FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs

in Journal of Endocrinology

Most hormones secreted from specific organs of the body in response to diverse stimuli contribute to the homeostasis of the whole organism. Fibroblast growth factor 21 (FGF21), a hormone induced by a variety of environmental or metabolic stimuli, plays a crucial role in the adaptive response to these stressful conditions. In addition to its role as a stress hormone, FGF21 appears to function as a mediator of the therapeutic effects of currently available drugs and those under development for treatment of metabolic diseases. In this review, we highlight molecular mechanisms and the functional importance of FGF21 induction in response to diverse stress conditions such as changes of nutritional status, cold exposure, and exercise. In addition, we describe recent findings regarding the role of FGF21 in the pathogenesis and treatment of diabetes associated with obesity, liver diseases, pancreatitis, muscle atrophy, atherosclerosis, cardiac hypertrophy, and diabetic nephropathy. Finally, we discuss the current understanding of the actions of FGF21 as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagon-like peptide 1 analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid.

Abstract

Most hormones secreted from specific organs of the body in response to diverse stimuli contribute to the homeostasis of the whole organism. Fibroblast growth factor 21 (FGF21), a hormone induced by a variety of environmental or metabolic stimuli, plays a crucial role in the adaptive response to these stressful conditions. In addition to its role as a stress hormone, FGF21 appears to function as a mediator of the therapeutic effects of currently available drugs and those under development for treatment of metabolic diseases. In this review, we highlight molecular mechanisms and the functional importance of FGF21 induction in response to diverse stress conditions such as changes of nutritional status, cold exposure, and exercise. In addition, we describe recent findings regarding the role of FGF21 in the pathogenesis and treatment of diabetes associated with obesity, liver diseases, pancreatitis, muscle atrophy, atherosclerosis, cardiac hypertrophy, and diabetic nephropathy. Finally, we discuss the current understanding of the actions of FGF21 as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagon-like peptide 1 analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid.

Introduction

All known organisms have the capability to maintain homeostasis in response to environmental challenges. The ability to modify gene expression is a fundamental organismal mechanism of adaptation to environmental stimuli. In particular, hormones secreted from specific organs are important mediators of these adaptive responses through autocrine, paracrine, and endocrine actions. For example, insulin and glucagon are well-known adaptive hormones that control whole-body glucose balance in response to changes in nutritional status. Emerging evidence has suggested that fibroblast growth factor 21 (FGF21) could also be an endocrine hormone contributing to the metabolic homeostasis. The FGF21 gene was cloned as the 21st member of the FGF family by Dr Nobuyuki Itoh's group in 2000 (Nishimura et al. 2000), and its biological function was first identified as a potent enhancer of glucose uptake by Dr Alexei Kharitonenkov's group at Lilly Research Laboratories in 2005 (Kharitonenkov et al. 2005). After this discovery, FGF21 has gained considerable attention as a key regulator in the maintenance of energy homeostasis and as a promising therapeutic molecule for the treatment of obesity and type 2 diabetes (T2D).

Numerous studies have suggested that FGF21 plays a crucial role in the control of glucose and lipid energy balance in response to changes of nutritional status, such as starvation and feeding (Badman et al. 2007, Inagaki et al. 2007, Coskun et al. 2008, Potthoff et al. 2009). FGF21 is also important in the maintenance of body temperature by enhancing thermogenesis in response to cold exposure (Fisher et al. 2012, Lee et al. 2014a). In addition, FGF21 participates in the pathogenesis and treatment of various diseases such as diabetes associated with obesity, liver diseases, muscle atrophy, cardiovascular diseases, and kidney injury. Intriguingly, FGF21 can mediate the therapeutic benefits of several anti-diabetic compounds such as metformin, glucagon/glucagon-like peptide 1 (GLP1) analogues, thiazolidinedione (TZD), and sirtuin 1 (Sirt1) activators. Here, we highlight recent insights regarding the role of FGF21 as an adaptive hormone in response to various physiological or pathological conditions and as a mediator of the beneficial metabolic effects of several therapeutic agents (Fig. 1).

Figure 1
Figure 1

Functional role of fibroblast growth factor 21 (FGF21) secreted from multiple organs in response to diverse stresses or stimuli. FGF21 expression is induced in multiple major organs, including white/brown adipose tissue, liver, pancreas, skeletal muscle, heart, and kidney, in various physiological and pathological conditions. FGF21 levels are also increased by several anti-diabetic drugs or compounds. Consequently, elevated FGF21 plays an adaptive role in response to diverse stressful conditions and acts a mediator of beneficial metabolic effects of anti-diabetic drugs through local and systemic actions in target organs. NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; HCC, hepatocellular carcinoma; GLP1, glucagon-like peptide 1.

Citation: Journal of Endocrinology 226, 1; 10.1530/JOE-15-0160

The role of stress-induced FGF21 in physiological conditions

FGF21 and nutritional status

FGF21 expression is regulated by nutritional status, and changes in the FGF21 level are important for adaption to changes of the nutritional balance such as deprivation or oversupply of macronutrients and changes of amino acid composition (Kim & Lee 2014). Alteration of FGF21 expression in response to nutritional alteration was first reported in 2007 (Badman et al. 2007, Inagaki et al. 2007). In starved mice, FGF21 is induced in the liver, contributing to metabolic adaptation to the fasting state by enhancing ketogenesis and β-oxidation in the liver. An increase of serum FGF21 level after fasting has been also observed in healthy human individuals (Galman et al. 2008). Fasting-induced hepatic FGF21 expression is mediated by the peroxisome proliferator-activated receptor alpha (PPARα; Badman et al. 2007, Inagaki et al. 2007), CREBH (Lee et al. 2011, Kim et al. 2014a), and Sirt1 (Li et al. 2014). Increased FGF21 also plays an important role in the regulation of fasting glucose levels by enhancing gluconeogenesis via upregulation of the hepatic PPARγ coactivator 1 alpha (PGC1α; Potthoff et al. 2009). Indeed, a recent study has shown that FGF21, produced in the fasted liver, enters into the brain and activates hypothalamic–pituitary–adrenal axis, leading to the enhancement of hepatic PGC1α expression and gluconeogenesis (Liang et al. 2014). These results suggest that FGF21 coordinates an adaptive response to fasting via liver–brain axis.

In addition to its role in fasting, FGF21 has been reported to enhance insulin-stimulated glucose uptake under acute refeeding conditions (Markan et al. 2014). The serum FGF21 level was increased during the early stage of refeeding in mice, when the insulin level was also elevated. Importantly, liver-specific Fgf21 knockout (Fgf21Δhep) mice exhibited reduced serum FGF21 levels in both fasting and early refeeding and displayed aggravation of fasting-induced glucose intolerance, whereas these findings were not observed in adipose tissue-specific Fgf21 knockout (Fgf21ΔAd) mice (Markan et al. 2014). These results suggest that the liver, but not adipose tissue, is a primary organ producing FGF21 during fasting and acute refeeding and that FGF21 acts as an insulin sensitizer to enhance insulin-stimulated glucose uptake during the early refeeding period. In addition to complete nutrient deprivation, a 50% food restriction causing malnutrition has been reported to increase serum FGF21 levels in mice (Kubicky et al. 2012). Fgf21 knockout (Fgf21/) mice were resistant to malnutrition-induced reduction of bone growth (Kubicky et al. 2012), suggesting that FGF21 is an important regulator of skeletal homeostasis as well as liver and adipose tissue. In contrast to malnutrition, caloric restriction without malnutrition did not result in FGF21 induction in mouse or human subjects (Zhang et al. 2012, Kim et al. 2013a, Lips et al. 2014). Moreover, caloric restriction-induced metabolic changes were not different between Fgf21/ and Fgf21+/+ mice (Kim et al. 2013a), suggesting that FGF21 does not mediate the effects of caloric restriction on energy metabolism.

An increasing body of evidence suggests that FGF21 expression is regulated by changes in specific macronutrients. After feeding a ketogenic diet with low carbohydrates and high fat, mimicking a fasting state, FGF21 was induced in the liver of mice in an PPARα-dependent manner; consequently, increased FGF21 contributes to the enhancement of β-oxidation and ketogenesis caused by a ketogenic diet (Badman et al. 2007). In parallel, ketogenic diet-fed Fgf21/ mice showed impaired adaptation to ketosis (Badman et al. 2009). A protein-restricted (low protein) diet has been also reported to increase hepatic FGF21 expression in mice through general control nonderepressible 2- and PPARα-dependent pathways. An increase in serum FGF21 levels was also observed in human subjects after a low protein diet (Laeger et al. 2014). The effects of a low protein diet on the enhancement of energy expenditure and decrease of fat mass were partially diminished in Fgf21/ mice compared to control mice, suggesting the importance of FGF21 induction in whole-body adaption to low protein intake (Laeger et al. 2014). Intriguingly, the serum FGF21 level and hepatic FGF21 expression were not increased in mice with a 50% reduction in food intake without changes of protein intake (Laeger et al. 2014). Furthermore, FGF21 induction in mice fed a ketogenic diet was not attenuated by carbohydrate supplements (Laeger et al. 2014), implying that the increase in FGF21 during food restriction and the ketogenic diet appears to be primarily driven by low protein intake rather than by reduced carbohydrate intake. A high-fat diet (HFD) has been also reported to cause hepatic FGF21 induction in mice (Muise et al. 2008, Fisher et al. 2010). In this process, free fatty acids appear to stimulate FGF21 gene expression in PPARα-dependent (Mai et al. 2009) or -independent pathways (Tanaka et al. 2015). Collectively, these results indicate that the induction of FGF21 in response to changes in macronutrient ingestion is important for metabolic adaption.

In addition to changes in the quantities of macronutrients, changes of amino acid composition in proteins and monosaccharide composition in carbohydrates influence FGF21 expression. Methionine restriction (approximately a 75–80% decrease of methionine intake) has been reported to extend the lifespan and lead to decreased fat mass and improved insulin sensitivity in rodents, probably by enhancing β-oxidation (Orentreich et al. 1993, Hasek et al. 2010). Importantly, methionine-restricted mice showed increases in the hepatic FGF21 expression and serum FGF21 level, accompanied by attenuation of obesity- or age-related insulin resistance (Ables et al. 2012, Lees et al. 2014). These results suggest that FGF21 may mediate beneficial metabolic effects of methionine restriction. However, metabolic effects of methionine restriction in Fgf21/ mice remain to be determined. Complete deprivation of a specific amino acid also affects FGF21 gene expression. Several studies have suggested that FGF21 was induced by the eukaryotic translation initiation factor 2 alpha (eIF2α)–activating transcription factor 4 (ATF4)-dependent pathway in the liver but not in adipose tissue or skeletal muscle of mice fed a leucine-deficient diet (De Sousa-Coelho et al. 2013, Kim et al. 2013a). Importantly, the enhanced glucose tolerance and reduced fat mass observed in WT mice fed a leucine-deficient diet were not shown in Fgf21/ mice, suggesting that hepatic FGF21 acts as a critical mediator of the changes in whole-body energy metabolism in response to amino acid deficiency (De Sousa-Coelho et al. 2013, Kim et al. 2013a). Saccharides also influence FGF21 gene expression. In line with FGF21 induction in the livers during refeeding of mice (Markan et al. 2014), glucose was shown to directly induce FGF21 gene expression in hepatocytes in vitro through activation of the carbohydrate response element binding protein (Iizuka et al. 2009, Uebanso et al. 2011). A recent study has shown that fructose ingestion also acutely increased circulating FGF21 levels in humans (Dushay et al. 2015), suggesting that FGF21 may play a role in the metabolism of fructose or other monosaccharides, as well as glucose. A fundamental physiological role of FGF21 in individual carbohydrate metabolism remains to be clarified.

FGF21, cold exposure, and exercise

Heat production is important in the maintenance of body temperature in response to cold exposure. Thermogenesis in brown adipose tissue (BAT) is a critical component of heat production. Emerging evidence has suggested that white adipose tissue (WAT) browning, conversion of WAT- to BAT-like tissues, participates in the regulation of the body temperature (Harms & Seale 2013). It has been reported that FGF21 is induced in BAT and WAT of mice and humans in an adaptive response to cold exposure (Fisher et al. 2012, Lee et al. 2014a), and thermogenic stimuli such as norepinephrine induce FGF21 gene expression in BAT via activation of the p38α–ATF2 axis (Hondares et al. 2011). Importantly, Fgf21/ mice had decreased core temperatures after cold exposure compared to control mice, due to an impaired browning (Fisher et al. 2012). Thyroid hormones (THs), another thermogenic inducer, have been also reported to increase FGF21 gene expression in adipose tissue (Adams et al. 2010). However, the effect of TH on energy expenditure was not different between Fgf21/ and Fgf21+/+ mice (Domouzoglou et al. 2014), suggesting that FGF21 regulates adaptive thermogenesis in cold environments but not that after TH treatment.

