwoerdKGde CooIFNicolayKPrompersJJSmeetsHJ2012Physical activity is the key determinant of skeletal muscle mitochondrial function in type 2 diabetes. Journal of Clinical Endocrinology and Metabolism9732613269. (doi:10.1210/jc.2011-3454)

    • Search Google Scholar
    • Export Citation
  • TimmersSNabbenMBosmaMvan BreeBLenaersEvan BeurdenDSchaartGWesterterp-PlantengaMSLanghansWHesselinkMK2012Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity. PNAS1091171111716. (doi:10.1073/pnas.1206868109)

    • Search Google Scholar
    • Export Citation
  • TonksKTNgYMillerSCosterACSamocha-BonetDIseliTJXuAPatrickEYangJYJunutulaJR2013Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects. Diabetologia56875885. (doi:10.1007/s00125-012-2811-y)

    • Search Google Scholar
    • Export Citation
  • TrenellMIHollingsworthKGLimELTaylorR2008Increased daily walking improves lipid oxidation without changes in mitochondrial function in type 2 diabetes. Diabetes Care3116441649. (doi:10.2337/dc08-0303)

    • Search Google Scholar
    • Export Citation
  • TschopMHSpeakmanJRArchJRAuwerxJBruningJCChanLEckelRHFareseRVJrGalganiJEHamblyC2012A guide to analysis of mouse energy metabolism. Nature Methods95763. (doi:10.1038/nmeth.1806)

    • Search Google Scholar
    • Export Citation
  • TurekFWJoshuCKohsakaALinEIvanovaGMcDearmonELaposkyALosee-OlsonSEastonAJensenDR2005Obesity and metabolic syndrome in circadian Clock mutant mice. Science30810431045. (doi:10.1126/science.1108750)

    • Search Google Scholar
    • Export Citation
  • TurinskyJO'SullivanDMBaylyBP19901,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo. Journal of Biological Chemistry2651688016885.

    • Search Google Scholar
    • Export Citation
  • TurnerNBruceCRBealeSMHoehnKLSoTRolphMSCooneyGJ2007Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes5620852092. (doi:10.2337/db07-0093)

    • Search Google Scholar
    • Export Citation
  • TurnerNHeilbronnLK2008Is mitochondrial dysfunction a cause of insulin resistance?Trends in Endocrinology and Metabolism19324330. (doi:10.1016/j.tem.2008.08.001)

    • Search Google Scholar
    • Export Citation
  • TurnerNKowalskiGMLeslieSJRisisSYangCLee-YoungRSBabbJRMeiklePJLancasterGIHenstridgeDC2013Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia5616381648. (doi:10.1007/s00125-013-2913-1)

    • Search Google Scholar
    • Export Citation
  • TurpinSMRyallJGSouthgateRDarbyIHevenerALFebbraioMAKempBELynchGSWattMJ2009Examination of ‘lipotoxicity’ in skeletal muscle of high-fat fed and ob/ob mice. Journal of Physiology58715931605. (doi:10.1113/jphysiol.2008.166033)

    • Search Google Scholar
    • Export Citation
  • VaagASkottPDamsboPGallMARichterEABeck-NielsenH1991Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus. Journal of Clinical Investigation8812821290. (doi:10.1172/JCI115432)

    • Search Google Scholar
    • Export Citation
  • VaagAAHandbergASkottPRichterEABeck-NielsenH1994Glucose-fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations. European Journal Endocrinology1307079. (doi:10.1530/eje.0.1300070)

    • Search Google Scholar
    • Export Citation
  • ViannaCRHuntgeburthMCoppariRChoiCSLinJKraussSBarbatelliGTzameliIKimYBCintiS2006Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance. Cell Metabolism4453464. (doi:10.1016/j.cmet.2006.11.003)

    • Search Google Scholar
    • Export Citation
  • VitzelKFBikopoulosGHungSPistorKEPattersonJDCuriRCeddiaRB2013Chronic treatment with the AMP-kinase activator AICAR increases glycogen storage and fatty acid oxidation in skeletal muscles but does not reduce hyperglucagonemia and hyperglycemia in insulin deficient rats. PLoS ONE8e62190. (doi:10.1371/journal.pone.0062190)

