PGC-1α, glucose metabolism and type 2 diabetes mellitus

in Journal of Endocrinology
Correspondence should be addressed to H Duan; Email: duanhuijun999@163.com
*(H Wu and X Deng contributed equally to this work)

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by glucose metabolic disturbance. A number of transcription factors and coactivators are involved in this process. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important transcription coactivator regulating cellular energy metabolism. Accumulating evidence has indicated that PGC-1α is involved in the regulation of T2DM. Therefore, a better understanding of the roles of PGC-1α may shed light on more efficient therapeutic strategies. Here, we review the most recent progress on PGC-1α and discuss its regulatory network in major glucose metabolic tissues such as the liver, skeletal muscle, pancreas and kidney. The significant associations between PGC-1α polymorphisms and T2DM are also discussed in this review.

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by glucose metabolic disturbance. A number of transcription factors and coactivators are involved in this process. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is an important transcription coactivator regulating cellular energy metabolism. Accumulating evidence has indicated that PGC-1α is involved in the regulation of T2DM. Therefore, a better understanding of the roles of PGC-1α may shed light on more efficient therapeutic strategies. Here, we review the most recent progress on PGC-1α and discuss its regulatory network in major glucose metabolic tissues such as the liver, skeletal muscle, pancreas and kidney. The significant associations between PGC-1α polymorphisms and T2DM are also discussed in this review.

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic metabolic isorder characterized by hyperglycemia in the context of insulin resistance (IR) and insulin secretion deficiency due to β-cell dysfunction. The global prevalence of T2DM is continuously rising, being held responsible for about 90% of all the 347 million diabetes cases worldwide (Yang et al. 2015). T2DM can cause serious microvascular and macrovascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, ischemic heart disease and cerebrovascular disease. These complications predominantly account for the increased mortality and economic burden. Many novel medicines are available, though the undesirable side effects (hypoglycemia, weight gain, gastrointestinal effects and cardiovascular complications) and imperfect glycemic control limit their use in long-term treatment. Therefore, the development of safe and effective drugs for T2DM is imperative, for which the molecular-level target therapy represents a promising approach.

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), also known as PPARGC1A or PGC-1, is a multifunctional regulatory factor originally identified as a coactivator of peroxisome proliferator-activated receptor gamma (PPARγ) in 1998 (Puigserver et al. 1998). The PGC-1α gene is located on chromosome 4p15.1 in humans, a region associated with basal insulin levels in Pima Indians (Pratley et al. 1998). This gene encodes a 91kDa protein, which is predominantly expressed in tissues with high energy demands, such as the heart, skeletal muscle and kidney (Esterbauer et al. 1999). As a coactivator, PGC-1α protein does not bind to DNA directly but is recruited to the template through interactions with a wide range of transcription factors involved in cellular energy metabolism. By regulating the activities of these transcription factors, PGC-1α acts as a molecular switch for multiple cellular processes, including mitochondrial biogenesis and respiration, gluconeogenesis and glucose transport, glycogenolysis, fatty acid oxidation, peroxisomal remodeling, muscle fiber-type switching, and oxidative phosphorylation (Corona & Duchen 2015). As such, PGC-1α is a very attractive target for antidiabetic therapy.

In this review, we summarize the major findings on the function of PGC-1α in glucose metabolism and discuss its potential therapeutic applications for T2DM. The close correlation between PGC-1α polymorphisms and T2DM is also discussed in this review.

PGC-1α and the liver

The liver is a vital organ responsible for glucose homeostasis. Normally, blood glucose concentration is stably maintained within a narrow range in both well-fed and fasting states. This is mainly determined by three factors: (i) glucose absorption by the intestine, (ii) gluconeogenesis by the liver and (iii) glucose utilization by skeletal muscle. In this process, the liver acts as a glucose reservoir that balances the glucose storage and release. In the well-fed state, the liver uptakes glucose from the blood and stores it in the form of glycogen (glycogenesis). In the fasting state, the liver synthesizes glucose through glycogenolysis and gluconeogenesis and releases it into the bloodstream. Impaired hepatic glucose uptake and excessive hepatic glucose production are partially responsible for hyperglycemia in T2DM. Especially, previous studies indicated that PGC-1α plays a central role in the regulatory network of glucose metabolism in the liver.

PGC-1α is a downstream sensor of metabolic, hor­monal and inflammatory signals that is responsible for the balance of hepatic gluconeogenesis, fatty acid β-oxidation and mitochondrial biogenesis. The process has been reviewed elsewhere (Sugden et al. 2010). Briefly, in the fasting state, the pancreatic alpha cells synthesize and release glucagon to maintain a normal blood glucose level. Glucagon binds to its receptor present on hepatocytes and subsequently triggers the conformational change of G protein, which results in the dissociation of α-subunit from the G-protein complex. Free α-subunits subsequently bind to adenylate cyclase, thereby catalyzing the conversion of adenosine triphosphate (ATP) into adenosine 3′,5′-monophosphate (cAMP). Two cAMP molecules bind to each regulatory subunit of protein kinase (PKA), releasing its catalytic subunit, which translocates into the nucleus and phosphorylates the cAMP response element (CRE)-binding protein (CREB) at Ser133. The phosphorylated CREB recruits CREB-binding protein (CBP) to the PGC-1α promoter and regulates its expression. PGC-1α can coactivate several transcriptional factors, including hepatocyte nuclear factor-4α (HNF-4α) and forkhead box O (FOXO) 1, and therefore control the transcription of the rate-limiting gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) and glucose-6-phosphatase (G6Pase). However, after a meal, pancreatic beta cells synthesize and release insulin which binds to its receptor and triggers the phosphorylation of Akt, which in turn phosphorylates PGC-1α and inhibits its activity. This results in the stimulation of glycogen synthesis and inhibition of gluconeogenesis in the liver (Fig. 1).

Figure 1
Figure 1

Signaling pathways of PGC-1α-regulated glucose metabolism in the liver.

Citation: Journal of Endocrinology 229, 3; 10.1530/JOE-16-0021

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Moreover, accumulating evidence suggests an important role for PGC-1α in the regulation of lipid and bile acid metabolism that could contribute to gluconeogenesis (Hashidume et al. 2011, Li et al. 2011). Recent studies have demonstrated that several signaling pathways, transcription factors and coactivators contribute to these processes through the regulation of PGC-1α expression and activity (Fig. 2). Abnormal activation of these glucose metabolic processes is closely implicated in the pathogenesis of hepatic IR and T2DM.

Figure 2
Figure 2

Interactions of PGC-1α with the main factors involved in hepatic glucose metabolism.

Citation: Journal of Endocrinology 229, 3; 10.1530/JOE-16-0021

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AMP-activated protein kinase