In addition to cold exposure, acute or chronic exercise has been reported to increase circulating FGF21 levels in mice and humans (Cuevas-Ramos et al. 2012, Kim et al. 2013b). While contradictory data have been reported (Lee et al. 2014a), FGF21 might act as a mediator of the metabolic improvement by exercise. Consistently, recent data showed that enhancement of glucose tolerance by exercise was diminished in Fgf21/ mice. Furthermore, exercise-induced AMP-activated protein kinase (AMPK) activation was markedly reduced in the skeletal muscle of Fgf21/ mice compared to control mice, suggesting that FGF21 mediates the beneficial effects of exercise on glucose intolerance (Loyd et al. 2014). Thus, all of these studies indicate that FGF21 is a crucial player in the physiological adaption to cold and exercise.

The role of stress-induced FGF21 in pathological conditions

FGF21 and diabetes associated with obesity

FGF21 levels are paradoxically increased in the serum of obese diabetic mice or human subjects with T2D and obesity (Chavez et al. 2009, Fisher et al. 2010). This increase of serum FGF21 in obesity is probably due to the upregulation of FGF21 gene expression in the liver and adipose tissue (Fisher et al. 2010). While the liver rather than adipose tissue primarily produces FGF21 during fasting (Markan et al. 2014), it is unclear which of the liver or adipose tissue is the main producer of FGF21 in obesity. Considering the pharmacotherapeutic effects of FGF21, obesity-mediated FGF21 induction may be an adaptive mechanism to metabolic derangement associated with obesity. In line with this notion, HFD-fed Fgf21/ mice showed aggravated glucose intolerance compared to HFD-fed Fgf21+/+ mice (Assini et al. 2015), although other investigators reported no difference of glucose intolerance between in Fgf21/ mice and Fgf21+/+ mice fed HFD (Fisher et al. 2010, Adams et al. 2013a). In parallel, leptin-deficient ob/ob mice exhibited aggravated glucose intolerance and insulin resistance when Fgf21 was genetically disrupted (Kim et al. 2015). Thus, FGF21 may act as a compensatory signal to mitigate metabolic stresses due to obesity.

In obesity, FGF21 signaling has been reported to be impaired in major metabolic organs, including pancreatic islets, liver, and WAT (Fisher et al. 2010, So et al. 2013). Based on these findings, we speculate that obesity-related endogenous FGF21 induction alone is not sufficient to overcome impaired FGF21 signaling or FGF21 resistance. Administration of exogenous FGF21 and FGF21 mimetics improves glucose tolerance or insulin sensitivity in diabetic rodents and monkeys (Coskun et al. 2008, Xu et al. 2009, Wu et al. 2011, Foltz et al. 2012). Two recent papers have shown that an engineered FGF21 variant (LY2405319) ameliorates metabolic parameters in obese human subjects with T2D as well as diabetic monkeys (Adams et al. 2013b, Gaich et al. 2013). Especially, LY2405319-received T2D subjects showed a significant decrease of body weight and fasting insulin levels and the improvement of dyslipidemia including reduced LDL cholesterol and increased HDL cholesterol levels compared to placebo-treated subjects (Gaich et al. 2013). The glucose lowering effect of LY2405319 was also observed, while statistical significance was marginal (Gaich et al. 2013).

These pharmacological effects of FGF21 and its mimetics are attributable to the action on various metabolic target organs, such as adipose tissue, brain, liver, and pancreatic β cells (Owen et al. 2015). Several studies have shown that FGF21 enhances insulin-induced glucose uptake and thermogenesis in adipose tissue (Kharitonenkov et al. 2005, Xu et al. 2009). In obese mice with whole-body deletion of β-klotho, a co-receptor for FGF21, the metabolic effects of FGF21 such as enhancement of energy expenditure or glucose tolerance and decrease of fat mass were diminished (Adams et al. 2012). Notably, these beneficial effects of FGF21 were also reduced in obese mice lacking β-klotho in adipose tissue or the brain (Ding et al. 2012, Owen et al. 2014). Furthermore, hepatic FGF21 actions such as alleviation of steatosis and suppression of hepatic glucose production were less pronounced in these mice, suggesting indirect FGF21 action on the liver. These findings suggest that both adipose tissue and the brain are major targets of systemic actions of FGF21 in metabolic improvement, although direct repressive effects of FGF21 on gluconeogenesis and lipogenesis in the liver have also been reported (Zhang et al. 2011, Kong et al. 2013). The importance of FGF21 action in adipose tissue has been also inferred from reduction of FGF21-mediated metabolic improvement in adiponectin knockout (Adipoq/) mice (Holland et al. 2013, Lin et al. 2013).

Additionally, FGF21 increases insulin content in pancreatic β cells and partially protects islets from glucolipotoxicity and cytokine-induced apoptosis (Wente et al. 2006). Chow-fed Fgf21/ mice showed impaired glucose-stimulated insulin secretion (GSIS), probably due to a lack of FGF21 action-inhibiting growth hormone (GH) signaling in β cells, and also displayed insulin resistance due to the increased GH signaling in insulin target tissues (So et al. 2015). Given that GH reportedly induces FGF21 gene expression (Chen et al. 2011, Yu et al. 2012), endogenous FGF21 induction may be a compensatory mechanism to alleviate insulin resistance induced by chronic GH treatment. In contrast, we have observed no difference in GSIS or insulin levels in the Fgf21/ mouse strain (Kim et al. 2015). Further study is needed to evaluate the effect of endogenous FGF21 on the pancreatic islet function. Taken together, these results suggest that FGF21 acts as a therapeutic agent for the treatment of T2D associated with obesity via its pleiotropic actions in diverse metabolic organs.

Several studies have suggested that FGF21 exerts its metabolic beneficial effects through the regulation of other hormones. As previously described, FGF21 increases the production of insulin and adiponectin in pancreatic β cells and adipose tissue respectively (Wente et al. 2006, Holland et al. 2013, Lin et al. 2013). It has been also reported that FGF21 reduces circulating glucagon levels in obese mice (Kharitonenkov et al. 2005). Given the role of glucagon in the aggravation of hyperglycemia through enhancing hepatic glucose production, glucagon could be a mediator for in vivo effect of FGF21. In addition, FGF21 is able to exert therapeutic effects in an insulin-dependent manner. While the effect of FGF21 on glucose lowering was still preserved in liver-specific insulin receptor knockout mice, the suppressive effects of FGF21 on circulating cholesterol and hepatic triglycerides were diminished in these mice (Emanuelli et al. 2014). These results suggest that FGF21 ameliorates hyperglycemia independent of insulin action in the liver of obese mice but affects hepatic lipid metabolism in an insulin-dependent manner. Given the metabolic action of insulin in various tissues, investigations on the relationship between FGF21 and insulin signaling in adipose tissue and the brain will also be of interest.

FGF21 and liver disease

FGF21 is implicated in various liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and liver cancer. Several studies have suggested that FGF21 was increased in the serum and liver of human subjects with NAFLD, and its level was correlated with hepatic triacylglycerol (TG) content (Dushay et al. 2010, Li et al. 2010). Molecular mechanisms underlying FGF21 induction in NAFLD have been recently identified (Jiang et al. 2014, Kim et al. 2015). Endoplasmic reticulum (ER) stress, which is implicated in the development and progression of NAFLD, appears to be responsible for FGF21 induction. Increased gene expression of both ER stress markers and FGF21 was observed in the livers of mice with steatosis or in those of human subjects with NAFLD (Jiang et al. 2014, Kim et al. 2015). Moreover, ER stressors are able to directly induce FGF21 gene expression in hepatocytes in vitro and in mouse livers in vivo. Consistently, ER stress-induced hepatic FGF21 expression was diminished in mice with the deletion of the inositol-requiring 1 alpha (Ire1α) gene (Jiang et al. 2014) or with Ser51Ala mutation of the Eif2α gene in the liver (Kim et al. 2015). These results suggest that the IRE1α-X-box binding protein 1 axis or the eIF2α–ATF4 axis is an important signaling pathway in ER stress-induced FGF21 expression. Furthermore, chemical-induced increases of ER stress marker gene expression and lipid accumulation in the livers of mice were reduced by recombinant FGF21 administration (Jiang et al. 2014) and in the livers of tetracycline-inducible Fgf21 transgenic mice (Kim et al. 2015). Fgf21/ ob/ob mice also had an increased expression of ER stress marker genes and aggravated liver injury compared to Fgf21+/+ ob/ob mice (Kim et al. 2015). Taken together, these results suggest that FGF21 plays a role in the adaptive response to ER stress induced by a pharmacological ER stressor or NAFLD.

In addition to NAFLD, FGF21 participates in the development and progression of NASH induced by a methionine–choline deficient (MCD) diet (Fisher et al. 2014). In mice fed an MCD diet, the serum FGF21 level was elevated, probably due to an increase in FGF21 expression in the liver but not in other organs. Fgf21/ mice fed the MCD diet showed increased progressive steatohepatitis and hepatic fibrosis compared to control mice. Furthermore, Fgf21/ mice showed aggravated hepatic peroxidative damage, probably due to the elevation of free fatty acids caused by reduced activity of acyl CoA synthetases, which convert long-chain fatty acids to acyl CoAs. Another Fgf21/ mouse strain also displayed increased lipid accumulation and ER stress response after an MCD diet (Tanaka et al. 2015). Indeed, FGF21 administration or FGF21 overexpression ameliorated MCD diet-induced metabolic derangements (Fisher et al. 2014). Thus, FGF21 induction in NASH may be a physiologic adaptation to hepatic stress responses, and FGF21 may be a promising therapeutic agent for the treatment of NAFLD or NASH.

NAFLD and NASH are risk factors for the development and progression of hepatocellular carcinoma (HCC; Michelotti et al. 2013). It has been reported that hepatic FGF21 expression was increased in diethylnitrosamine (DEN)-induced liver tumors and in livers of humans with HCC (Yang et al. 2013). Furthermore, Fgf21 transgenic mice showed a delayed appearance of DEN-induced liver tumors, although the incidence and burden of HCC were similar between Fgf21 transgenic and control mice (Huang et al. 2006). These findings suggest that FGF21 induction may be an adaptive mechanism to protect or delay the development and progression of liver cancer. Notably, an Fgf21 transgenic mouse strain in this study did not show reduced body weight, in contrast to other Fgf21 transgenic mouse strains. This discrepancy is probably due to a difference in mouse background (FVB vs C57BL/6) or a difference in serum FGF21 concentration between mouse strains. Further studies are needed to evaluate the fundamental role of FGF21 in hepatic carcinogenesis.

Liver is a primary organ to detoxify diverse toxic chemicals. It has been reported that FGF21 expression is increased depending on the aryl hydrocarbon receptor in the liver of mice after administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic and carcinogenic chemical (Cheng et al. 2014). Fgf21/ mice were susceptible to TCDD-induced mortality compared to control mice (Cheng et al. 2014), suggesting that FGF21 induction may be a protective signal against toxin-induced injury. It remains to be determined whether FGF21 regulates activity and expression of the detoxification enzyme or whether this action exerts a protective effect against toxin-induced injury.

FGF21 and pancreatitis

It has been reported that FGF21 is expressed in pancreatic acinar and islet cells (Wente et al. 2006, Johnson et al. 2009). Several studies have shown that FGF21 modulates the development and progression of pancreatitis, a known risk factor for pancreatic cancer (Johnson et al. 2009, 2014). In mice with cerulein-induced acute pancreatitis, FGF21 expression was increased in acinar cells but not in islet cells. Importantly, pancreatic inflammation and fibrosis were increased in Fgf21/ mice compared to control mice and, conversely, were decreased in Fgf21 transgenic mice (Johnson et al. 2009). Furthermore, FGF21 expression was markedly reduced in acinar cells of Mist1 knockout mice showing early events of pancreatitis such as the premature activation of digestive enzymes and acinar disorganization (Johnson et al. 2014). These results suggest that FGF21 induction may be an adaptive mechanism to protect the development and progression of pancreatitis. Given the protective role of FGF21 in pancreatitis, it will be of interest to study whether FGF21 exerts anti-cancer activity in the progression of pancreatic cancer.