    • Search Google Scholar
    • Export Citation
  • WangYMSeibenhenerMLVandenplasMLWootenMW1999Atypical PKC zeta is activated by ceramide, resulting in coactivation of NF-kappaB/JNK kinase and cell survival. Journal of Neuroscience Research55293302. (doi:10.1002/(SICI)1097-4547(19990201)55:3%3C;293::AID-JNR4%3E;3.0.CO;2-9)

    • Search Google Scholar
    • Export Citation
  • WassermanDH2009Four grams of glucose. American Journal of Physiology. Endocrinology and Metabolism296E11E21. (doi:10.1152/ajpendo.90563.2008)

    • Search Google Scholar
    • Export Citation
  • WassermanDHKangLAyalaJEFuegerPTLee-YoungRS2011The physiological regulation of glucose flux into muscle in vivo. Journal of Experimental Biology214254262. (doi:10.1242/jeb.048041)

    • Search Google Scholar
    • Export Citation
  • WattMJHoyAJ2012Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. American Journal of Physiology. Endocrinology and Metabolism302E1315E1328. (doi:10.1152/ajpendo.00561.2011)

    • Search Google Scholar
    • Export Citation
  • WestwickJKBielawskaAEDbaiboGHannunYABrennerDA1995Ceramide activates the stress-activated protein kinases. Journal of Biological Chemistry2702268922692. (doi:10.1074/jbc.270.39.22689)

    • Search Google Scholar
    • Export Citation
  • WhitePJCharbonneauACooneyGJMaretteA2010Nitrosative modifications of protein and lipid signaling molecules by reactive nitrogen species. American Journal of Physiology. Endocrinology and Metabolism299E868E878. (doi:10.1152/ajpendo.00510.2010)

    • Search Google Scholar
    • Export Citation
  • WhiteheadJPMoleroJCClarkSMartinSMeneillyGJamesDE2001The role of Ca2+ in insulin-stimulated glucose transport in 3T3-L1 cells. Journal of Biological Chemistry2762781627824. (doi:10.1074/jbc.M011590200)

    • Search Google Scholar
    • Export Citation
  • WinderWWHolmesBFRubinkDSJensenEBChenMHolloszyJO2000Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. Journal of Applied Physiology8822192226.

    • Search Google Scholar
    • Export Citation
  • WredenbergAFreyerCSandstromMEKatzAWibomRWesterbladHLarssonNG2006Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochemical and Biophysical Research Communications350202207. (doi:10.1016/j.bbrc.2006.09.029)

    • Search Google Scholar
    • Export Citation
  • WuJCohenPSpiegelmanBM2013Adaptive thermogenesis in adipocytes: is beige the new brown?Genes and Development27234250. (doi:10.1101/gad.211649.112)

    • Search Google Scholar
    • Export Citation
  • YuCChenYClineGWZhangDZongHWangYBergeronRKimJKCushmanSWCooneyGJ2002Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. Journal of Biological Chemistry2775023050236. (doi:10.1074/jbc.M200958200)

    • Search Google Scholar
    • Export Citation
This paper is one of four papers that form part of a thematic review section on Energy, Insulin Resistance and Metabolic Syndrome. The Guest Editor for this section was Shaodong Guo, Texas A&M University, TX, USA.

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    Pathways of substrate metabolism in muscle. Oxidation pathways of glucose, FAs and amino acids converge at the level of acetyl CoA. The energy of oxidation is conserved as NADH+H+ and FADH2, which are used by the electron transport chain to produce a chemiosmotic gradient across the inner mitochondrial membrane. This proton motive force is dissipated by ATP synthesis and by proton leak via the adenine nucleotide transporter (ANT) and activated uncoupling proteins (UCPx). Demand for ATP and proton leak are greater determinants of oxygen consumption and heat production than the substrate being oxidised.