AMP-activated protein kinase (AMPK) is a highly conservative serine/threonine protein kinase. It acts as a sensor of cellular energy status critical to the regulation of glucose and lipid metabolism in various organs, especially the skeletal muscle and liver. Activation of hepatic AMPK was reported to decrease glucose production and increase fatty acid oxidation (Viollet et al. 2009). Thus, AMPK is now recognized as a promising drug target for the treatment of T2DM. There is a strong correlation between AMPK/PGC-1α signaling pathway and T2DM (Weickert & Pfeiffer 2006). For instance, metformin, one of the most widely prescribed drugs for T2DM, exerts a strong antihyperglycemic effect partly though the increasing of PGC-1α expression, via its upstream kinase AMPK (Aatsinki et al. 2014). These results are consistent with the previous study showing that AMPK activator metformin and adenoviral overexpression of AMPK increase PGC-1α transcriptional activity in a phosphorylation-dependent manner (Buler et al. 2012b). In addition, several Chinese herbal medicines for diabetes mellitus recover glucose homeostasis by regulating the AMPK/PGC-1α signaling pathway. Yuan and Piao (2011) reported that an active ingredient from Artemisia sacrorum Ledeb. decreased PGC-1α, G6Pase and PEPCK gene expression through AMPK-mediated inhibitory phosphorylation of glycogen synthase kinase-3β (pGSK-3β) and CREB in human HepG2 cells. In 2012, Yuan and coworkers subsequently reported that ginsenoside Rg2 also suppresses hepatic gluconeogenesis through AMPK/PGC-1α signaling pathway (Yuan et al. 2012). The phosphorylation of AMPK induced by Rg2 decreases the phosphorylation of CREB via pGSK-3β and disrupts the interaction of CREB and CREB-regulated transcription coactivator 2 (CRTC2) via induction of Src homology region 2 (SH2) domain-containing phosphatase (SHP) expression, which subsequently inhibits PGC-1α-dependent gluconeogenic enzyme gene expression. In a recent study, the same research team reported the effects of eugenol on hepatic glucose production in hepatocytes and C57BL/6J mice and obtained analogous results (Jeong et al. 2014). Moreover, berberine, an isoquinoline alkaloid isolated from genera Berberis and Coptis, can increase the phosphorylation of AMPK (Thr172) and reduce the expression of PGC-1α, resulting in a significant improvement in glucose tolerance in diabetic rats (Zhang et al. 2012). The effect of above-mentioned herbal medicines on gluconeogenesis can be abolished by the compound C (an AMPK inhibitor).

In addition, AMPK/PGC-1α signaling pathway alleviates IR and T2DM by modulating hepatic lipogenesis and fatty acid synthesis. For instance, deletion of the mammalian homolog of Drosophila Indy in mice attenuates hepatic lipogenesis and IR through the regulation of AMPK/PGC-1α signaling pathway (Birkenfeld et al. 2011). Recent research has indicated that monascin and ankaflavin can prevent fatty acid accumulation partly mediated by the activation of AMPK and subsequent promotion of fatty acid oxidation by PGC-1α (Hsu et al. 2014). Furthermore, it is also reported that interference of AMPK/PGC-1α pathway by metformin triggers the expression of anti-inflammatory interleukin 1 receptor antagonist (IL1RA) (Buler et al. 2012b). IL1RA is a naturally occurring anti-inflammatory antagonist of IL-1, IL-6, leptin, TNF-α, and several other IL-1-dependent cytokines and chemokines, and improves β-cell function and reduces hepatic lipogenic gene expression (Tack et al. 2012, Negrin et al. 2014).

Estrogen-related receptors

Estrogen-related receptors (ERRα, ERRβ and ERRγ) are orphan nuclear receptors. Notably, through interaction with PGC-1α, ERRα and ERRγ are involved in the regulation of mitochondrial biogenesis and fatty acid β-oxidation. Recent study has shown that PGC-1α can coactivate ERRα to induce the expression of glucokinase, a key enzyme of glucose metabolism in the liver (Zhu et al. 2010). Especially, a study reported that ERRα acted as a repressor of gluconeogenesis by directly binding to the glucocorticoid accessory factor 3 (gAF3) site of the PEPCK promoter, which in turn inhibited the recruitment of PGC-1α to the PEPCK gene promoter (Herzog et al. 2006). Taken together, PGC-1α/ERRα-negative feedback loop participates in the regulation of hepatic glucose metabolism by repressing gluconeogenesis and increasing glucose utilization. Moreover, it was also demonstrated that ERRγ, along with coactivator PGC-1α, significantly increased the phosphatidic acid phosphatase function of lipins and subsequently diminished insulin-stimulated Akt phosphorylation, resulting in dysregulation of insulin signaling in HepG2 cells (Kim et al. 2011). A subsequent study from the same laboratory also found that ERRγ appeared to be an important downstream target of the glucagon signaling pathway. Glucagon-mediated activation of CREB–CRTC2 induces hepatic ERRγ gene expression, which in turn increases G6Pase and PEPCK gene expression along with coactivator PGC-1α (Kim et al. 2012a). How ERRα and ERRγ differentially affect PGC-1α activity remains largely elusive.

Hepatocyte nuclear factor-4α

Hepatocyte nuclear factor-4α (HNF-4α) is an orphan nuclear receptor as are the ERRs and a liver-enriched transcription factor that regulates the metabolism of glucose, fatty acids, amino acids, cholesterol, lipids, bile acids and drugs, whereas its dysfunction leads to impaired glucose transport and glycolysis. It is coactivated by PGC-1α. Several studies have shown its strong correlation with T2DM (Andrulionyte et al. 2006, Jafar-Mohammadi et al. 2011). Full transcriptional activation of the PEPCK promoter requires coactivation of the HNF-4α by PGC-1α (Yoon et al. 2001). PGC-1α protein contains three LXXLL motifs responsible for the interaction with HNF-4α. These LXXLL motifs synergistically activate HNF-4α-mediated transcription (Rha et al. 2009). Additionally, a study carried out in the mouse hepatocytes demonstrated that the region between –298 and –180 of the G6Pase promo­ter contained several HNF-4α-binding sites responsible for the activation of G6Pase by PGC-1α (Rhee et al. 2003). Interestingly, in the same year, HNF-4α was reported to mediate this activation by binding to the region between −76 and −64 of the mouse G6Pase promoter (Boustead et al. 2003). In addition to the HNF-4α-binding site located between −76 and −64, a 3bp sequence discovered by the same team was found to be a crucial site for HNF-4α-binding activity (Schilling et al. 2008). In addition, many other transcription factors and coactivator proteins, such as DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), sterol regula­tory element-binding proteins (SREBPs), vanin-1, cAMP, xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme, HNF-6, and FOXO1, also contribute to the PGC-1α/HNF-4α-mediated transcriptional regulation of the gluconeogenic genes (Yamamoto et al. 2004, Beaudry et al. 2006, Arpiainen et al. 2008, Schilling et al. 2008, Nedumaran et al. 2009, Dankel et al. 2010, Chen et al. 2014).

Sirtuins (SIRTs)

The mammalian SIRTs (SIRT1–7), a family of NAD(+)-dependent deacetylases, are implicated in a variety of cellular processes, including aging, gene transcription, DNA repair, cellular stress, apoptosis, energy metabolism, cancer and inflammation. SIRT1 is the most studied SIRT that regulates the expression of gluconeogenic and glycolytic enzymes and promotes the hepatic glucose output. These effects are mediated, at least in part, by interacting with PGC-1α and deacetylating it (Ghiraldini et al. 2013). Consistently, treatment with the specific SIRT1 activator SRT1720 increases mitochondrial membrane potential and cellular ATP content in HepG2 cells, and this effect was blocked by PGC-1α knockdown (Minor et al. 2011). This result was subsequently confirmed by other groups using liver-specific SIRT1 knockout mice (Rodgers & Puigserver 2007). Taken together, the SIRT1 deacetylates PGC-1α and increases its activity, and thus plays a pivotal role in the hepatic glucose metabolism and diabetes, both in vitro and in vivo. SIRT1/PGC-1α axis also affects fatty acid and cholesterol metabolism in the liver. For example, silencing SIRT1 in the liver by adenovirus-delivered SIRT1 small hairpin RNA reduces the gene expression of enzymes involved in fatty acids and triglyceride metabolism. These effects are partly dependent on PGC-1α (Rodgers & Puigserver 2007). It is then further revealed using liver-specific SIRT1 knockout mice that reduced SIRT1 expression impaired PPARα-mediated fatty acid metabolism through PGC-1α, a key coactivator of PPARα (Purushotham et al. 2009). Indeed, in a genome-wide coactivation study, PGC-1α was found to enhance the recruitment of 60 kDa BRG-1/Brm-associated factor subunit A (BAF60A) to the PPARα-binding sites (PPREs), which further activated PPARα-mediated peroxisomal and mitochondrial fat oxidation genes in the liver (Li et al. 2008). Recently, resistin has been reported to weaken the interaction between SIRT1 and PPARα as well as PGC-1α (Yu et al. 2013). Given that resistin was initially described as an adipokine increasing hepatic IR and glucose metabolism through an AMPK-dependent pathway, it is plausible that the activity of PGC-1α in the liver may be governed by a complex network of interactions among SIRT1, AMPK and PPARα. This is in accordance with another study that indicates a critical role of PGC-1α in cholesterol synthesis (Rodrigue-Way et al. 2014). In addition, it is also reported that SIRT1/PGC-1α axis regulated glucose and lipid metabolism through a PPARα-independent pathway (Peeters et al. 2011, Alberdi et al. 2013). Moreover, several lines of evidence have indicated that PGC-1α activated by SIRT1 also modulates the effects of thyroid hormone on lipid and glucose homeostasis (Suh et al. 2013, Thakran et al. 2013). These findings suggest certain connections between hormonal signaling and SIRT1/PGC-1α axis in the regulation of energy metabolism.