FGF21 and muscle disease

Emerging evidence has suggested that FGF21 is expressed in skeletal muscle and that its expression is upregulated under muscle stress conditions, such as atrophy or myopathy (Izumiya et al. 2008, Tyynismaa et al. 2010). In transgenic mice expressing a mutant form of mitochondrial helicase Twinkle or muscle-specific cytochrome c oxidase 10 (Cox10) knockout mice showing impairment of the mitochondrial respiratory chain and myopathy, skeletal muscle FGF21 expression was upregulated along with serum FGF21 levels (Tyynismaa et al. 2010). Moreover, serum FGF21 levels were increased in human subjects with mitochondrial respiratory chain deficiencies (Suomalainen et al. 2011), suggesting that FGF21 is a biomarker of muscle-manifesting mitochondrial respiratory chain disorders. Skeletal muscle-specific autophagy knockout mice showing muscle atrophy also exhibited increased muscular FGF21 induction, probably due to aggravated mitochondrial stress caused by autophagy deficiency (Kim et al. 2013a). Furthermore, it has been reported that several mitochondrial stressors, such as mitochondrial complex inhibitors, directly induce FGF21 expression via the eIF2α–ATF4 pathway (Kim et al. 2013a). Notably, all of these mice had reduced fat mass, probably due to increased energy expenditure and fatty acid catabolism induced by FGF21. Based on a report showing the beneficial effect of FGF21 on mitochondrial respiratory capacity (Chau et al. 2010), we speculate that FGF21 acts as an adaptive regulator counteracting muscle stress imposed by mitochondrial dysfunction or autophagy deficiency. Further studies are necessary to prove the protective role of FGF21 in the diseases associated with mitochondrial dysfunction.

FGF21 and cardiovascular disease

Accumulating evidence has suggested that FGF21 can modulate the development of coronary artery disease (CAD) and atherosclerosis. It has been reported that FGF21 was increased in the serum of human subjects with CAD and carotid artery plaques, and increased FGF21 levels were associated with adverse lipid profiles in CAD subjects (Lin et al. 2010, Chow et al. 2013). A recent study has shown that the serum FGF21 level was also increased in atherosclerosis-prone apolipoprotein E knockout (Apoe/) mice fed an atherogenic diet (Wu et al. 2014). FGF21 administration improved atherogenic diet-induced dyslipidemia and vascular atherosclerotic lesions in Apoe/ mice, probably by mitigating ER stress, a contributing factor in the pathogenesis of atherosclerosis (Wu et al. 2014). In addition, FGF21 treatment improved aggravated lipid profiles in atherosclerotic rats through its antioxidant effects (Zhu et al. 2014). The enhancement of cellular cholesterol efflux from macrophage-derived foam cells by FGF21 may also contribute to the improvement of atherosclerosis (Lin et al. 2014). Taken together, these findings suggest that FGF21 plays an adaptive and protective role in response to atherogenic stress, although further studies are needed to validate these findings.

Cardiokines, which are secreted from the heart in response to various cardiac stresses, play an important role in the maintenance of normal cardiac function through autocrine, paracrine, or endocrine mechanisms (Shimano et al. 2012). It has been reported that FGF21 expression was induced through a Sirt1–PPARα-dependent mechanism in the hearts of mice under various cardiac stress conditions such as isoproterenol/phenylephrine infusion, coronary artery ligation-induced myocardial infarction (ischemia), or transverse aortic constriction (Planavila et al. 2013). In addition, FGF21 expression was increased in the hearts of human subjects with dilated cardiomyopathy or advanced heart failure (Planavila et al. 2015). However, the source of FGF21 in these conditions is controversial, because another study showed FGF21 induction in the liver and adipose tissue but not in the ischemic myocardium of mice (Liu et al. 2013). Importantly, stress-induced cardiac hypertrophy was increased in Fgf21/ mice, while exogenous FGF21 administration ameliorated cardiac hypertrophy in these mice (Liu et al. 2013, Planavila et al. 2013). These results suggest that cardiac stress-induced FGF21 expression is a compensatory signal to protect against cardiac failure or cardiac dysfunction. Several mechanisms of improved stress-induced cardiac hypertrophy by FGF21 have been suggested. A role for the FGF receptor 1/β-klotho/protein kinase B (PKB/AKT) pathway in this process has been suggested in an in vivo study employing the strategy of siRNA administration to the anterior ventricular wall (Liu et al. 2013). In addition, i.m. injection of the adenovirus expressing FGF21 increased serum adiponectin levels and attenuated cardiac hypertrophy in mice with experimental myocardial infarction (Joki et al. 2015). Notably, FGF21-mediated cardiac protection was diminished in Adipoq/ mice, indicating that adiponectin mediates the beneficial effects of FGF21 on cardiac function. Enhancement of the antioxidant capacity via upregulation of antioxidant enzyme gene expression may contribute to the protective effects of FGF21 (Planavila et al. 2015). These results collectively suggest that FGF21 may be a pharmacological agent for treatment of myocardial injury.

FGF21 and kidney disease

It has been reported that serum FGF21 levels were increased in subjects with acute or chronic kidney diseases (Stein et al. 2009, Hindricks et al. 2014), and circulating FGF21 was elevated in proportion to the severity of kidney diseases (Lin et al. 2011). Increasingly, studies have suggested that FGF21 elicits protective effects against the progression of diabetic nephropathy, a leading cause of chronic renal failure (Kim et al. 2013c, Zhang et al. 2013a). FGF21 administration prevented renal lipid accumulation, oxidative stress, inflammation, and fibrosis in mice after treatment of excessive fatty acids or streptozotocin (Zhang et al. 2013a) and in leptin receptor-deficient db/db mice with diabetic nephropathy (Kim et al. 2013c). Conversely, Fgf21/ mice exhibited more aggravated lipotoxicity and renal damage compared to the control mice (Zhang et al. 2013a). These findings suggest that FGF21 induction is an adaptive mechanism to protect against renal injury in diabetic conditions and that FGF21 is a potential therapeutic agent for the treatment of diabetic nephropathy.

The role of FGF21 in pharmacologic agent-induced metabolic benefits

A growing body of evidence suggests that several pharmacologic agents that are currently available or are being developed for the treatment of metabolic diseases have a potential to induce FGF21. Here, we will review the functional role and molecular mechanisms of FGF21 induction by anti-diabetic drugs.

Metformin and FGF21

Metformin is a first-line agent for patients with T2D, according to the guidelines of the European Association for the Study of Diabetes and the American Diabetes Association. Metformin likely exerts its glucose-lowering effect through inhibition of glucose absorption in the intestine, suppression of gluconeogenesis in the liver, and enhancement of insulin actions in the liver, adipose tissue, or skeletal muscle (Foretz et al. 2014). The changes of composition or alterations of microbial metabolism in the gut microbiota are also involved in the beneficial metabolic effects of metformin (Cabreiro et al. 2013, Shin et al. 2014). The effect of metformin on suppression of gluconeogenesis has been reported to be dependent on AMPK, which functions as a conserved cellular energy sensor in an adaptive response to diverse energy stress conditions (Shaw et al. 2005, He et al. 2009). Metformin-induced AMPK activation causes a decrease in the transcription of hepatic gluconeogenic enzyme genes, which depends on diverse factors such as CREB-regulated transcription coactivator 2 (He et al. 2009) and the small heterodimer partner (Kim et al. 2008). Metformin also improves hepatic lipid homeostasis by enhancing β-oxidation and suppressing lipogenesis in the liver via AMPK-mediated phosphorylation of acetyl CoA carboxylase (Fullerton et al. 2013). However, metformin is also able to suppress hepatic glucose production by altering the energy charge in an AMPK-independent manner without affecting gluconeogenic gene expression (Foretz et al. 2010). These effects are mediated by a reduced ATP level or an increased AMP/ATP ratio via partial inhibition of mitochondrial respiratory-chain complex I (Foretz et al. 2010, Miller et al. 2013).

Secretory proteins (or hormones) derived from major metabolic organs such as adipose tissue, muscle, and liver play a key role in the maintenance of energy homeostasis (Ouchi et al. 2011, Pedersen & Febbraio 2012, Stefan & Haring 2013). These secretory proteins may be involved in beneficial metabolic effects of metformin. Metformin treatment increased serum GLP1 levels in human subjects with or without T2D (Mannucci et al. 2004), as well as in obese diabetic mice (Kim et al. 2014b). In addition, metformin has been reported to induce FGF21 expression in hepatocytes through an AMPK-dependent pathway (Nygaard et al. 2012). We have observed that metformin causes FGF21 upregulation, which is dependent on the eIF2α–ATF4 axis but not on AMPK (Kim et al. 2013d). Moreover, serum FGF21 levels in human subjects with T2D were shown to increase after 6 months of metformin treatment (Kim et al. 2013d). Hence, FGF21 induction by metformin may contribute to its metabolic effects. However, it has been also reported that the administration of metformin to human subjects with T2D for 1 week led to decreased serum FGF21 levels (Zhang et al. 2013b). Serum FGF21 levels in HIV-infected subjects treated with metformin for 12 months were not significantly different from those in the placebo group (Srinivasa et al. 2015). These discrepancies could be attributable to differences in patient selection, experimental analyses, or duration of metformin treatment. Since the numbers of human subjects studied were small, large-scale studies are needed to evaluate the role of FGF21 induction in the therapeutic effects of metformin.

Glucagon, GLP1, and FGF21

Glucagon secreted from pancreatic islet α cells is a well-known counterregulatory hormone that maintains glucose homeostasis by increasing gluconeogenesis and glycogenolysis in response to fasting or hypoglycemia. Hyperglucagonemia is observed in the early phase of insulin resistance/T2D and contributes to hyperglycemia by increasing the rate of hepatic glucose output and enhancing glycogen breakdown (Unger & Cherrington 2012). Lipid metabolism and energy expenditure are also regulated by glucagon or glucagon agonism. Some studies have shown that glucagon decreased the levels of plasma TG and cholesterol in rats with or without hyperlipidemia (Eaton 1973). Glucagon also promotes lipolysis by activating hormone-sensitive lipase in white adipocytes (Slavin et al. 1994), enhances β oxidation, and suppresses lipogenesis in hepatocytes (Prip-Buus et al. 1990). In addition, glucagon has been reported to increase energy expenditure in mice or human subjects, probably by stimulating oxygen consumption and heat production in BAT (Doi & Kuroshima 1982, Tan et al. 2013). Thus, glucagon-induced beneficial effects on dyslipidemia and obesity make it an attractive therapeutic agent for treatment of metabolic disease, despite its potential ability to increase blood glucose level.

Intriguingly, glucagon and glucagon agonists have been reported to induce hepatic FGF21 gene expression, leading to the increase of serum FGF21 levels in mice and healthy human volunteers (Arafat et al. 2013, Habegger et al. 2013). The effects of glucagon agonism inducing body weight loss, hypocholesterolemia, and increased energy expenditure were lower in Fgf21/ mice than in control mice (Habegger et al. 2013). Given that FGF21 reduces fat mass or serum cholesterol levels and enhances thermogenesis, FGF21 may act as a mediator of metabolic improvement by glucagon. A recent paper has shown that glucagon stimulates hepatic FGF21 secretion via PKA and Epac (exchange protein directly activated by cAMP)-dependent pathways without change of FGF21 mRNA expression (Cyphert et al. 2014), suggesting that glucagon increases FGF21 levels through post-translational mechanisms as well as transcriptional mechanisms.