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    Proposed mechanisms for the build-up of bioactive lipid species and how they interfere with insulin action in muscle to produce insulin resistance. DAG can activate lipid-sensitive kinases to serine phosphorylate and reduce tyrosine phosphorylation of IRS1. Ceramide can inhibit Akt phosphorylation and reduce transduction through the insulin signalling pathway. Circulating cytokines or FAs themselves are reported to activate inflammatory pathway serine kinases that interfere with insulin signalling. Reduced or dysregulated FA oxidation in mitochondria could create a build-up of bioactive lipids and generate reactive oxygen species (ROS) that also activate kinases that interfere with insulin signalling.

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    Nodes of control of glucose metabolism other than insulin-stimulated translocation of GLUT4 that could be influenced by the excess availability of FAs. Utilisation of glucose and FAs is dependent on their availability in the circulation and delivery to the muscle tissue. The phosphorylation of glucose and conversion to glycogen are regulated by substrate availability and G-6-P concentration. PDH is a critical regulator balancing glucose use and FA oxidation to support energy requirements. The regulation of FA sequestration in, or release from, muscle fat droplets can control the level of bioactive lipid species. The regulation of FA metabolism at the AMPK–ACC2–malonyl CoA–CPT1 axis also has a significant impact on the balance between FA and glucose metabolism. There are a number of newly recognised post-translational modifications that can occur on key metabolic or signalling proteins and would be expected to be influenced by changes in the availability and metabolism of FAs.

  • Abu-ElheigaLMatzukMMAbo-HashemaKAWakilSJ2001Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science29126132616. (doi:10.1126/science.1056843)

    • Search Google Scholar
    • Export Citation
  • Abu-ElheigaLOhWKordariPWakilSJ2003Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. PNAS1001020710212. (doi:10.1073/pnas.1733877100)

    • Search Google Scholar
    • Export Citation
  • AkpanIGoncalvesMDDhirRYinXPistilliEEBogdanovichSKhuranaTSUcranJLacheyJAhimaRS2009The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. International Journal of Obesity3312651273. (doi:10.1038/ijo.2009.162)

    • Search Google Scholar
    • Export Citation
  • AlkhateebHChabowskiAGlatzJFLuikenJFBonenA2007Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity. American Journal of Physiology. Endocrinology and Metabolism293E783E793. (doi:10.1152/ajpendo.00685.2006)

    • Search Google Scholar
    • Export Citation
  • AmatiFDubeJJAlvarez-CarneroEEdreiraMMChomentowskiPCoenPMSwitzerGEBickelPEStefanovic-RacicMToledoFG2011Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes?Diabetes6025882597. (doi:10.2337/db10-1221)

    • Search Google Scholar
    • Export Citation
  • AndersonEJLustigMEBoyleKEWoodliefTLKaneDALinCTPriceJWIIIKangLRabinovitchPSSzetoHH2009Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. Journal of Clinical Investigation119573581. (doi:10.1172/JCI37048)

    • Search Google Scholar
    • Export Citation
  • AndreyevAYKushnarevaYEStarkovAA2005Mitochondrial metabolism of reactive oxygen species. Biochemistry70200214.

  • AndrikopoulosSBlairARDelucaNFamBCProiettoJ2008Evaluating the glucose tolerance test in mice. American Journal of Physiology. Endocrinology and Metabolism295E1323E1332. (doi:10.1152/ajpendo.90617.2008)

    • Search Google Scholar
    • Export Citation
  • ArchJRHislopDWangSJSpeakmanJR2006Some mathematical and technical issues in the measurement and interpretation of open-circuit indirect calorimetry in small animals. International Journal of Obesity3013221331. (doi:10.1038/sj.ijo.0803280)

    • Search Google Scholar
    • Export Citation
  • AyalaJEBracyDPMcGuinnessOPWassermanDH2006Considerations in the design of hyperinsulinemic–euglycemic clamps in the conscious mouse. Diabetes55390397. (doi:10.2337/diabetes.55.02.06.db05-0686)

    • Search Google Scholar
    • Export Citation
  • BangsboJ2000Muscle oxygen uptake in humans at onset of and during intense exercise. Acta Physiologica Scandinavica168457464. (doi:10.1046/j.1365-201x.2000.00697.x)