Moreover, recent studies have shed light on the relationship between other SIRTs and PGC-1α in hepatic metabolism. For instance, it has been demonstrated that PGC-1α can strongly promote SIRT3 gene expression and is mediated by coactivation of ERRα (Buler et al. 2012a). Further study has illuminated the complex relationship between these transcription factors. Recent research on ubiquinol-10 has indicated that SIRT3 is under the control of cAMP/AMPK/SIRT1/PGC-1α signaling (Tian et al. 2014), whereas SIRT5 is reported to increase ATP synthesis and oxygen consumption in HepG2 cells, which is antagonized by PGC-1α and AMPK (Buler et al. 2014). Surprisingly, recent study suggests that the deacetylase SIRT6 can suppress hepatic glucose production by acting as a positive regulator of general control non-derepressible 5 (GCN5)-mediated acetylation of PGC-1α (Dominy et al. 2012). These findings expand the spectrum of SIRTs/PGC-1α axis and provide new therapeutic strategies for T2DM.

p38 mitogen-activated protein kinase (p38 MAPK) and other post-translational modulators

The serine/threonine protein kinase p38 mitogen-activated protein kinase (p38 MAPK) is a member of the MAPK family (also including JNK, ERK1/2 and ERK5), which is specifically activated by phosphorylation in response to a variety of extracellular stimuli. It plays an important role in pathological conditions, such as diabetes. p38 MAPK can regulate hepatic glucose, under the control of free fatty acids (FFAs), glucagon and insulin. PGC-1α is directly phosphorylated and activated by p38 MAPK, and then mediates FFA-induced gluconeogenesis in primary hepatocytes (Collins et al. 2006). This is consistent with a previous report showing that inhibition of p38 MAPK by SB203580 or siRNA can attenuate the stimulatory effect of glucagon on PGC-1α promoter activation (Cao et al. 2005). Similarly, the control of PGC-1α by p38 MAPK appears to be also involved in fatty acid metabolism. Acetyl-coenzyme A carboxylase-α (ACCα) is the rate-limiting enzyme for fatty acid synthesis. Inhibiting p38 MAPK with SB203580 upregulates ACCα gene expression by modulating the expression of PGC-1α (Talukdar et al. 2007). Interestingly, ACC is also regulated by thyroid hormone and AMPK (Huang & Freake 1998, Chang et al. 2013), suggesting a complex crosstalk among these signaling pathways. In addition to acetylation and phosphorylation, the activity of PGC-1α is also strongly modulated by O-GlcNAcylation and ubiquitination. For example, O-GlcNAcylated PGC-1α has increased affinity to the deubiquitinase BAP1. This recruitment subsequently decreases ubiquitination of PGC-1α, thereby enhancing PGC-1α stability and promoting hepatic gluconeogenesis (Ruan et al. 2012).

Hepatitis C virus

Hepatitis C virus (HCV) infection is a global health problem affecting about 130–150 million people. It predisposes the infected to both type 1 diabetes mellitus (T1DM) and T2DM (Antonelli et al. 2014). PGC-1α expression is dramatically elevated in HCV-infected cells, accompanied by an upregulated expression of PEPCK and G6Pase (Qadri et al. 2012, Shlomai et al. 2012). In addition, the HCV nonstructural protein 5A induces metabolic dysregulation and IR in human hepatoma cells, in which PGC-1α could be involved (Parvaiz et al. 2014). These results emphasize the important role of PGC-1α in bridging the HCV infection to hepatic IR and diabetes mellitus. In addition, oxidative stress and endoplasmic reticulum (ER) stress are also responsible for the association of HCV with diabetes mellitus. Treatment of HCV replicon cells with the antioxidant N-acetylcysteine can attenuate the PGC-1α expression induced by HCV, suggesting that HCV-promoted PGC-1α induction is mediated by oxidative stress and inflammation (Shlomai et al. 2012). In addition, a recent study has reported that HCV infection induces PGC-1α expression and ER stress. Moreover, pharmacological induction of ER stress upregulates PGC-1α expression, and pharmacological inhibition of HCV-induced ER stress impairs PGC-1α upregulation (Yao et al. 2014).

Glucocorticoids

Glucocorticoids (GCs), such as dexamethasone, predni­sone and hydrocortisone, are often prescribed as anti-inflammatory agents. Recently, they have been gradually recognized as the important regulators of diabetes mellitus because of their critical roles in peripheral IR and β-cell insulin secretion. In the liver, the function of GCs is ultimately complex and partly mediated by PGC-1α. First, overexpression of PGC-1α can strongly potentiate the activity of PEPCK promoter in response to dexamethasone (Herzig et al. 2001), which can be explained by the following facts. Synergistic with cAMP, GCs significantly induced the expression of PGC-1α in hepatocytes (Felder et al. 2011). PGC-1α has the ability to physically interact with glucocorticoid receptor (GR) and increase its activity (Knutti et al. 2000). Subsequently, GR interacts with the glucocorticoid response unit in the PEPCK promoter and promotes its transcriptional activation (Herzig et al. 2001). Secondly, ubiquitin-specific protease 2 (USP2) is another downstream target of hepatic GCs/PGC-1α signaling to stimulate hepatic gluconeogenesis and glucose output (Molusky et al. 2012b). Intriguingly, USP2 is reported to induce 11β-hydroxysteroid dehydrogenase (11β-HSD) expression, which subsequently converts GCs into active forms (Molusky et al. 2012a). Finally, microRNA-29a-c ameliorates forskolin/dexamethasone-induced hepatic glucose production by reducing PGC-1α and G6Pase gene expression (Liang et al. 2013), indicating an alternative strategy for alleviating glucocorticoid-induced IR. Collectively, GCs interact with PGC-1α signaling in a positive feedback loop to regulate glucose homeostasis.

PGC-1α and skeletal muscle

The skeletal muscle is a major site of glucose and fatty acid utilization. It is generally accepted that glucose uptake and disposal are the most important limiting factors in fuel metabolism and energy homeostasis of skeletal muscle. Thus, a widespread opinion holds that IR in obesity and T2DM are primarily due to the defects in one or both of these factors. These defects are always accompanied by oxidative stress, ER stress, mitochondrial insufficiency and chronic low-grade inflammation. In contrast to the liver and islets, the expression of PGC-1α is downregulated in human diabetic muscle. Notably, researchers have successfully established a causal relationship between PGC-1α dysregulation in skeletal muscle and abnormal energy homeostasis, as well as IR and T2DM. Furthermore, PGC-1α is also involved in the regulation of muscle fiber-type switching (Wang et al. 2013) and autophagy (Yu & Long 2015).