GLP1, a proglucagon-derived peptide hormone, is secreted from L cells of the intestine in response to nutrients. GLP1 plays a key role in the control of glucose homeostasis by enhancing insulin release and suppressing glucagon secretion (Meier 2012). GLP1 also inhibits gastric emptying and induces satiety, which contributes to the suppression of food intake (Meier 2012). Five GLP1 receptor agonists (liraglutide, exenatide, lixisenatide, albiglutide and dulaglutide) are currently being used for the treatment of T2D. Intriguingly, GLP1 analogues also stimulate FGF21 expression, similar to glucagon or glucagon agonists. Treatment with liraglutide, a derivative of human GLP1 with a fatty acid chain, induced FGF21 gene expression in the liver but not in adipose tissue of KK-Ay mice (Nonogaki et al. 2014); consequently, serum FGF21 levels were increased in liraglutide-treated KK-Ay mice showing amelioration of hyperglycemia and obesity. Moreover, treatment with exendin-4 (the naturally occurring form of exenatide) for 10 weeks increased hepatic FGF21 gene expression in HFD-fed mice compared to control HFD-fed mice (Lee et al. 2014b). Dissimilar results regarding the effect of exendin-4 on FGF21 expression have also been reported. Hepatic FGF21 expression and serum FGF21 levels were decreased in HFD-fed mice treated with exendin-4 for 4 weeks compared to saline treatment (Samson et al. 2011). Consistent with this result, the addition of exenatide reduced FGF21 levels in T2D subjects undergoing pioglitazone treatment (Samson et al. 2011). Furthermore, a decrease in hepatic FGF21 levels was correlated with reduction in hepatic TG content and liver weight in HFD-fed mice after exendin-4 treatment, implying that reduction of FGF21 due to exendin-4 may be secondary to reduced lipid accumulation. Further studies are needed to evaluate the relationship between FGF21 induction and metabolic benefits by GLP1 analogues.

Combined glucagon/GLP1 dual agonists that retain the anti-hyperglycemic potential of GLP1 while avoiding the hyperglycemic effects of pure glucagon are being evaluated in clinical trials. The glucagon/GLP1 dual agonist is an attractive therapeutic agent as an anti-obesity drug as well as an anti-diabetic drug, due to the lipolytic and thermogenic properties of glucagon (Sadry & Drucker 2013). Glucagon/GLP1 dual agonists also increased hepatic FGF21 expression and improved obesity-induced metabolic deterioration in mice, similar to glucagon or GLP1 agonists (Pocai et al. 2009). However, the role of FGF21 in glucagon/GLP1 dual agonism remains to be determined.

PPARγ agonist (TZD) and FGF21

TZD, a PPARγ agonist, is an anti-diabetic drug used for the treatment of T2D. TZD has been reported to enhance glucose uptake in adipose tissue or skeletal muscle and inhibit gluconeogenesis in the liver by reinforcing insulin action (Soccio et al. 2014). In addition to its role as an insulin sensitizer, TZD directly converts macrophage polarity from pro-inflammatory M1 to anti-inflammatory M2 type (Bouhlel et al. 2007) or indirectly via lipid partitioning (Prieur et al. 2011), probably leading to attenuation of obesity-induced adipose inflammation and insulin resistance. TZD may also elicit beneficial metabolic effects by regulating the levels or actions of hormones. Treatment with TZD caused an increase in serum adiponectin levels in obese mice and consequently improved obesity-induced glucose intolerance (Nawrocki et al. 2006). The effectiveness of TZD was diminished in obese Adipoq/ mice, suggesting that adiponectin is an important contributor to TZD-mediated improvement of whole-body glucose metabolism (Nawrocki et al. 2006). In addition, TZD has been reported to increase FGF21 gene expression in adipose tissue, but not in the liver, through activation of PPARγ and, consequently, serum FGF21 levels are higher in TZD-treated mice compared to control mice (Muise et al. 2008). These results suggest a possible role of FGF21 in the anti-diabetic actions of TZD. In line with this assumption, obese Fgf21/ mice were refractory to the metabolic effects of TZD (Dutchak et al. 2012). Notably, these effects of TZD are associated with the local action of FGF21 in adipose tissue but not with the systemic action. Adipose-derived FGF21 induction by TZD suppresses sumoylation of PPARγ and consequently enhances PPARγ activity in adipose tissue, probably contributing to anti-diabetic effects of TZD (Dutchak et al. 2012). However, another paper reported that Fgf21/ mice exhibited metabolic responses to TZD similar to those of Fgf21+/+ mice (Adams et al. 2013a). Furthermore, PPARγ sumoylation in adipose tissue did not differ between the two groups after TZD treatment (Adams et al. 2013a). There is no clear explanation for these discrepancies, which might be attributable to the differences in knockout mouse strains or experimental procedures. Further studies are required to understand the relationship between FGF21 and PPARγ in TZD-induced pharmacologic actions. Given that both TZD and FGF21 induce browning of WAT (Vernochet et al. 2009, Petrovic et al. 2010, Fisher et al. 2012), it will also be interesting to study the role of FGF21 in TZD-induced browning.

Sirt1 activators and FGF21

Sirt1, an NAD-dependent deacetylase, is an important regulator of cellular or whole-body energy metabolism through the modulation of acetylation/deacetylation of histones or non-histone proteins. Sirt1 gain- or loss-of-function studies in the whole-body or in specific organs have suggested that Sirt1 is a promising therapeutic target for the treatment of insulin resistance and T2D (Boutant & Canto 2014). Pharmacologic studies have suggested that several Sirt1 activators have therapeutic efficacy in T2D associated with obesity. Resveratrol, a natural polyphenol product derived from grapes, is a well-known Sirt1 activator that improves metabolic profiles in obese mice (Baur et al. 2006, Lagouge et al. 2006) and human subjects with obesity or T2D (Timmers et al. 2011). SRT1720, a synthetic small molecule activator of Sirt1, improves insulin sensitivity and glucose tolerance (Milne et al. 2007). Sirt1-mediated regulation of glucose and lipid homeostasis may be elicited by various mechanisms, including an increase of PGC1α-mediated β oxidation and mitochondrial biogenesis (Feige et al. 2008), suppression of sterol regulatory element-binding protein 1c-mediated fatty acid synthesis (Ponugoti et al. 2010), reduction of nuclear factor-kappa B-mediated macrophage inflammation (Schug et al. 2010), or enhancement of PPARγ-mediated browning (Qiang et al. 2012). In addition, Sirt1-mediated changes in the levels of certain hormones may contribute to its beneficial metabolic action. Sirt1 induces adiponectin gene expression through deacetylation of forkhead box O1 (Qiao & Shao 2006), which may help improve glucose tolerance and insulin sensitivity. Additionally, it has been reported that Sirt1 increases insulin secretion through the suppression of transcription of uncoupling protein 2 (Bordone et al. 2006). Resveratrol has been also reported to enhance insulin release from pancreatic β cells (Vetterli et al. 2011). A recent paper reported that Sirt1 or its activators (resveratrol and SRT1720) induced FGF21 gene expression in the liver of mice and that liver-specific Sirt1 knockout (Sirt1Δhep) mice had a reduced hepatic expression and serum level of FGF21 compared to control mice in response to fasting (Li et al. 2014). Importantly, Sirt1Δhep mice exhibited reduced ketogenesis and increased hepatic lipid accumulation in fasting conditions; this was rescued by adenovirus-mediated hepatic FGF21 overexpression (Li et al. 2014). These results suggest that Sirt1-mediated FGF21 induction plays an important role in the adaptive metabolic response to fasting. Furthermore, Sirt1 may participate in GLP1 receptor agonist-induced FGF21 expression in hepatocytes (Lee et al. 2014b). Further studies will be necessary to elucidate the role of FGF21 in the metabolic improvement by Sirt1 activators.

Other pharmacological compounds and FGF21

A growing body of evidence suggests that other therapeutic reagents influence FGF21 gene expression. Lipoic acid, also known as thioctic acid, is an octanoic acid-derived organosulfur compound that is naturally synthesized in small amounts in the body (Shay et al. 2009). Lipoic acid plays an important role in the maintenance of mitochondrial respiratory capacity as a cofactor that covalently binds to mitochondrial complex enzymes (Shay et al. 2009). Numerous studies have suggested that lipoic acid supplements improved glucose intolerance and insulin sensitivity in mice and human subjects (Jacob et al. 1999). In Germany, lipoic acid is medically approved for the treatment of adult-onset T2D and diabetic complications such as diabetic neuropathy. Lipoic acid has been reported to regulate glucose and lipid metabolism by modulating the activity of Sirt1 or AMPK (Park et al. 2008, Yang et al. 2014). Importantly, lipoic acid has been also reported to induce FGF21 expression in hepatocytes and in the livers of mice, probably via upregulation of CREBH (Bae et al. 2014). However, a biological role of FGF21 in lipoic acid-induced metabolic improvement remains to be determined. Acarbose, an α-glycoside hydrolase inhibitor that is being used as an anti-diabetic drug, has been reported to increase serum FGF21 levels in aged mice (Harrison et al. 2014). Given the effects of acarbose on the enhancement of the life-span and improvement of metabolic derangement (Harrison et al. 2014), these findings suggest that acarbose may elicit its metabolic actions through FGF21. This issue awaits further investigation.

Conclusions

Numerous studies have suggested that FGF21 is a promising therapeutic agent for the treatment of obesity-related insulin resistance due to its multiple actions on diverse metabolic target organs. In addition to the metabolic effects of FGF21, we discussed the importance of FGF21 induction in several disease conditions such as muscle atrophy, liver injury, cardiovascular disease, and renal injury. FGF21 may also play a protective role against glutamate-induced neuronal excitotoxicity (Leng et al. 2015) or chemical-induced testicular injury (Jiang et al. 2013). Chronic FGF21 overexpression has been reported to extend the life-span in mice, probably through a mechanism involving suppression of the GH/insulin-like growth factor 1 signaling pathway (Zhang et al. 2012). Despite diverse beneficial effects of FGF21, it may have side effects such as growth retardation (Inagaki et al. 2008), bone loss (Wei et al. 2012), and female infertility (Owen et al. 2013). Further studies are needed to evaluate the legitimate therapeutic role of FGF21 or its mimetics in several diseases, which will provide new strategies to develop novel agents without adverse effects. In addition, further work on the elucidation of uncharacterized downstream effectors of FGF21 in specific organs will help develop promising drug targets capable of mimicking the beneficial effects of FGF21.

Declaration of interest

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

Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2013R1A6A3A04065825 to K H K) and by the Global Research Laboratory Grant of the National Research Foundation of Korea (K21004000003-10A0500-00310 to M-S L). M-S L is the recipient of the Ulsan National Institute of Science and Technology Research Fund (2014M3A9D8034459).

References

  • AblesGPPerroneCEOrentreichDOrentreichN2012Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PLoS ONE7e51357. (doi:10.1371/journal.pone.0051357)

    • Search Google Scholar
    • Export Citation
  • AdamsACAstapovaIFisherFMBadmanMKKurganskyKEFlierJSHollenbergANMaratos-FlierE2010Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARα-dependent manner. Journal of Biological Chemistry2851407814082. (doi:10.1074/jbc.C110.107375)

    • Search Google Scholar
    • Export Citation
  • AdamsACChengCCCoskunTKharitonenkovA2012FGF21 requires βklotho to act in vivo. PLoS ONE7e49977. (doi:10.1371/journal.pone.0049977)

  • AdamsACCoskunTChengCCO'FarrellLSDuboisSLKharitonenkovA2013aFibroblast growth factor 21 is not required for the antidiabetic actions of the thiazolidinediones. Molecular Metabolism2205214. (doi:10.1016/j.molmet.2013.05.005)

    • Search Google Scholar
    • Export Citation
  • AdamsACHalsteadCAHansenBCIrizarryARMartinJAMyersSRReynoldsVLSmithHWWroblewskiVJKharitonenkovA2013bLY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys. PLoS ONE8e65763. (doi:10.1371/journal.pone.0065763)

    • Search Google Scholar
    • Export Citation
  • ArafatAMKaczmarekPSkrzypskiMPruszynska-OszmalekEKolodziejskiPSzczepankiewiczDSassekMWojciechowiczTWiedenmannBPfeifferAF2013Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?Diabetologia56588597. (doi:10.1007/s00125-012-2803-y)

    • Search Google Scholar
    • Export Citation
  • AssiniJMMulvihillEEBurkeACSutherlandBGTelfordDEChhokerSSSawyezCGDrangovaMAdamsACKharitonenkovA2015Naringenin prevents obesity, hepatic steatosis and glucose intolerance in male mice independent of fibroblast growth factor 21. Endocrinology15620872102. (doi:10.1210/en.2014-2003)

    • Search Google Scholar
    • Export Citation
  • BadmanMKPissiosPKennedyARKoukosGFlierJSMaratos-FlierE2007Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metabolism5426437. (doi:10.1016/j.cmet.2007.05.002)

    • Search Google Scholar
    • Export Citation
  • BadmanMKKoesterAFlierJSKharitonenkovAMaratos-FlierE2009Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology15049314940. (doi:10.1210/en.2009-0532)