    • Search Google Scholar
    • Export Citation
  • BassJ2012Circadian topology of metabolism. Nature491348356. (doi:10.1038/nature11704)

  • BefroyDEPetersenKFDufourSMasonGFde GraafRARothmanDLShulmanGI2007Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes5613761381. (doi:10.2337/db06-0783)

    • Search Google Scholar
    • Export Citation
  • BergmanBCHunerdosseDMKeregeAPlaydonMCPerreaultL2012Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia5511401150. (doi:10.1007/s00125-011-2419-7)

    • Search Google Scholar
    • Export Citation
  • BodenGChenXRuizJWhiteJVRossettiL1994Mechanisms of fatty acid-induced inhibition of glucose uptake. Journal of Clinical Investigation9324382446. (doi:10.1172/JCI117252)

    • Search Google Scholar
    • Export Citation
  • BodenMJBrandonAETid-AngJDPrestonEWilksDStuartECleasbyMETurnerNCooneyGJKraegenEW2012Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle. American Journal of Physiology. Endocrinology and Metabolism303E798E805. (doi:10.1152/ajpendo.00577.2011)

    • Search Google Scholar
    • Export Citation
  • BondMRHanoverJA2013O-GlcNAc cycling: a link between metabolism and chronic disease. Annual Review of Nutrition33205229. (doi:10.1146/annurev-nutr-071812-161240)

    • Search Google Scholar
    • Export Citation
  • BosmaMKerstenSHesselinkMKSchrauwenP2012Re-evaluating lipotoxic triggers in skeletal muscle: relating intramyocellular lipid metabolism to insulin sensitivity. Progress in Lipid Research513649. (doi:10.1016/j.plipres.2011.11.003)

    • Search Google Scholar
    • Export Citation
  • BoushelRGnaigerESchjerlingPSkovbroMKraunsoeRDelaF2007Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia50790796. (doi:10.1007/s00125-007-0594-3)

    • Search Google Scholar
    • Export Citation
  • BouskilaMHunterRWIbrahimAFDelattreLPeggieMvan DiepenJAVosholPJJensenJSakamotoK2010Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle. Cell Metabolism12456466. (doi:10.1016/j.cmet.2010.10.006)

    • Search Google Scholar
    • Export Citation
  • BrandMDHarperMETaylorHC1993Control of the effective P/O ratio of oxidative phosphorylation in liver mitochondria and hepatocytes. Biochemical Journal291739748.

    • Search Google Scholar
    • Export Citation
  • BrayMSRatcliffeWFGrenettMHBrewerRAGambleKLYoungME2013Quantitative analysis of light-phase restricted feeding reveals metabolic dyssynchrony in mice. International Journal of Obesity37843852. (doi:10.1038/ijo.2012.137)

    • Search Google Scholar
    • Export Citation
  • BruceCRHoyAJTurnerNWattMJAllenTLCarpenterKCooneyGJFebbraioMAKraegenEW2009Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes58550558. (doi:10.2337/db08-1078)

    • Search Google Scholar
    • Export Citation
  • BruceCRRisisSBabbJRYangCLee-YoungRSHenstridgeDCFebbraioMA2013The sphingosine-1-phosphate analog FTY720 reduces muscle ceramide content and improves glucose tolerance in high fat-fed male mice. Endocrinology1546576. (doi:10.1210/en.2012-1847)

    • Search Google Scholar
    • Export Citation
  • BruceCRThrushABMertzVABezaireVChabowskiAHeigenhauserGJDyckDJ2006Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. American Journal of Physiology. Endocrinology and Metabolism291E99E107. (doi:10.1152/ajpendo.00587.2005)

    • Search Google Scholar
    • Export Citation
  • BuhlESJessenNSchmitzOPedersenSBPedersenOHolmanGDLundS2001Chronic treatment with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes501217. (doi:10.2337/diabetes.50.1.12)

    • Search Google Scholar
    • Export Citation
  • ButlerAAKozakLP2010A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes59323329. (doi:10.2337/db09-1471)