Glucose uptake

The skeletal muscle accounts for about 80% of insulin-stimulated glucose disposal. Glucose transporter 4 (GLUT4) is a major glucose transporter expressed in the skeletal muscle, adipocyte and cardiac muscle. Insulin facilitates glucose uptake in skeletal muscle by promoting GLUT4 translocation from intracellular compartments to the plasma membrane. Therefore, impairment of insulin-stimulated GLUT4 translocation results in reduced glucose disposal and peripheral IR in T2DM. It has been reported that overexpression of PGC-1α significantly activates GLUT4 expression and increases glucose uptake (Wende et al. 2007). Overexpression of PGC-1α-related coactivator (PRC) exerts a similar effect (Philp et al. 2011). These findings highlight the importance of PGC-1α in the regulation of GLUT4 expression and translocation in muscle. At least two mechanisms are involved in this process. (1) Pessin and his colleagues (Thai et al. 1998, Mora & Pessin 2000) have reported that myocyte enhancer factor 2A (MEF2A) binds to the GLUT4 promoter and mediates GLUT4 transcription in skeletal muscles. PGC-1α can increase the expression of MEF2A by activating nuclear respiratory factor 1 (NRF1) (Ramachandran et al. 2008). Moreover, PGC-1 also binds to MEF2C and coactivates it to increase GLUT4 expression (Michael et al. 2001). However, the overexpression of MEF2C alone is necessary but not sufficient to drive GLUT4 transcription (Handschin et al. 2003), suggesting that PGC-1α may mediate GLUT4 expression via a MEF2-independent signaling pathway. (2) AMPK activator (AICAR), alone or in combination with insulin, increases Akt substrate of 160kDa (AS160) phosphorylation in skeletal muscle (Kramer et al. 2006). Phosphorylation of AS160 can activate Rab proteins in GLUT4 vesicles and promote its translocation to the plasma membrane (Satoh 2014). Two recent reports have reported that PGC-1α is essential for AICAR-induced expression of GLUT4 (Leick et al. 2010, Suwa et al. 2015). These results are consistent with the previous report that modest PGC-1α overexpression in obese Zucker rat muscles can increase insulin-induced AS160 phosphorylation (Benton et al. 2010). Several transcription factors and coactivators are implicated in PGC-1α-induced translocation and activation of GLUT4, either dependent on or independent of insulin, including AMPK (Jager et al. 2007), SIRT1 (Zhang et al. 2011), p38 MAPK (Wright 2007), ERR (Cho et al. 2013), and PPARγ (Kang et al. 2013). Specifically, some antidiabetic and antioxidative agents, such as lipoic acid, oligomannuronate, metformin and selenium-enriched exopolysaccharides, can improve skeletal muscle glucose uptake through AMPK/PGC-1α/GLUT4 pathway (Wang et al. 2010, Hao et al. 2011, Zhou et al. 2014). Consistently, both ER stress and oxidative stress are reported to impair GLUT4 production and glucose uptake via a PGC-1α-dependent signaling pathway (Raciti et al. 2010, Aoi et al. 2013). Moreover, aberrant DNA methylation in the PGC-1α promoter sequence also contributes to impaired glucose tolerance by influencing the expression of PGC-1α and GLUT4 in skeletal muscle (Zeng et al. 2013). In addition, PGC-1α has been shown to directly induce angiogenesis in skeletal muscle by enhancing the delivery of oxygen and glucose (Arany et al. 2008, Rowe et al. 2014), although not in all studies (Sawada et al. 2014). Thus, PGC-1α-mediated increase in skeletal muscle glucose uptake is probably due to the modulation of blood flow. Taken together, these findings reveal a significant association between PGC-1α and glucose uptake.

Glucose disposal

Impaired glucose disposal in skeletal muscle reduces insulin sensitivity and contributes to the development of T2DM. PGC-1α sets a strict control on glucose disposal in skeletal muscle, including suppression of glycolysis and glucose oxidation, inhibition of glycogen degradation, and augmentation of glycogen synthesis and fatty acid oxidation (Wende et al. 2007, Mormeneo et al. 2012). As described previously, PGC-1α activity is regulated by a variety of posttranslational modifications, especially by phosphorylation and acetylation. PGC-1α is involved in many signaling pathways that are critical to glucose storage and utilization, including AMPK (Li et al. 2014), p38 MAPK (Hong et al. 2011), and SIRT1 pathways (Gao et al. 2014). Furthermore, a series of studies have shed light on the role of posttranslational modifications of PGC-1α in glucose metabolism. For example, Silvestre and coworkers have reported that skeletal muscle-specific AMPKα1/2 knockout mice display impaired glucose tolerance and downregulated SIRT1, in association with decreased PGC-1α gene expression and deacetylation (Silvestre et al. 2014). The authors further show that SIRT1 inversely activates AMPK activity through phosphorylation of Thr172. However, as the relationship between p38 MAPK and AMPK pathways is particularly complicated, whether AMPK lies upstream of p38 MAPK is still debated. The mechanisms of how PGC-1α is regulated by p38 MAPK are significantly different. First, p38 MAPK directly phosphorylates PGC-1α at three sites (threonine 262, serine 265 and threonine 298) (Puigserver et al. 2001), which disrupts the binding and repression of PGC-1α by repressors such as p160 Myb binding protein (p160MBP), and greatly enhances the transcriptional activity of PGC-1α (Fan et al. 2004). These findings provide new insights into the regulation of PGC-1α by p38 MAPK. Second, p38 MAPK can indirectly increase PGC-1α expression. PGC-1α promoter comprises several positive regulatory domains that bind different cooperative transcription factors. Phosphorylation of MEF2 and ATF2 by p38 MAPK stimulates PGC-1α expression by binding to the regulatory domains on the PGC1α promoter, respectively (Fernandez-Marcos  Auwerx 2011). Conversely, angiotensin II stimulates p38 MAPK-dependent PGC-1α serine 570 phosphorylation and the subsequent GCN5-dependent acetylation, repression of PGC-1α cotranscriptional activity, and downregulation of catalase expression in vascular smooth muscle cells. Whether p38 MAPK plays a positive or negative role in PGC-1α gene expression and activity remains controversial.

PGC-1α and pancreas

Pancreatic β cells are responsible for synthesizing and secreting insulin, which helps to maintain blood glucose levels within a normal range. The reduction of pancreatic β cells mass is now widely acknowledged as an important pathophysiological factor implicated in T2DM. To date, several studies have reported the close relationship between PGC-1α and pancreatic β-cell dysfunction. For instance, adenovirus-mediated overexpression of PGC-1α in isolated rat islets results in a decrease in glucose-stimulated insulin secretion (Yoon et al. 2003). Although the exact mechanism through which PGC-1α affects the pancreatic islet function is still not completely elucidated, the explanation that follows here seems reasonable.

Pancreatic β-cell apoptosis

PGC-1α is an important regulator of pancreatic β-cell apoptosis. On one hand, PGC-1α is involved in the glucotoxicity-induced pancreatic β cells apoptosis. Glucokinase, a key regulatory enzyme that catalyzes glucose to glucose-6-phosphate, plays an important role in the regulation of glucose-stimulated insulin secretion by acting as a ‘glucose sensor’ in pancreatic islets. It has been reported that YH-GKA, a novel benzamide activator of glucokinase, dramatically reduces the mRNA level of PGC-1α and prevents glucotoxicity-induced INS-1 pancreatic β-cell apoptosis (Oh et al. 2014). Interestingly, PGC-1α overexpression in isolated rat islets induces the expression of G6Pase and suppresses glucokinase and glycerol-3-phosphate dehydrogenase, and therefore blunts membrane depolarization and insulin exocytosis in response to glucose (Yoon et al. 2003). On the other hand, PGC-1α mediates the FFA-induced pancreatic β-cell apoptosis in the development of T2DM, a process known as ‘lipotoxicity’. Zhang and coworkers demonstrated that there is a direct correlation between FFAs and PGC-1α (Zhang et al. 2005). After 72-h incubation, elevated FFAs (oleate/palmitate) not only dose-dependently increase PGC-1α expression level in isolated islets but also increase PGC-1α mRNA level in isolated islets and in mouse β-cell-derived bTC3 cell lines. Furthermore, recent data demonstrate that NADH-cytochrome b5 oxidoreductase (Ncb5or)-null mice, characterized by increased intracellular saturated fatty acid accumulation and hyperglycemia, show significantly higher islet transcript level of PGC-1α accompanied by accelerated β-cell injury (Guo et al. 2012). Taken together, these results indicate that the effects of PGC-1α on pancreatic β-cell apoptosis may at least in part be mediated by altered FFA metabolism. However, some recent conflicting reports showed that palmitic acid (PA) can extensively reduce the expression of PGC-1α mRNA and increase pancreatic β-cell apoptosis (He et al. 2011). The reason for the discrepancy is currently unclear.