    • Search Google Scholar
    • Export Citation
  • BaeKHMinAKKimJGLeeIKParkKG2014Alpha lipoic acid induces hepatic fibroblast growth factor 21 expression via up-regulation of CREBH. Biochemical and Biophysical Research Communications455212217. (doi:10.1016/j.bbrc.2014.10.147)

    • Search Google Scholar
    • Export Citation
  • BaurJAPearsonKJPriceNLJamiesonHALerinCKalraAPrabhuVVAllardJSLopez-LluchGLewisK2006Resveratrol improves health and survival of mice on a high-calorie diet. Nature444337342. (doi:10.1038/nature05354)

    • Search Google Scholar
    • Export Citation
  • BordoneLMottaMCPicardFRobinsonAJhalaUSApfeldJMcDonaghTLemieuxMMcBurneyMSzilvasiA2006Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS Biology4e31. (doi:10.1371/journal.pbio.0040031)

    • Search Google Scholar
    • Export Citation
  • BouhlelMADerudasBRigamontiEDievartRBrozekJHaulonSZawadzkiCJudeBTorpierGMarxN2007PPARγ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metabolism6137143. (doi:10.1016/j.cmet.2007.06.010)

    • Search Google Scholar
    • Export Citation
  • BoutantMCantoC2014SIRT1 metabolic actions: integrating recent advances from mouse models. Molecular Metabolism3518. (doi:10.1016/j.molmet.2013.10.006)

    • Search Google Scholar
    • Export Citation
  • CabreiroFAuCLeungKYVergara-IrigarayNCochemeHMNooriTWeinkoveDSchusterEGreeneNDGemsD2013Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell153228239. (doi:10.1016/j.cell.2013.02.035)

    • Search Google Scholar
    • Export Citation
  • ChauMDGaoJYangQWuZGromadaJ2010Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway. PNAS1071255312558. (doi:10.1073/pnas.1006962107)

    • Search Google Scholar
    • Export Citation
  • ChavezAOMolina-CarrionMAbdul-GhaniMAFolliFDefronzoRATripathyD2009Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care3215421546. (doi:10.2337/dc09-0684)

    • Search Google Scholar
    • Export Citation
  • ChenWHooRLKonishiMItohNLeePCYeHYLamKSXuA2011Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. Journal of Biological Chemistry2863455934566. (doi:10.1074/jbc.M111.285965)

    • Search Google Scholar
    • Export Citation
  • ChengXVisputeSGLiuJChengCKharitonenkovAKlaassenCD2014Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR). Toxicology and Applied Pharmacology2786571. (doi:10.1016/j.taap.2014.04.013)

    • Search Google Scholar
    • Export Citation
  • ChowWSXuAWooYCTsoAWCheungSCFongCHTseHFChauMTCheungBMLamKS2013Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arteriosclerosis Thrombosis and Vascular Biology3324542459. (doi:10.1161/ATVBAHA.113.301599)

    • Search Google Scholar
    • Export Citation
  • CoskunTBinaHASchneiderMADunbarJDHuCCChenYMollerDEKharitonenkovA2008Fibroblast growth factor 21 corrects obesity in mice. Endocrinology14960186027. (doi:10.1210/en.2008-0816)

    • Search Google Scholar
    • Export Citation
  • Cuevas-RamosDAlmeda-ValdesPMeza-AranaCEBrito-CordovaGGomez-PerezFJMehtaROseguera-MoguelJAguilar-SalinasCA2012Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS ONE7e38022. (doi:10.1371/journal.pone.0038022)

    • Search Google Scholar
    • Export Citation
  • CyphertHAAlongeKMIppaguntaSMHillgartnerFB2014Glucagon stimulates hepatic FGF21 secretion through a PKA- and EPAC-dependent posttranscriptional mechanism. PLoS ONE9e94996. (doi:10.1371/journal.pone.0094996)

    • Search Google Scholar
    • Export Citation
  • De Sousa-CoelhoALRelatJHondaresEPerez-MartiARibasFVillarroyaFMarreroPFHaroD2013FGF21 mediates the lipid metabolism response to amino acid starvation. Journal of Lipid Research5417861797. (doi:10.1194/jlr.M033415)

    • Search Google Scholar
    • Export Citation
  • DingXBoney-MontoyaJOwenBMBookoutALCoateKCMangelsdorfDJKliewerSA2012βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metabolism16387393. (doi:10.1016/j.cmet.2012.08.002)

    • Search Google Scholar
    • Export Citation
  • DoiKKuroshimaA1982Thermogenic response to glucagon in cold-acclimated mice. Japanese Journal of Physiology32377385. (doi:10.2170/jjphysiol.32.377)

    • Search Google Scholar
    • Export Citation
  • DomouzoglouEMFisherFMAstapovaIFoxECKharitonenkovAFlierJSHollenbergANMaratos-FlierE2014Fibroblast growth factor 21 and thyroid hormone show mutual regulatory dependency but have independent actions in vivo. Endocrinology15520312040. (doi:10.1210/en.2013-1902)

    • Search Google Scholar
    • Export Citation
  • DushayJChuiPCGopalakrishnanGSVarela-ReyMCrawleyMFisherFMBadmanMKMartinez-ChantarMLMaratos-FlierE2010Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology139456463. (doi:10.1053/j.gastro.2010.04.054)

    • Search Google Scholar
    • Export Citation
  • DushayJRToschiEMittenEKFisherFMHermanMAMaratos-FlierE2015Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Molecular Metabolism45157. (doi:10.1016/j.molmet.2014.09.008)

    • Search Google Scholar
    • Export Citation
  • DutchakPAKatafuchiTBookoutALChoiJHYuRTMangelsdorfDJKliewerSA2012Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell148556567. (doi:10.1016/j.cell.2011.11.062)

    • Search Google Scholar
    • Export Citation
  • EatonRP1973Hypolipemic action of glucagon in experimental endogenous lipemia in the rat. Journal of Lipid Research14312318.

  • EmanuelliBVienbergSGSmythGChengCStanfordKIArumugamMMichaelMDAdamsACKharitonenkovAKahnCR2014Interplay between FGF21 and insulin action in the liver regulates metabolism. Journal of Clinical Investigation124515527. (doi:10.1172/JCI67353)

    • Search Google Scholar
    • Export Citation
  • FeigeJNLagougeMCantoCStrehleAHoutenSMMilneJCLambertPDMatakiCElliottPJAuwerxJ2008Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metabolism8347358. (doi:10.1016/j.cmet.2008.08.017)

    • Search Google Scholar
    • Export Citation
  • FisherFMChuiPCAntonellisPJBinaHAKharitonenkovAFlierJSMaratos-FlierE2010Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes5927812789. (doi:10.2337/db10-0193)

    • Search Google Scholar
    • Export Citation
  • FisherFMKleinerSDourisNFoxECMepaniRJVerdeguerFWuJKharitonenkovAFlierJSMaratos-FlierE2012FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes and Development26271281. (doi:10.1101/gad.177857.111)

    • Search Google Scholar
    • Export Citation
  • FisherFMChuiPCNasserIAPopovYCunniffJCLundasenTKharitonenkovASchuppanDFlierJSMaratos-FlierE2014Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology14710731083.(e1076) (doi:10.1053/j.gastro.2014.07.044)

    • Search Google Scholar
    • Export Citation
  • FoltzINHuSKingCWuXYangCWangWWeiszmannJStevensJChenJSNuanmaneeN2012Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Science Translational Medicine4162ra153. (doi:10.1126/scitranslmed.3004690)

    • Search Google Scholar
    • Export Citation
  • ForetzMHebrardSLeclercJZarrinpashnehESotyMMithieuxGSakamotoKAndreelliFViolletB2010Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. Journal of Clinical Investigation12023552369. (doi:10.1172/JCI40671)

    • Search Google Scholar
    • Export Citation
  • ForetzMGuigasBBertrandLPollakMViolletB2014Metformin: from mechanisms of action to therapies. Cell Metabolism20953966. (doi:10.1016/j.cmet.2014.09.018)

    • Search Google Scholar
    • Export Citation
  • FullertonMDGalicSMarcinkoKSikkemaSPulinilkunnilTChenZPO'NeillHMFordRJPalanivelRO'BrienM2013Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine1916491654. (doi:10.1038/nm.3372)

    • Search Google Scholar
    • Export Citation
  • GaichGChienJYFuHGlassLCDeegMAHollandWLKharitonenkovABumolTSchilskeHKMollerDE2013The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metabolism18333340. (doi:10.1016/j.cmet.2013.08.005)

    • Search Google Scholar
    • Export Citation
  • GalmanCLundasenTKharitonenkovABinaHAErikssonMHafstromIDahlinMAmarkPAngelinBRudlingM2008The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metabolism8169174. (doi:10.1016/j.cmet.2008.06.014)

    • Search Google Scholar
    • Export Citation
  • HabeggerKMStemmerKChengCMullerTDHeppnerKMOttawayNHollandJHembreeJLSmileyDGelfanovV2013Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes6214531463. (doi:10.2337/db12-1116)

    • Search Google Scholar
    • Export Citation
  • HarmsMSealeP2013Brown and beige fat: development, function and therapeutic potential. Nature Medicine1912521263. (doi:10.1038/nm.3361)

    • Search Google Scholar
    • Export Citation
  • HarrisonDEStrongRAllisonDBAmesBNAstleCMAtamnaHFernandezEFlurkeyKJavorsMANadonNL2014Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell13273282. (doi:10.1111/acel.12170)

    • Search Google Scholar
    • Export Citation
  • HasekBEStewartLKHenaganTMBoudreauALenardNRBlackCShinJHuypensPMalloyVLPlaisanceEP2010Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. American Journal of Physiology. Regulatory Integrative and Comparative Physiology299R728R739. (doi:10.1152/ajpregu.00837.2009)

    • Search Google Scholar
    • Export Citation
  • HeLSabetADjedjosSMillerRSunXHussainMARadovickSWondisfordFE2009Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell137635646. (doi:10.1016/j.cell.2009.03.016)

    • Search Google Scholar
    • Export Citation
  • HindricksJEbertTBachmannAKralischSLossnerUKratzschJStolzenburgJUDietelABeigeJAndersM2014Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clinical Endocrinology80918924. (doi:10.1111/cen.12380)

    • Search Google Scholar
    • Export Citation
  • HollandWLAdamsACBrozinickJTBuiHHMiyauchiYKusminskiCMBauerSMWadeMSinghalEChengCC2013An FGF21–adiponectin–ceramide axis controls energy expenditure and insulin action in mice. Cell Metabolism17790797. (doi:10.1016/j.cmet.2013.03.019)

    • Search Google Scholar
    • Export Citation
  • HondaresEIglesiasRGiraltAGonzalezFJGiraltMMampelTVillarroyaF2011Thermogenic activation induces FGF21 expression and release in brown adipose tissue. Journal of Biological Chemistry2861298312990. (doi:10.1074/jbc.M110.215889)

    • Search Google Scholar
    • Export Citation
  • HuangXYuCJinCYangCXieRCaoDWangFMcKeehanWL2006Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Molecular Carcinogenesis45934942. (doi:10.1002/mc.20241)

    • Search Google Scholar
    • Export Citation
  • IizukaKTakedaJHorikawaY2009Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes. FEBS Letters58328822886. (doi:10.1016/j.febslet.2009.07.053)

    • Search Google Scholar
    • Export Citation
  • InagakiTDutchakPZhaoGDingXGautronLParameswaraVLiYGoetzRMohammadiMEsserV2007Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metabolism5415425. (doi:10.1016/j.cmet.2007.05.003)

    • Search Google Scholar
    • Export Citation
  • InagakiTLinVYGoetzRMohammadiMMangelsdorfDJKliewerSA2008Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metabolism87783. (doi:10.1016/j.cmet.2008.05.006)

    • Search Google Scholar
    • Export Citation
  • IzumiyaYBinaHAOuchiNAkasakiYKharitonenkovAWalshK2008FGF21 is an Akt-regulated myokine. FEBS Letters58238053810. (doi:10.1016/j.febslet.2008.10.021)

    • Search Google Scholar
    • Export Citation
  • JacobSRettKHenriksenEJHaringHU1999Thioctic acid – effects on insulin sensitivity and glucose-metabolism. BioFactors10169174. (doi:10.1002/biof.5520100212)

    • Search Google Scholar
    • Export Citation
  • JiangXZhangCXinYHuangZTanYHuangYWangYFengWLiXLiW2013Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial- and endoplasmic reticulum stress-dependent pathways in the mouse model. Toxicology Letters2196576. (doi:10.1016/j.toxlet.2013.02.022)