Pancreatic β-cell regeneration

The development of T2DM partly depends on the balance between β-cell proliferation and death (apoptosis). Therefore, the regeneration of pancreatic β cells is considered to be a potentially curative treatment for T2DM. A recent study has demonstrated that the increased expression of PGC-1α is closely related to glucocorticoid-suppressed expansion and transdifferentiation of porcine neonatal pancreatic cell clusters into β cells (Kim et al. 2012b). Subsequently in 2014, the same research team reported that the silencing of PGC-1α by siPGC-1α significantly improved the glucocorticoid-suppressed expansion and transdifferentiation of porcine neonatal pancreatic cell clusters via the FOXO1–PDX1 pathway (Kim et al. 2014). These data indicate that PGC-1α is a critical regulator of pancreatic β-cell regeneration.

Insulin secretion

Impaired insulin secretion by pancreatic β cells is a characteristic feature of T2DM. Uncoupling protein 2 (UCP2), a mitochondrial transporter protein, has been reported to participate in the regulation of glucose-stimulated insulin secretion from pancreatic β cells (Sun et al. 2011). In cold-exposed rats, inhibition of islet PGC-1α expression by antisense oligonucleotide corrects UCP2 expression level and partially normalizes insulin secretion in pancreatic islets (De Souza et al. 2003). Oberkofler and coworkers subsequently characterize the underlying mechanism that PGC-1α can enhance the expression of sterol regulatory element-binding protein isoforms (SREBP)-1c via coactivation of the liver X receptor and upregulate the expression of SREBP2 via coactivation of the GR, resulting in an increase in UCP2 expression in INS-1E β cells (Oberkofler et al. 2006).

Mitochondrial dysfunction

In pancreatic β cells, mitochondrial metabolism is respon­sible for the generation of metabolic signals and coupling glucose recognition with insulin secretion. Mitochondrial dysfunction is known to produce excessive reactive oxygen species (ROS), eventually leading to oxidative stress and pancreatic β-cell dysfunction. PGC-1α, as a crucial factor responsible for mitochondrial biogenesis, is closely associated with oxidative stress-induced pancreatic β-cell dysfunction. For instance, transient exposure of INS-1E β cells to oxidative stress results in increased mitochondrial ROS formation, decreased PGC-1α expression, and reduced 15mM glucose-stimulated insulin secretion (Li et al. 2009). GW501516, a specific PPARδ agonist, decreases basal insulin secretion, but not glucose-stimulated insulin secretion (GSIS) in palmitate-exposed HIT-T15 pancreatic β cells (Jiang et al. 2010). These changes correlate with improved mitochondrial energy metabolism and increased mRNA expression of PGC-1α. Recently, mitochondrial dysfunction in pancreatic islets of congenitally malnourished offspring has also been studied. Prenatal malnutrition leads to a reduction of insulin secretion in 3-month-old male and female offsprings, due to mitochondrial dysfunction and higher PGC-1α expression (Theys et al. 2011). Glutathione peroxidase (GPX) is a major antioxidant enzyme that converts hydrogen peroxide into water and protects cells against oxidative stress. Thus, a recent study shows that GPX mimic ebselen enhances GSIS in islets of GPX1 knockout mice, and knockdown of PGC-1α by siRNA can largely eliminate this effect (Wang et al. 2014).

PGC-1α and diabetic nephropathy

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus and the leading cause of end-stage renal disease, affecting approximately one-third of diabetic patients, with no effective treatment available so far. Several studies, both in human beings and in animal models, have provided important clues to its etiology and pathogenesis. Considering the key role of mitochondrial dysfunction in DN, many researchers have focused their attention on PGC-1α. The mRNA and protein expression of PGC-1α are markedly downregulated in renal tubular cells of streptozotocin-induced diabetic rats. Rap1, a member of the RAS-like small GTP-binding protein superfamily, can significantly ameliorate renal tubular mitochondrial dysfunction, oxidative stress and apoptosis concomitant with the increased expression of PGC-1α and ameliorated tubular injury (Xiao et al. 2014). In two other diabetic models, transgenic OVE26 and Akt2-KO mouse, PGC-1α expression is also markedly downregulated, associated with significant changes in several glucose metabolism-related regulators (Sun et al. 2014). The pathogenesis of DN may, at least in part, be due to PGC-1α-mediated mitochondrial biogenesis.

The AMPK/SIRT1/PGC-1α pathway is a fundamental signaling system in energy metabolism and mitochondrial biogenesis. Recent studies relate the AMPK/SIRT1/PGC-1α signaling pathway to the progression of DN. For example, resveratrol, a type of natural phenol extracted primarily from the traditional Chinese medicinal herb Polygonum cuspidatum, has been reported to prevent DN in db/db mice through the phosphorylation of AMPK and the activation of SIRT1/PGC-1α signaling (Kim et al. 2013). In 2014, another kind of natural plant polyphenol, the grape seed proanthocyanidin extract, is also reported to ameliorate podocyte injury in low-dose streptozotocin- and high-carbohydrate/high-fat diet-induced diabetic rats through the activation of AMPK/SIRT1/PGC-1α signaling pathway (Bao et al. 2014). Moreover, several studies have evaluated the therapeutic efficacy of PGC-1α on DN. For instance, both telmisartan and fenofibrate exert their renoprotective effects in animal models of DN by activating PGC-1α expression and reducing oxidative stress (Lakshmanan et al. 2011, Hong et al. 2014), indicating the therapeutic potential of PGC-1α in the treatment of DN. Nonetheless, researchers from Korea have shown conflicting results, reporting that PGC-1α is increased in response to high-glucose (25mM) or IL-6 treatment. PGC-1α overexpression contributes to high glucose-induced apoptosis and growth arrest of renal podocytes (Kim & Park 2013). Although the discrepancy is not yet fully explained, it can be hypothesized that sustained activation of PGC-1α may change the energy supply–demand balance and cause different pathogenic outcomes in DN.

PGC-1α, oxidative stress and T2DM

As mentioned previously, PGC-1α is a crucial factor responsible for mitochondrial biogenesis. Mitochondrial dysfunction will produce excessive ROS, eventually leading to oxidative stress. Therefore, PGC-1α and oxidative stress are deeply implicated in T2DM and its complications. First, in the hepatocytes, it has been indicated that elevated endogenous asymmetric dimethylarginine (ADMA) contributes to the suppression of hepatic mitochondrial biogenesis, PGC-1α transcription and diabetes. These effects of ADMA could be inhibited by treatments with antioxidant (Chen et al. 2011). This is consistent with another report showing that the downregulation of GLUT2 and PGC-1α induced by glucose oxidase was evidently inhibited by NAC in rats and in hepatocytes (Wang et al. 2012). Secondly, in arsenic-treated mouse adipocytes and myotubes, the expression of SIRT3 and its associated transcription factor, FOXO3a, was dramatically decreased. Arsenic decreased the binding affinity of FOXO3a to the PGC-1α promoter. Overexpression of SIRT3 can stimulate FOXO3a deacetylation and the subsequent PGC-1α and MnSOD upregulation, which facilitates ROS detoxification in response to chronic arsenic exposure (Padmaja Divya et al. 2015). Thirdly, in dorsal root ganglion (DRG) neurons, Choi and coworkers reported that adenoviral overexpression of PGC-1α can prevent high glucose-induced oxidative stress (Choi et al. 2014). Fourthly, in rat glomerular mesangial cells, high glucose treatment resulted in the downregulation of PGC-1α, accompanied by an increase in ROS generation and mesangial cell hypertrophy. The transfection of pcDNA3–PGC-1α can significantly reverse these pathological changes (Guo et al. 2015). Finally, recent study, in cardiac cells, has demonstrated that sulforaphane treatment can increase fatty acid oxidation and prevent cardiomyopathy probably by reversing oxidative stress-induced inhibition of LKB1/AMPK/PGC-1α signaling pathway (Zhang et al. 2014). Taken together, these findings indicate a significant cooperative role of PGC-1α and oxidative stress in the pathogenesis of diabetes.