    • Search Google Scholar
    • Export Citation
  • JiangSYanCFangQCShaoMLZhangYLLiuYDengYPShanBLiuJQLiHT2014Fibroblast growth factor 21 is regulated by the IRE1α–XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis. Journal of Biological Chemistry2892975129765. (doi:10.1074/jbc.M114.565960)

    • Search Google Scholar
    • Export Citation
  • JohnsonCLWestonJYChadiSAFazioENHuffMWKharitonenkovAKoesterAPinCL2009Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology13717951804. (doi:10.1053/j.gastro.2009.07.064)

    • Search Google Scholar
    • Export Citation
  • JohnsonCLMehmoodRLaingSWStepniakCVKharitonenkovAPinCL2014Silencing of the fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1. American Journal of Physiology. Endocrinology and Metabolism306E916E928. (doi:10.1152/ajpendo.00559.2013)

    • Search Google Scholar
    • Export Citation
  • JokiYOhashiKYuasaDShibataRItoMMatsuoKKambaraTUemuraYHayakawaSHiramatsu-ItoM2015FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochemical and Biophysical Research Communications459124130. (doi:10.1016/j.bbrc.2015.02.081)

    • Search Google Scholar
    • Export Citation
  • KharitonenkovAShiyanovaTLKoesterAFordAMMicanovicRGalbreathEJSanduskyGEHammondLJMoyersJSOwensRA2005FGF-21 as a novel metabolic regulator. Journal of Clinical Investigation11516271635. (doi:10.1172/JCI23606)

    • Search Google Scholar
    • Export Citation
  • KimKHLeeMS2014FGF21 as a stress hormone: the roles of FGF21 in stress adaptation and the treatment of metabolic diseases. Diabetes & Metabolism Journal38245251. (doi:10.4093/dmj.2014.38.4.245)

    • Search Google Scholar
    • Export Citation
  • KimYDParkKGLeeYSParkYYKimDKNedumaranBJangWGChoWJHaJLeeIK2008Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes57306314. (doi:10.2337/db07-0381)

    • Search Google Scholar
    • Export Citation
  • KimKHJeongYTOhHKimSHChoJMKimYNKimSSKim doHHurKYKimHK2013aAutophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nature Medicine198392. (doi:10.1038/nm.3014)

    • Search Google Scholar
    • Export Citation
  • KimKHKimSHMinYKYangHMLeeJBLeeMS2013bAcute exercise induces FGF21 expression in mice and in healthy humans. PLoS ONE8e63517. (doi:10.1371/journal.pone.0063517)

    • Search Google Scholar
    • Export Citation
  • KimHWLeeJEChaJJHyunYYKimJELeeMHSongHKNamDHHanJYHanSY2013cFibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology15433663376. (doi:10.1210/en.2012-2276)

    • Search Google Scholar
    • Export Citation
  • KimKHJeongYTKimSHJungHSParkKSLeeHYLeeMS2013dMetformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation. Biochemical and Biophysical Research Communications4407681. (doi:10.1016/j.bbrc.2013.09.026)

    • Search Google Scholar
    • Export Citation
  • KimHMendezRZhengZChangLCaiJZhangRZhangK2014aLiver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21. Endocrinology155769782. (doi:10.1210/en.2013-1490)

    • Search Google Scholar
    • Export Citation
  • KimMHJeeJHParkSLeeMSKimKWLeeMK2014bMetformin enhances glucagon-like peptide 1 via cooperation between insulin and Wnt signaling. Journal of Endocrinology220117128. (doi:10.1530/JOE-13-0381)

    • Search Google Scholar
    • Export Citation
  • KimSHKimKHKimHKKimMJBackSHKonishiMItohNLeeMS2015Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia58809818. (doi:10.1007/s00125-014-3475-6)

    • Search Google Scholar
    • Export Citation
  • KongLJFengWWrightMChenYDallas-yangQZhouYPBergerJP2013FGF21 suppresses hepatic glucose production through the activation of atypical protein kinase Cι/λ. European Journal of Pharmacology702302308. (doi:10.1016/j.ejphar.2012.11.065)

    • Search Google Scholar
    • Export Citation
  • KubickyRAWuSKharitonenkovADe LucaF2012Role of fibroblast growth factor 21 (FGF21) in undernutrition-related attenuation of growth in mice. Endocrinology15322872295. (doi:10.1210/en.2011-1909)

    • Search Google Scholar
    • Export Citation
  • LaegerTHenaganTMAlbaradoDCRedmanLMBrayGANolandRCMunzbergHHutsonSMGettysTWSchwartzMW2014FGF21 is an endocrine signal of protein restriction. Journal of Clinical Investigation12439133922. (doi:10.1172/JCI74915)

    • Search Google Scholar
    • Export Citation
  • LagougeMArgmannCGerhart-HinesZMezianeHLerinCDaussinFMessadeqNMilneJLambertPElliottP2006Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell12711091122. (doi:10.1016/j.cell.2006.11.013)

    • Search Google Scholar
    • Export Citation
  • LeeJHGiannikopoulosPDuncanSAWangJJohansenCTBrownJDPlutzkyJHegeleRAGlimcherLHLeeAH2011The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nature Medicine17812815. (doi:10.1038/nm.2347)

    • Search Google Scholar
    • Export Citation
  • LeePLindermanJDSmithSBrychtaRJWangJIdelsonCPerronRMWernerCDPhanGQKammulaUS2014aIrisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metabolism19302309. (doi:10.1016/j.cmet.2013.12.017)

    • Search Google Scholar
    • Export Citation
  • LeeJHongSWParkSERheeEJParkCYOhKWParkSWLeeWY2014bExendin-4 regulates lipid metabolism and fibroblast growth factor 21 in hepatic steatosis. Metabolism6310411048. (doi:10.1016/j.metabol.2014.04.011)

    • Search Google Scholar
    • Export Citation
  • LeesEKKrolEGrantLShearerKWyseCMoncurEBykowskaASModyNGettysTWDelibegovicM2014Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging Cell13817827. (doi:10.1111/acel.12238)

    • Search Google Scholar
    • Export Citation
  • LengYWangZTsaiLKLeedsPFesslerEBWangJChuangDM2015FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers. Molecular Psychiatry20215223. (doi:10.1038/mp.2013.192)

    • Search Google Scholar
    • Export Citation
  • LiHFangQGaoFFanJZhouJWangXZhangHPanXBaoYXiangK2010Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. Journal of Hepatology53934940. (doi:10.1016/j.jhep.2010.05.018)

    • Search Google Scholar
    • Export Citation
  • LiYWongKGilesAJiangJLeeJWAdamsACKharitonenkovAYangQGaoBGuarenteL2014Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology146539549.e7. (doi:10.1053/j.gastro.2013.10.059)

    • Search Google Scholar
    • Export Citation
  • LiangQZhongLZhangJWangYBornsteinSRTriggleCRDingHLamKSXuA2014FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes6340644075. (doi:10.2337/db14-0541)

    • Search Google Scholar
    • Export Citation
  • LinZWuZYinXLiuYYanXLinSXiaoJWangXFengWLiX2010Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS ONE5e15534. (doi:10.1371/journal.pone.0015534)

    • Search Google Scholar
    • Export Citation
  • LinZZhouZLiuYGongQYanXXiaoJWangXLinSFengWLiX2011Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. PLoS ONE6e18398. (doi:10.1371/journal.pone.0018398)

    • Search Google Scholar
    • Export Citation
  • LinZTianHLamKSLinSHooRCKonishiMItohNWangYBornsteinSRXuA2013Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metabolism17779789. (doi:10.1016/j.cmet.2013.04.005)

    • Search Google Scholar
    • Export Citation
  • LinXLHeXLZengJFZhangHZhaoYTanJKWangZ2014FGF21 increases cholesterol efflux by upregulating ABCA1 through the ERK1/2–PPARγ–LXRα pathway in THP1 macrophage-derived foam cells. DNA and Cell Biology33514521. (doi:10.1089/dna.2013.2290)

    • Search Google Scholar
    • Export Citation
  • LipsMAde GrootGHBerendsFJWiezerRvan WagensveldBASwankDJLuijtenAvan DijkKWPijlHJansenPL2014Calorie restriction and Roux-en-Y gastric bypass have opposing effects on circulating FGF21 in morbidly obese subjects. Clinical Endocrinology81862870. (doi:10.1111/cen.12496)

    • Search Google Scholar
    • Export Citation
  • LiuSQRobertsDKharitonenkovAZhangBHansonSMLiYCZhangLQWuYH2013Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Scientific Reports32767. (doi:10.1038/srep02767)

    • Search Google Scholar
    • Export Citation
  • LoydCMagrissoIJHaasMBalusuSItohNSandovalDAObiciSPerez-TilveDHabeggerKM2014Fibroblast growth factor 21 mediates the beneficial effects of exercise on diet-induced glucose intolerance. Diabetes63 (Supplement 1) A1A102.

    • Search Google Scholar
    • Export Citation
  • MaiKAndresJBiedasekKWeichtJBobbertTSabathMMeinusSReineckeFMohligMWeickertMO2009Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. Diabetes5815321538. (doi:10.2337/db08-1775)

    • Search Google Scholar
    • Export Citation
  • MannucciETesiFBardiniGOgnibeneAPetraccaMGCianiSPezzatiniABrogiMDicembriniICremascoF2004Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without type 2 diabetes. Diabetes Nutrition & Metabolism17336342.

    • Search Google Scholar
    • Export Citation
  • MarkanKRNaberMCAmekaMKAndereggMDMangelsdorfDJKliewerSAMohammadiMPotthoffMJ2014Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes6340574063. (doi:10.2337/db14-0595)

    • Search Google Scholar
    • Export Citation
  • MeierJJ2012GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nature Reviews. Endocrinology8728742. (doi:10.1038/nrendo.2012.140)

    • Search Google Scholar
    • Export Citation
  • MichelottiGAMachadoMVDiehlAM2013NAFLD, NASH and liver cancer. Nature Reviews. Gastroenterology & Hepatology10656665. (doi:10.1038/nrgastro.2013.183)

    • Search Google Scholar
    • Export Citation
  • MillerRAChuQXieJForetzMViolletBBirnbaumMJ2013Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature494256260. (doi:10.1038/nature11808)

    • Search Google Scholar
    • Export Citation
  • MilneJCLambertPDSchenkSCarneyDPSmithJJGagneDJJinLBossOPerniRBVuCB2007Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature450712716. (doi:10.1038/nature06261)

    • Search Google Scholar
    • Export Citation
  • MuiseESAzzolinaBKuoDWEl-SherbeiniMTanYYuanXMuJThompsonJRBergerJPWongKK2008Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor γ and altered metabolic states. Molecular Pharmacology74403412. (doi:10.1124/mol.108.044826)

    • Search Google Scholar
    • Export Citation
  • NawrockiARRajalaMWTomasEPajvaniUBSahaAKTrumbauerMEPangZChenASRudermanNBChenH2006Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists. Journal of Biological Chemistry28126542660. (doi:10.1074/jbc.M505311200)

    • Search Google Scholar
    • Export Citation
  • NishimuraTNakatakeYKonishiMItohN2000Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochimica et Biophysica Acta1492203206. (doi:10.1016/S0167-4781(00)00067-1)

    • Search Google Scholar
    • Export Citation
  • NonogakiKHazamaMSatohN2014Liraglutide suppresses obesity and hyperglycemia associated with increases in hepatic fibroblast growth factor 21 production in KKAy mice. BioMed Research International2014751930. (doi:10.1155/2014/751930)

    • Search Google Scholar
    • Export Citation
  • NygaardEBVienbergSGOrskovCHansenHSAndersenB2012Metformin stimulates FGF21 expression in primary hepatocytes. Experimental Diabetes Research2012465282. (doi:10.1155/2012/465282)

    • Search Google Scholar
    • Export Citation
  • OrentreichNMatiasJRDeFeliceAZimmermanJA1993Low methionine ingestion by rats extends life span. Journal of Nutrition123269274.

  • OuchiNParkerJLLugusJJWalshK2011Adipokines in inflammation and metabolic disease. Nature Reviews. Immunology118597. (doi:10.1038/nri2921)

    • Search Google Scholar
    • Export Citation
  • OwenBMBookoutALDingXLinVYAtkinSDGautronLKliewerSAMangelsdorfDJ2013FGF21 contributes to neuroendocrine control of female reproduction. Nature Medicine1911531156. (doi:10.1038/nm.3250)

    • Search Google Scholar
    • Export Citation
  • OwenBMDingXMorganDACoateKCBookoutALRahmouniKKliewerSAMangelsdorfDJ2014FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metabolism20670677. (doi:10.1016/j.cmet.2014.07.012)

    • Search Google Scholar
    • Export Citation
  • OwenBMMangelsdorfDJKliewerSA2015Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends in Endocrinology and Metabolism262229. (doi:10.1016/j.tem.2014.10.002)

    • Search Google Scholar
    • Export Citation
  • ParkKGMinAKKohEHKimHSKimMOParkHSKimYDYoonTSJangBKHwangJS2008Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. Hepatology4814771486. (doi:10.1002/hep.22496)

    • Search Google Scholar
    • Export Citation
  • PedersenBKFebbraioMA2012Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nature Reviews. Endocrinology8457465. (doi:10.1038/nrendo.2012.49)

    • Search Google Scholar
    • Export Citation
  • PetrovicNWaldenTBShabalinaIGTimmonsJACannonBNedergaardJ2010Chronic peroxisome proliferator-activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. Journal of Biological Chemistry28571537164. (doi:10.1074/jbc.M109.053942)

    • Search Google Scholar
    • Export Citation
  • PlanavilaARedondoIHondaresEVinciguerraMMuntsCIglesiasRGabrielliLASitgesMGiraltMvan BilsenM2013Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nature Communications42019. (doi:10.1038/ncomms3019)

    • Search Google Scholar
    • Export Citation
  • PlanavilaARedondo-AnguloIRibasFGarrabouGCasademontJGiraltMVillarroyaF2015Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovascular Research1061931. (doi:10.1093/cvr/cvu263)

    • Search Google Scholar
    • Export Citation
  • PocaiACarringtonPEAdamsJRWrightMEiermannGZhuLDuXPetrovALassmanMEJiangG2009Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes5822582266. (doi:10.2337/db09-0278)

    • Search Google Scholar
    • Export Citation
  • PonugotiBKimDHXiaoZSmithZMiaoJZangMWuSYChiangCMVeenstraTDKemperJK2010SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. Journal of Biological Chemistry2853395933970. (doi:10.1074/jbc.M110.122978)

    • Search Google Scholar
    • Export Citation
  • PotthoffMJInagakiTSatapatiSDingXHeTGoetzRMohammadiMFinckBNMangelsdorfDJKliewerSA2009FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. PNAS1061085310858. (doi:10.1073/pnas.0904187106)

    • Search Google Scholar
    • Export Citation
  • PrieurXMokCYVelagapudiVRNunezVFuentesLMontanerDIshikawaKCamachoABarbarrojaNO'RahillyS2011Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes60797809. (doi:10.2337/db10-0705)

    • Search Google Scholar
    • Export Citation
  • Prip-BuusCPegorierJPDueePHKohlCGirardJ1990Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit. Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes. Biochemical Journal269409415.

    • Search Google Scholar
    • Export Citation
  • QiangLWangLKonNZhaoWLeeSZhangYRosenbaumMZhaoYGuWFarmerSR2012Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell150620632. (doi:10.1016/j.cell.2012.06.027)

    • Search Google Scholar
    • Export Citation
  • QiaoLShaoJ2006SIRT1 regulates adiponectin gene expression through Foxo1–C/enhancer-binding protein α transcriptional complex. Journal of Biological Chemistry2813991539924. (doi:10.1074/jbc.M607215200)

    • Search Google Scholar
    • Export Citation
  • SadrySADruckerDJ2013Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nature Reviews. Endocrinology9425433. (doi:10.1038/nrendo.2013.47)

    • Search Google Scholar
    • Export Citation
  • SamsonSLSathyanarayanaPJogiMGonzalezEVGutierrezAKrishnamurthyRMuthupillaiRChanLBajajM2011Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia5430933100. (doi:10.1007/s00125-011-2317-z)

    • Search Google Scholar
    • Export Citation
  • SchugTTXuQGaoHPeres-da-SilvaADraperDWFesslerMBPurushothamALiX2010Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Molecular and Cellular Biology3047124721. (doi:10.1128/MCB.00657-10)

    • Search Google Scholar
    • Export Citation
  • ShawRJLamiaKAVasquezDKooSHBardeesyNDepinhoRAMontminyMCantleyLC2005The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science31016421646. (doi:10.1126/science.1120781)

    • Search Google Scholar
    • Export Citation
  • ShayKPMoreauRFSmithEJSmithARHagenTM2009Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochimica et Biophysica Acta179011491160. (doi:10.1016/j.bbagen.2009.07.026)

    • Search Google Scholar
    • Export Citation
  • ShimanoMOuchiNWalshK2012Cardiokines: recent progress in elucidating the cardiac secretome. Circulation126e327e332. (doi:10.1161/CIRCULATIONAHA.112.150656)

    • Search Google Scholar
    • Export Citation
  • ShinNRLeeJCLeeHYKimMSWhonTWLeeMSBaeJW2014An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut63727735. (doi:10.1136/gutjnl-2012-303839)

    • Search Google Scholar
    • Export Citation
  • SlavinBGOngJMKernPA1994Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes. Journal of Lipid Research3515351541.

    • Search Google Scholar
    • Export Citation
  • SoWYChengQChenLEvans-MolinaCXuALamKSLeungPS2013High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor γ signaling. Diabetes6237513759. (doi:10.2337/db13-0645)

    • Search Google Scholar
    • Export Citation
  • SoWYChengQXuALamKSLeungPS2015Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice. Cell Death & Disease6e1707. (doi:10.1038/cddis.2015.80)

    • Search Google Scholar
    • Export Citation
  • SoccioREChenERLazarMA2014Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metabolism20573591. (doi:10.1016/j.cmet.2014.08.005)

    • Search Google Scholar
    • Export Citation
  • SrinivasaSWongKFitchKVWeiJPetrowECypessAMTorrianiMGrinspoonSK2015Effects of lifestyle modification and metformin on irisin and FGF21 among HIV-infected subjects with the metabolic syndrome. Clinical Endocrinology82678685. (doi:10.1111/cen.12582)

    • Search Google Scholar
    • Export Citation
  • StefanNHaringHU2013The role of hepatokines in metabolism. Nature Reviews. Endocrinology9144152. (doi:10.1038/nrendo.2012.258)

  • SteinSBachmannALossnerUKratzschJBluherMStumvollMFasshauerM2009Serum levels of the adipokine FGF21 depend on renal function. Diabetes Care32126128. (doi:10.2337/dc08-1054)

    • Search Google Scholar
    • Export Citation
  • SuomalainenAEloJMPietilainenKHHakonenAHSevastianovaKKorpelaMIsohanniPMarjavaaraSKTyniTKiuru-EnariS2011FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet. Neurology10806818. (doi:10.1016/S1474-4422(11)70155-7)

    • Search Google Scholar
    • Export Citation
  • TanTMFieldBCMcCulloughKATrokeRCChambersESSalemVGonzalez MaffeJBaynesKCDe SilvaAViardotA2013Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes6211311138. (doi:10.2337/db12-0797)

    • Search Google Scholar
    • Export Citation
  • TanakaNTakahashiSZhangYKrauszKWSmithPBPattersonADGonzalezFJ2015Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochimica et Biophysica Acta185212421252. (doi:10.1016/j.bbadis.2015.02.012)

    • Search Google Scholar
    • Export Citation
  • TimmersSKoningsEBiletLHoutkooperRHvan de WeijerTGoossensGHHoeksJvan der KriekenSRyuDKerstenS2011Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metabolism14612622. (doi:10.1016/j.cmet.2011.10.002)

    • Search Google Scholar
    • Export Citation
  • TyynismaaHCarrollCJRaimundoNAhola-ErkkilaSWenzTRuhanenHGuseKHemminkiAPeltola-MjosundKETulkkiV2010Mitochondrial myopathy induces a starvation-like response. Human Molecular Genetics1939483958. (doi:10.1093/hmg/ddq310)

    • Search Google Scholar
    • Export Citation
  • UebansoTTaketaniYYamamotoHAmoKOminamiHAraiHTakeiYMasudaMTanimuraAHaradaN2011Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor?PLoS ONE6e22976. (doi:10.1371/journal.pone.0022976)

    • Search Google Scholar
    • Export Citation
  • UngerRHCherringtonAD2012Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. Journal of Clinical Investigation122412. (doi:10.1172/JCI60016)

    • Search Google Scholar
    • Export Citation
  • VernochetCPeresSBDavisKEMcDonaldMEQiangLWangHSchererPEFarmerSR2009C/EBPα and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor γ agonists. Molecular and Cellular Biology2947144728. (doi:10.1128/MCB.01899-08)

    • Search Google Scholar
    • Export Citation
  • VetterliLBrunTGiovannoniLBoscoDMaechlerP2011Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E β-cells and human islets through a SIRT1-dependent mechanism. Journal of Biological Chemistry28660496060. (doi:10.1074/jbc.M110.176842)

    • Search Google Scholar
    • Export Citation
  • WeiWDutchakPAWangXDingXBookoutALGoetzRMohammadiMGerardRDDechowPCMangelsdorfDJ2012Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. PNAS10931433148. (doi:10.1073/pnas.1200797109)

    • Search Google Scholar
    • Export Citation
  • WenteWEfanovAMBrennerMKharitonenkovAKosterASanduskyGESewingSTreiniesIZitzerHGromadaJ2006Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes5524702478. (doi:10.2337/db05-1435)

    • Search Google Scholar
    • Export Citation
  • WuALKolumamGStawickiSChenYLiJZavala-SolorioJPhamluongKFengBLiLMarstersS2011Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Science Translational Medicine3113ra126. (doi:10.1126/scitranslmed.3002669)

    • Search Google Scholar
    • Export Citation
  • WuXQiYFChangJRLuWWZhangJSWangSPChengSJZhangMFanQLvYPossible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE miceHeart and Vessels2014[in press]doi:10.1007/s00380-014-0557-9)

    • Search Google Scholar
    • Export Citation
  • XuJLloydDJHaleCStanislausSChenMSivitsGVonderfechtSHechtRLiYSLindbergRA2009Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes58250259. (doi:10.2337/db08-0392)

    • Search Google Scholar
    • Export Citation
  • YangCLuWLinTYouPYeMHuangYJiangXWangCWangFLeeMH2013Activation of liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterology1367. (doi:10.1186/1471-230X-13-67)

    • Search Google Scholar
    • Export Citation
  • YangYLiWLiuYSunYLiYYaoQLiJZhangQGaoYGaoL2014Alpha-lipoic acid improves high-fat diet-induced hepatic steatosis by modulating the transcription factors SREBP-1, FoxO1 and Nrf2 via the SIRT1/LKB1/AMPK pathway. Journal of Nutritional Biochemistry2512071217. (doi:10.1016/j.jnutbio.2014.06.001)

    • Search Google Scholar
    • Export Citation
  • YuJZhaoLWangAEleswarapuSGeXChenDJiangH2012Growth hormone stimulates transcription of the fibroblast growth factor 21 gene in the liver through the signal transducer and activator of transcription 5. Endocrinology153750758. (doi:10.1210/en.2011-1591)

    • Search Google Scholar
    • Export Citation
  • ZhangYLeiTHuangJFWangSBZhouLLYangZQChenXD2011The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes. Molecular and Cellular Endocrinology3424147. (doi:10.1016/j.mce.2011.05.003)

    • Search Google Scholar
    • Export Citation
  • ZhangYXieYBerglundEDCoateKCHeTTKatafuchiTXiaoGPotthoffMJWeiWWanY2012The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife1e00065. (doi:10.7554/eLife.00065)

    • Search Google Scholar
    • Export Citation
  • ZhangCShaoMYangHChenLYuLCongWTianHZhangFChengPJinL2013aAttenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS ONE8e82275. (doi:10.1371/journal.pone.0082275)

    • Search Google Scholar
    • Export Citation
  • ZhangMLiuYXiongZYDengZYSongHLAnZM2013bChanges of plasma fibroblast growth factor-21 (FGF-21) in oral glucose tolerance test and effects of metformin on FGF-21 levels in type 2 diabetes mellitus. Endokrynologia Polska64220224.