PGC-1α polymorphisms and T2DM

Several previous studies have demonstrated a close correlation between polymorphisms in the PGC-1α gene and T2DM. For example, Gly482Ser, the most common polymorphism in the PGC-1α gene, is positively associated with T2DM in different populations, including the Chinese (Lu et al. 2007); Danish (Ek et al. 2001); Japanese (Hara et al. 2002); and Canadian, German, Austrian, Finnish, Norwegian and Spanish (Andrulionyte et al. 2004).

The underlying mechanisms are as follows: on the one hand, the Gly482Ser polymorphism of PGC-1α gene is associated with a decreased PGC-1α mRNA expression and reduced insulin secretion (Ling et al. 2008). Additionally, an autosomal genomic scan shows that fasting plasma insulin concentration is linked to chromosome 4p15-q12 (Pratley et al. 1998). Interestingly, chromosome 4p15-q12 is syntenic to the chromosome 4p15.1, a region where PGC-1α gene has been mapped (Esterbauer et al. 1999). On the other hand, several published studies have found significant association between the Gly482Ser variant of PGC-1α gene and IR (Fanelli et al. 2005, Goyenechea et al. 2008). First, PGC-1α variants with Gly/Gly at the 482nd amino acid impair the transcription of mitochondrial transcriptional factor A (TFAM), resulting in mitochondrial dysfunction and IR (Choi et al. 2006). TFAM is a DNA-binding protein with high-mobility group (HMG)-box domains and acts as a link between the nucleus and the mitochondria during mitochondrial DNA (mtDNA) replication, transcription and inheritance. Recently, some studies have suggested that the expression of Tfam is significantly downregulated in the liver (Kim et al. 2015) and muscle cells (Taheripak et al. 2013) of db/db type 2 diabetic mice and DRG neurons (Choi et al. 2014) of streptozotocin-induced type 1 diabetic mice. Collectively, these findings strongly suggest that the TFAM may be closely associated with diabetes mellitus. Further investigations subsequently elucidate the underlying mechanism. PGC-1α can induce NRF-1 expression, which, in turn, activates Tfam to directly regulate mitochondrial biogenesis (Hickey et al. 2011, Agrawal et al. 2014). This association has been confirmed by the in vivo (Choi et al. 2014) and in vitro (Yan et al. 2013) results. Secondly, PGC-1α participates in insulin-stimulated glucose uptake in muscle cells by binding with the muscle-selective transcription factor MEF2C and coactivating it, thus controlling the level of GLUT4 expression (Michael et al. 2001). The Gly482Ser polymorphism can weaken the binding of PGC-1α and MEF2C, thereby increasing the risk of T2DM in Chinese Han population (Lu et al. 2007). In a recently published study, Zhang and coworkers further propose the following molecular mechanism (Zhang et al. 2010): the region at 400–500 amino acids of PGC-1α harbors a tetrapeptide. The region just distal to this tetrapeptide is required for coactivation of the GLUT4 via MEF2C. Hence, mutations in this region may decrease the transcription of GLUT4 and dysregulate insulin-dependent glucose transportation in skeletal muscle cells, contributing to IR. Thirdly, plasma adiponectin concentration is inversely related to the risk of developing T2DM, IR, obesity, atherosclerosis and gastrointestinal malignancies. Recently, a decreased plasma adiponectin level has been associated with Gly482Ser polymorphism of the PGC-1α gene in Japanese type 2 diabetic men but not women (Okauchi et al. 2008). However, the mechanism behind the linkage disequilibrium is still not fully understood. Finally, Ha and coworkers report that lifestyle factors, including PA and body fat, may modulate the genetic effects of the PGC-1α Gly482Ser polymorphism on IR in Korean children (Ha et al. 2015). Despite some limitations, this cross-sectional study strongly suggests the association between PGC-1α polymorphisms and diabetes.

Several other polymorphisms in PGC-1α gene are also reported to be associated with IR and T2DM. For example, the relationship between Thr394Thr variant and T2DM as well as its related mechanism is investigated in several populations. In Asian Indian population, the A allele of Thr394Thr (ACG→ACA) polymorphism is significantly associated with T2DM, and the XA genotype confers 1.6 times higher risk for T2DM compared with the GG genotype in this population (Vimaleswaran et al. 2005). Subsequently in 2007, a replicate case–control study reported the effect of PGC-1α Thr394Thr and Gly482Ser variants on T2DM in two North Indian populations, obtaining the same results (Bhat et al. 2007). In addition, the PGC-1α Thr394Thr polymorphism can affect the therapeutic effect of rosiglitazone, an oral antidiabetic medicine that directly binds with PPARγ and activates it to reduce hepatic glucose output and to increase peripheral glucose disposal. A recent study reported that the Chinese T2DM patients with Thr394Thr polymorphism experienced a decreased therapeutic response than patients with the wild-type genotype (Zhang et al. 2010). In order to elucidate the underlying mechanism of Thr394Thr variants, the bacterial two-hybrid system has been used in a study carried out in southern Chinese population. The results indicate that the 482Ser variant is less efficient than the 482Gly variant in binding with MEF2C, whereas the 394Thr (A) has a synergistic effect on the interaction between 482Ser variant and MEF2C (Zhang et al. 2007).

However, conflicting findings are reported on the relationship between the PGC-1α polymorphism and the risk of diabetes. For example, the Gly482Ser polymor­phism of PGC-1α has no association with diabetes in French Caucasians and non-diabetic German and Dutch and Northern Chinese Han populations (Lacquemant et al. 2002, Chen et al. 2004, Stumvoll et al. 2004). It is also shown that Gly482Ser, Thr528Thr and Thr612Met polymorphisms in the PGC-1α gene are not associated with T2DM or body mass index among Hispanics and Non-Hispanic Whites from Colorado (Nelson et al. 2007). Explanations for these discrepancies may include differences in ethnic, genetic and environmental heterogeneity; gene pools; and sample size. In any case, further investigation is needed.

Conclusions and future perspectives

In summary, the current findings highlight the central role of PGC-1α in the regulatory network of glucose metabolism. Obviously, the expression and activity of PGC-1α are regulated by various cytokines, transcription factors, and other external stimuli via multiple intracellular signaling pathways. This complex pathway should be considered as a novel therapeutic strategy and potential pharmacological agent for T2DM treatment. However, it should be noted that PGC-1α not only is differentially expressed in different tissues but also has distinct and even opposite functions in different cells (Fig. 3). In addition, most of studies did not take into account the complex crosstalk between different signaling pathways. Further investigation is needed to determine the precise role of PGC-1α pathway in the T2DM, and it largely relies on the development of novel PGC-1α-targeting reagents and tissue-specific transgenic or knockout animal models.

Figure 3
Figure 3

The main functions of PGC-1α in different tissues.

Citation: Journal of Endocrinology 229, 3; 10.1530/JOE-16-0021

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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 study was supported by the National Natural Science Foundation of China (81270804, 81370825 and 81470966), Hebei Science and Technology Department Program (12966118D), and Medical Research Program of the Hebei Provincial Health and Family Planning Commission (ZL20140063).

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  • Signaling pathways of PGC-1α-regulated glucose metabolism in the liver.