    • Search Google Scholar
    • Export Citation
  • ZhuWWangCLiuLLiYLiXCaiJWangH2014Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo. Canadian Journal of Physiology and Pharmacology92927935. (doi:10.1139/cjpp-2014-0227)

    • Search Google Scholar
    • Export Citation

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    Functional role of fibroblast growth factor 21 (FGF21) secreted from multiple organs in response to diverse stresses or stimuli. FGF21 expression is induced in multiple major organs, including white/brown adipose tissue, liver, pancreas, skeletal muscle, heart, and kidney, in various physiological and pathological conditions. FGF21 levels are also increased by several anti-diabetic drugs or compounds. Consequently, elevated FGF21 plays an adaptive role in response to diverse stressful conditions and acts a mediator of beneficial metabolic effects of anti-diabetic drugs through local and systemic actions in target organs. NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; HCC, hepatocellular carcinoma; GLP1, glucagon-like peptide 1.

  • AblesGPPerroneCEOrentreichDOrentreichN2012Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PLoS ONE7e51357. (doi:10.1371/journal.pone.0051357)

    • Search Google Scholar
    • Export Citation
  • AdamsACAstapovaIFisherFMBadmanMKKurganskyKEFlierJSHollenbergANMaratos-FlierE2010Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARα-dependent manner. Journal of Biological Chemistry2851407814082. (doi:10.1074/jbc.C110.107375)

    • Search Google Scholar
    • Export Citation
  • AdamsACChengCCCoskunTKharitonenkovA2012FGF21 requires βklotho to act in vivo. PLoS ONE7e49977. (doi:10.1371/journal.pone.0049977)

  • AdamsACCoskunTChengCCO'FarrellLSDuboisSLKharitonenkovA2013aFibroblast growth factor 21 is not required for the antidiabetic actions of the thiazolidinediones. Molecular Metabolism2205214. (doi:10.1016/j.molmet.2013.05.005)

    • Search Google Scholar
    • Export Citation
  • AdamsACHalsteadCAHansenBCIrizarryARMartinJAMyersSRReynoldsVLSmithHWWroblewskiVJKharitonenkovA2013bLY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys. PLoS ONE8e65763. (doi:10.1371/journal.pone.0065763)

    • Search Google Scholar
    • Export Citation
  • ArafatAMKaczmarekPSkrzypskiMPruszynska-OszmalekEKolodziejskiPSzczepankiewiczDSassekMWojciechowiczTWiedenmannBPfeifferAF2013Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?Diabetologia56588597. (doi:10.1007/s00125-012-2803-y)

    • Search Google Scholar
    • Export Citation
  • AssiniJMMulvihillEEBurkeACSutherlandBGTelfordDEChhokerSSSawyezCGDrangovaMAdamsACKharitonenkovA2015Naringenin prevents obesity, hepatic steatosis and glucose intolerance in male mice independent of fibroblast growth factor 21. Endocrinology15620872102. (doi:10.1210/en.2014-2003)

    • Search Google Scholar
    • Export Citation
  • BadmanMKPissiosPKennedyARKoukosGFlierJSMaratos-FlierE2007Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metabolism5426437. (doi:10.1016/j.cmet.2007.05.002)

    • Search Google Scholar
    • Export Citation
  • BadmanMKKoesterAFlierJSKharitonenkovAMaratos-FlierE2009Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology15049314940. (doi:10.1210/en.2009-0532)

    • Search Google Scholar
    • Export Citation
  • BaeKHMinAKKimJGLeeIKParkKG2014Alpha lipoic acid induces hepatic fibroblast growth factor 21 expression via up-regulation of CREBH. Biochemical and Biophysical Research Communications455212217. (doi:10.1016/j.bbrc.2014.10.147)

    • Search Google Scholar
    • Export Citation
  • BaurJAPearsonKJPriceNLJamiesonHALerinCKalraAPrabhuVVAllardJSLopez-LluchGLewisK2006Resveratrol improves health and survival of mice on a high-calorie diet. Nature444337342. (doi:10.1038/nature05354)

    • Search Google Scholar
    • Export Citation
  • BordoneLMottaMCPicardFRobinsonAJhalaUSApfeldJMcDonaghTLemieuxMMcBurneyMSzilvasiA2006Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS Biology4e31. (doi:10.1371/journal.pbio.0040031)

    • Search Google Scholar
    • Export Citation
  • BouhlelMADerudasBRigamontiEDievartRBrozekJHaulonSZawadzkiCJudeBTorpierGMarxN2007PPARγ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metabolism6137143. (doi:10.1016/j.cmet.2007.06.010)

    • Search Google Scholar
    • Export Citation
  • BoutantMCantoC2014SIRT1 metabolic actions: integrating recent advances from mouse models. Molecular Metabolism3518. (doi:10.1016/j.molmet.2013.10.006)

    • Search Google Scholar
    • Export Citation
  • CabreiroFAuCLeungKYVergara-IrigarayNCochemeHMNooriTWeinkoveDSchusterEGreeneNDGemsD2013Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell153228239. (doi:10.1016/j.cell.2013.02.035)

    • Search Google Scholar
    • Export Citation
  • ChauMDGaoJYangQWuZGromadaJ2010Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway. PNAS1071255312558. (doi:10.1073/pnas.1006962107)

    • Search Google Scholar
    • Export Citation
  • ChavezAOMolina-CarrionMAbdul-GhaniMAFolliFDefronzoRATripathyD2009Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care3215421546. (doi:10.2337/dc09-0684)

    • Search Google Scholar
    • Export Citation
  • ChenWHooRLKonishiMItohNLeePCYeHYLamKSXuA2011Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. Journal of Biological Chemistry2863455934566. (doi:10.1074/jbc.M111.285965)

    • Search Google Scholar
    • Export Citation
  • ChengXVisputeSGLiuJChengCKharitonenkovAKlaassenCD2014Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR). Toxicology and Applied Pharmacology2786571. (doi:10.1016/j.taap.2014.04.013)

    • Search Google Scholar
    • Export Citation
  • ChowWSXuAWooYCTsoAWCheungSCFongCHTseHFChauMTCheungBMLamKS2013Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arteriosclerosis Thrombosis and Vascular Biology3324542459. (doi:10.1161/ATVBAHA.113.301599)

    • Search Google Scholar
    • Export Citation
  • CoskunTBinaHASchneiderMADunbarJDHuCCChenYMollerDEKharitonenkovA2008Fibroblast growth factor 21 corrects obesity in mice. Endocrinology14960186027. (doi:10.1210/en.2008-0816)

    • Search Google Scholar
    • Export Citation
  • Cuevas-RamosDAlmeda-ValdesPMeza-AranaCEBrito-CordovaGGomez-PerezFJMehtaROseguera-MoguelJAguilar-SalinasCA2012Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS ONE7e38022. (doi:10.1371/journal.pone.0038022)

    • Search Google Scholar
    • Export Citation
  • CyphertHAAlongeKMIppaguntaSMHillgartnerFB2014Glucagon stimulates hepatic FGF21 secretion through a PKA- and EPAC-dependent posttranscriptional mechanism. PLoS ONE9e94996. (doi:10.1371/journal.pone.0094996)

    • Search Google Scholar
    • Export Citation
  • De Sousa-CoelhoALRelatJHondaresEPerez-MartiARibasFVillarroyaFMarreroPFHaroD2013FGF21 mediates the lipid metabolism response to amino acid starvation. Journal of Lipid Research5417861797. (doi:10.1194/jlr.M033415)

    • Search Google Scholar
    • Export Citation
  • DingXBoney-MontoyaJOwenBMBookoutALCoateKCMangelsdorfDJKliewerSA2012βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metabolism16387393. (doi:10.1016/j.cmet.2012.08.002)

    • Search Google Scholar
    • Export Citation
  • DoiKKuroshimaA1982Thermogenic response to glucagon in cold-acclimated mice. Japanese Journal of Physiology32377385. (doi:10.2170/jjphysiol.32.377)

    • Search Google Scholar
    • Export Citation
  • DomouzoglouEMFisherFMAstapovaIFoxECKharitonenkovAFlierJSHollenbergANMaratos-FlierE2014Fibroblast growth factor 21 and thyroid hormone show mutual regulatory dependency but have independent actions in vivo. Endocrinology15520312040. (doi:10.1210/en.2013-1902)

    • Search Google Scholar
    • Export Citation
  • DushayJChuiPCGopalakrishnanGSVarela-ReyMCrawleyMFisherFMBadmanMKMartinez-ChantarMLMaratos-FlierE2010Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology139456463. (doi:10.1053/j.gastro.2010.04.054)

    • Search Google Scholar
    • Export Citation
  • DushayJRToschiEMittenEKFisherFMHermanMAMaratos-FlierE2015Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Molecular Metabolism45157. (doi:10.1016/j.molmet.2014.09.008)

    • Search Google Scholar
    • Export Citation
  • DutchakPAKatafuchiTBookoutALChoiJHYuRTMangelsdorfDJKliewerSA2012Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell148556567. (doi:10.1016/j.cell.2011.11.062)

    • Search Google Scholar
    • Export Citation
  • EatonRP1973Hypolipemic action of glucagon in experimental endogenous lipemia in the rat. Journal of Lipid Research14312318.

  • EmanuelliBVienbergSGSmythGChengCStanfordKIArumugamMMichaelMDAdamsACKharitonenkovAKahnCR2014Interplay between FGF21 and insulin action in the liver regulates metabolism. Journal of Clinical Investigation124515527. (doi:10.1172/JCI67353)

    • Search Google Scholar
    • Export Citation
  • FeigeJNLagougeMCantoCStrehleAHoutenSMMilneJCLambertPDMatakiCElliottPJAuwerxJ2008Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metabolism8347358. (doi:10.1016/j.cmet.2008.08.017)

    • Search Google Scholar
    • Export Citation
  • FisherFMChuiPCAntonellisPJBinaHAKharitonenkovAFlierJSMaratos-FlierE2010Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes5927812789. (doi:10.2337/db10-0193)

    • Search Google Scholar
    • Export Citation
  • FisherFMKleinerSDourisNFoxECMepaniRJVerdeguerFWuJKharitonenkovAFlierJSMaratos-FlierE2012FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes and Development26271281. (doi:10.1101/gad.177857.111)

    • Search Google Scholar
    • Export Citation
  • FisherFMChuiPCNasserIAPopovYCunniffJCLundasenTKharitonenkovASchuppanDFlierJSMaratos-FlierE2014Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology14710731083.(e1076) (doi:10.1053/j.gastro.2014.07.044)

    • Search Google Scholar
    • Export Citation
  • FoltzINHuSKingCWuXYangCWangWWeiszmannJStevensJChenJSNuanmaneeN2012Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Science Translational Medicine4162ra153. (doi:10.1126/scitranslmed.3004690)

    • Search Google Scholar
    • Export Citation
  • ForetzMHebrardSLeclercJZarrinpashnehESotyMMithieuxGSakamotoKAndreelliFViolletB2010Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. Journal of Clinical Investigation12023552369. (doi:10.1172/JCI40671)

    • Search Google Scholar
    • Export Citation
  • ForetzMGuigasBBertrandLPollakMViolletB2014Metformin: from mechanisms of action to therapies. Cell Metabolism20953966. (doi:10.1016/j.cmet.2014.09.018)

    • Search Google Scholar
    • Export Citation
  • FullertonMDGalicSMarcinkoKSikkemaSPulinilkunnilTChenZPO'NeillHMFordRJPalanivelRO'BrienM2013Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine1916491654. (doi:10.1038/nm.3372)

    • Search Google Scholar
    • Export Citation
  • GaichGChienJYFuHGlassLCDeegMAHollandWLKharitonenkovABumolTSchilskeHKMollerDE2013The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metabolism18333340. (doi:10.1016/j.cmet.2013.08.005)

    • Search Google Scholar
    • Export Citation
  • GalmanCLundasenTKharitonenkovABinaHAErikssonMHafstromIDahlinMAmarkPAngelinBRudlingM2008The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metabolism8169174. (doi:10.1016/j.cmet.2008.06.014)

    • Search Google Scholar
    • Export Citation
  • HabeggerKMStemmerKChengCMullerTDHeppnerKMOttawayNHollandJHembreeJLSmileyDGelfanovV2013Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes6214531463. (doi:10.2337/db12-1116)

    • Search Google Scholar
    • Export Citation
  • HarmsMSealeP2013Brown and beige fat: development, function and therapeutic potential. Nature Medicine1912521263. (doi:10.1038/nm.3361)

    • Search Google Scholar
    • Export Citation
  • HarrisonDEStrongRAllisonDBAmesBNAstleCMAtamnaHFernandezEFlurkeyKJavorsMANadonNL2014Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell13273282. (doi:10.1111/acel.12170)