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  • Interactions of PGC-1α with the main factors involved in hepatic glucose metabolism.

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  • The main functions of PGC-1α in different tissues.

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References

AatsinkiSMBulerMSalomakiHKouluMPavekPHakkolaJ2014Metformin induces PGC-1alpha expression and selectively affects hepatic PGC-1alpha functions. British Journal of Pharmacology17123512363. (doi:10.1111/bph.12585)

AgrawalRZhuangYCummingsBPStanhopeKLGrahamJLHavelPJGomez-PinillaF2014Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes. Biochimica et Biophysica Acta184213131323. (doi:10.1016/j.bbadis.2014.05.007)

AlberdiGRodriguezVMMacarullaMTMirandaJChurrucaIPortilloMP2013Hepatic lipid metabolic pathways modified by resveratrol in rats fed an obesogenic diet. Nutrition29562567. (doi:10.1016/j.nut.2012.09.011)

AndrulionyteLZacharovaJChiassonJLLaaksoM2004Common polymorphisms of the PPAR-gamma2 (Pro12Ala) and PGC-1alpha (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial. Diabetologia4721762184. (doi:10.1007/s00125-004-1577-2)

AndrulionyteLLaukkanenOChiassonJLLaaksoM2006Single nucleotide polymorphisms of the HNF4alpha gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial. Journal of Molecular Medicine84701708. (doi:10.1007/s00109-006-0063-3)

AntonelliAFerrariSMGiuggioliDDi DomenicantonioARuffilliICorradoAFabianiSMarchiSFerriCFerranniniE2014Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World Journal of Diabetes5586600. (doi:10.4239/wjd.v5.i5.586)

AoiWNaitoYYoshikawaT2013Role of oxidative stress in impaired insulin signaling associated with exercise-induced muscle damage. Free Radical Biology and Medicine6512651272. (doi:10.1016/j.freeradbiomed.2013.09.014)

AranyZFooSYMaYRuasJLBommi-ReddyAGirnunGCooperMLaznikDChinsomboonJRangwalaSM2008HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature45110081012. (doi:10.1038/nature06613)

ArpiainenSJarvenpaaSMManninenAViitalaPLangMAPelkonenOHakkolaJ2008Coactivator PGC-1alpha regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes. Toxicology and Applied Pharmacology232135141. (doi:10.1016/j.taap.2008.06.001)

BaoLCaiXDaiXDingYJiangYLiYZhangZLiY2014Grape seed proanthocyanidin extracts ameliorate podocyte injury by activating peroxisome proliferator-activated receptor-gamma coactivator 1alpha in low-dose streptozotocin-and high-carbohydrate/high-fat diet-induced diabetic rats. Food & Function518721880. (doi:10.1039/c4fo00340c)

BeaudryJBPierreuxCEHayhurstGPPlumb-RudewiezNWeissMCRousseauGGLemaigreFP2006Threshold levels of hepatocyte nuclear factor 6 (HNF-6) acting in synergy with HNF-4 and PGC-1alpha are required for time-specific gene expression during liver development. Molecular and Cellular Biology2660376046. (doi:10.1128/MCB.02445-05)

BentonCRHollowayGPHanXXYoshidaYSnookLALallyJGlatzJFLuikenJJChabowskiABonenA2010Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats. Diabetologia5320082019. (doi:10.1007/s00125-010-1773-1)

BhatAKoulARaiESharmaSDharMKBamezaiRN2007PGC-1alpha Thr394Thr and Gly482Ser variants are significantly associated with T2DM in two North Indian populations: a replicate case-control study. Human Genetics121609614. (doi:10.1007/s00439-007-0352-0)

BirkenfeldALLeeHYGuebre-EgziabherFAlvesTCJurczakMJJornayvazFRZhangDHsiaoJJMartin-MontalvoAFischer-RosinskyA2011Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metabolism14184195. (doi:10.1016/j.cmet.2011.06.009)

BousteadJNStadelmaierBTEedsAMWiebePOSvitekCAOeserJKO’BrienRM2003Hepatocyte nuclear factor-4 alpha mediates the stimulatory effect of peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) on glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells. Biochemical Journal3691722. (doi:10.1042/bj20021382)

BulerMAatsinkiSMIzziVHakkolaJ2012aMetformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism.PLoS ONE7e49863. (doi:10.1371/journal.pone.0049863)

BulerMAatsinkiSMSkoumalRKomkaZTothMKerkelaRGeorgiadiAKerstenSHakkolaJ2012bEnergy-sensing factors coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and AMP-activated protein kinase control expression of inflammatory mediators in liver: induction of interleukin 1 receptor antagonist. Journal of Biological Chemistry28718471860. (doi:10.1074/jbc.M111.302356)

BulerMAatsinkiSMIzziVUusimaaJHakkolaJ2014SIRT5 is under the control of PGC-1alpha and AMPK and is involved in regulation of mitochondrial energy metabolism. FASEB Journal2832253237. (doi:10.1096/fj.13-245241)

CaoWCollinsQFBeckerTCRobidouxJLupoEGJrXiongYDanielKWFloeringLCollinsS2005p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. Journal of Biological Chemistry2804273142737. (doi:10.1074/jbc.M506223200)

ChangJJHsuMJHuangHPChungDJChangYCWangCJ2013Mulberry anthocyanins inhibit oleic acid induced lipid accumulation by reduction of lipogenesis and promotion of hepatic lipid clearance. Journal of Agricultural and Food Chemistry6160696076. (doi:10.1021/jf401171k)

ChenSYanWHuangJYangWGuD2004Peroxisome proliferator-activated receptor-gamma coactivator-1alpha polymorphism is not associated with essential hypertension and type 2 diabetes mellitus in Chinese population. Hypertension Research27813820. (doi:10.1291/hypres.27.813)

ChenNLengYPXuWJLuoJDChenMSXiongY2011Contribution of endogenous inhibitor of nitric oxide synthase to hepatic mitochondrial dysfunction in streptozotocin-induced diabetic rats. Cellular Physiology and Biochemistry27341352. (doi:10.1159/000327960)

ChenSZhangWTangCTangXLiuLLiuC2014Vanin-1 is a key activator for hepatic gluconeogenesis. Diabetes6320732085. (doi:10.2337/db13-0788)

ChoYHazenBCRussellAPKralliA2013Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1)- and estrogen-related receptor (ERR)-induced regulator in muscle 1 (Perm1) is a tissue-specific regulator of oxidative capacity in skeletal muscle cells. Journal of Biological Chemistry2882520725218. (doi:10.1074/jbc.M113.489674)

ChoiYSHongJMLimSKoKSPakYK2006Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter. Biochemical and Biophysical Research Communications344708712. (doi:10.1016/j.bbrc.2006.03.193)

ChoiJChandrasekaranKInoueTMuragundlaARussellJW2014PGC-1alpha regulation of mitochondrial degeneration in experimental diabetic neuropathy. Neurobiology Disorders64118130. (doi:10.1016/j.nbd.2014.01.001)

CollinsQFXiongYLupoEGJrLiuHYCaoW2006p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes. Journal of Biological Chemistry2812433624344. (doi:10.1074/jbc.M602177200)

CoronaJCDuchenMR2015PPARgamma and PGC-1alpha as therapeutic targets in Parkinson’s. Neurochemical Research40308316. (doi:10.1007/s11064-014-1377-0)

DankelSNHoangTFlagengMHSagenJVMellgrenG2010cAMP-mediated regulation of HNF-4alpha depends on the level of coactivator PGC-1alpha. Biochimica et Biophysica Acta180310131019. (doi:10.1016/j.bbamcr.2010.05.008)

De SouzaCTGasparettiALPereira-da-SilvaMAraujoEPCarvalheiraJBSaadMJBoscheroACCarneiroEMVellosoLA2003Peroxisome proliferator-activated receptor gamma coactivator-1-dependent uncoupling protein-2 expression in pancreatic islets of rats: a novel pathway for neural control of insulin secretion. Diabetologia4615221531. (doi:10.1007/s00125-003-1222-5)

DominyJEJrLeeYJedrychowskiMPChimHJurczakMJCamporezJPRuanHBFeldmanJPierceKMostoslavskyR2012The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Molecular Cell48900913. (doi:10.1016/j.molcel.2012.09.030)

EkJAndersenGUrhammerSAGaedePHDrivsholmTBorch-JohnsenKHansenTPedersenO2001Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia4422202226. (doi:10.1007/s001250100032)

EsterbauerHOberkoflerHKremplerFPatschW1999Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. Genomics6298102. (doi:10.1006/geno.1999.5977)

FanMRheeJSt-PierreJHandschinCPuigserverPLinJJaegerSErdjument-BromageHTempstPSpiegelmanBM2004Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. Genes and Development18278289. (doi:10.1101/gad.1152204)

FanelliMFilippiESentinelliFRomeoSFallarinoMBuzzettiRLeonettiFBaroniMG2005The Gly482Ser missense mutation of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) gene associates with reduced insulin sensitivity in normal and glucose-intolerant obese subjects. Disease Markers21175180. (doi:10.1155/2005/576748)

FelderTKSoyalSMOberkoflerHHahnePAuerSWeissRGadermaierGMillerKKremplerFEsterbauerH2011Characterization of novel peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) isoform in human liver. Journal of Biological Chemistry2864292342936. (doi:10.1074/jbc.M111.227496)

Fernandez-MarcosPJAuwerxJ2011Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. American Journal of Clinical Nutrition93884S890S. (doi:10.3945/ajcn.110.001917)

GaoSMcMillanRPJacasJZhuQLiXKumarGKCasalsNHegardtFGRobbinsPDLopaschukGD2014Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin. Diabetes6332423252. (doi:10.2337/db14-0388)

GhiraldiniFGCrispimACMelloML2013Effects of hyperglycemia and aging on nuclear sirtuins and DNA damage of mouse hepatocytes. Molecular Biology of the Cell2424672476. (doi:10.1091/mbc.E13-04-0186)

GoyenecheaECrujeirasABAbeteIParraDMartinezJA2008Enhanced short-term improvement of insulin response to a low-caloric diet in obese carriers the Gly482Ser variant of the PGC-1alpha gene. Diabetes Research and Clinical Practice82190196. (doi:10.1016/j.diabres.2008.08.011)

GuoYXuMDengBFronteraJRKoverKLAiresDDingHCarlsonSETurkJWangW2012Beta-cell injury in Ncb5or-null mice is exacerbated by consumption of a high-fat diet. European Journal of Lipid Science and Technology114233243. (doi:10.1002/ejlt.201100309)

GuoKLuJHuangYWuMZhangLYuHZhangMBaoYHeJCChenH2015Protective role of PGC-1alpha in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling. PLoS ONE10e0125176. (doi:10.1371/journal.pone.0125176)

HaCDChoJKHanTLeeSHKangHS2015Relationship of PGC-1alpha gene polymorphism with insulin resistance syndrome in Korean children. AsiaPacific Journal of Public Health27NP544NP551. (doi:10.1177/1010539513477685)

HandschinCRheeJLinJTarrPTSpiegelmanBM2003An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. PNAS10071117116. (doi:10.1073/pnas.1232352100)

HaoCHaoJWangWHanZLiGZhangLZhaoXYuG2011Insulin sensitizing effects of oligomannuronate-chromium (III) complexes in C2C12 skeletal muscle cells. PLoS ONE6e24598. (doi:10.1371/journal.pone.0024598)

HaraKTobeKOkadaTKadowakiHAkanumaYItoCKimuraSKadowakiT2002A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes. Diabetologia45740743. (doi:10.1007/s00125-002-0803-z)

HashidumeTSasakiTInoueJSatoR2011Consumption of soy protein isolate reduces hepatic SREBP-1c and lipogenic gene expression in wild-type mice, but not in FXR-deficient mice. Bioscience Biotechnology and Biochemistry7517021707. (doi:10.1271/bbb.110224)

HeTTCaoXPChenRZZhuXNWangXLLiYBXiaoHP2011Down-regulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha expression in fatty acid-induced pancreatic beta-cell apoptosis involves nuclear factor-kappaB pathway. Chinese Medical Journal12436573663.

HerzigSLongFJhalaUSHedrickSQuinnRBauerARudolphDSchutzGYoonCPuigserverP2001CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature413179183. (doi:10.1038/35093131)

HerzogBCardenasJHallRKVillenaJABudgePJGiguereVGrannerDKKralliA2006Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription. Journal of Biological Chemistry28199106. (doi:10.1074/jbc.M509276200)

HickeyFBCorcoranJBDochertyNGGriffinBBhreathnachUFurlongFMartinFGodsonCMurphyM2011IHG-1 promotes mitochondrial biogenesis by stabilizing PGC-1alpha. Journal of the American Society of Nephrology2214751485. (doi:10.1681/ASN.2010111154)

HongTNingJYangXLiuHYHanJLiuZCaoW2011Fine-tuned regulation of the PGC-1alpha gene transcription by different intracellular signaling pathways. American Journal of Physiology: Endocrinology and Metabolism300E500E507. (doi:10.1152/ajpendo.00225.2010)

HongYALimJHKimMYKimTWKimYYangKSParkHSChoiSRChungSKimHW2014Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1alpha in db/db mice. PLoS ONE9e96147. (doi:10.1371/journal.pone.0096147)

HsuWHChenTHLeeBHHsuYWPanTM2014Monascin and ankaflavin act as natural AMPK activators with PPARalpha agonist activity to down-regulate nonalcoholic steatohepatitis in high-fat diet-fed C57BL/6 mice. Food and Chemical Toxicology6494103. (doi:10.1016/j.fct.2013.11.015)

HuangCFreakeHC1998Thyroid hormone regulates the acetyl-CoA carboxylase PI promoter. Biochemical and Biophysical Research Communications249704708. (doi:10.1006/bbrc.1998.9217)

Jafar-MohammadiBGrovesCJGjesingAPHerreraBMWincklerWStringhamHMMorrisAPLauritzenTDoneyASMorrisAD2011A role for coding functional variants in HNF4A in type 2 diabetes susceptibility. Diabetologia54111119. (doi:10.1007/s00125-010-1916-4)

JagerSHandschinCSt-PierreJSpiegelmanBM2007AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. PNAS1041201712022. (doi:10.1073/pnas.0705070104)

JeongKJKim doYQuanHYJoHKKimGWChungSH2014Effects of eugenol on hepatic glucose production and AMPK signaling pathway in hepatocytes and C57BL/6J mice. Fitoterapia93150162. (doi:10.1016/j.fitote.2013.12.023)

JiangLWanJKeLQLuQGTongNW2010Activation of PPARdelta promotes mitochondrial energy metabolism and decreases basal insulin secretion in palmitate-treated beta-cells. Molecular and Cellular Biochemistry343249256. (doi:10.1007/s11010-010-0520-8)

KangJLeeJKwonDSongY2013Effect of Opuntia humifusa supplementation and acute exercise on insulin sensitivity and associations with PPAR-gamma and PGC-1alpha protein expression in skeletal muscle of rats. International Journal of Molecular Sciences1471407154. (doi:10.3390/ijms14047140)

KimDIParkSH2013Sequential signaling cascade of IL-6 and PGC-1alpha is involved in high glucose-induced podocyte loss and growth arrest. Biochemical and Biophysical Research Communications435702707. (doi:10.1016/j.bbrc.2013.05.046)

KimDKKimJRKohMKimYDLeeJMChandaDParkSBMinJJLeeCHParkTS2011Estrogen-related receptor gamma (ERRgamma) is a novel transcriptional regulator of phosphatidic acid phosphatase, LIPIN1, and inhibits hepatic insulin signaling. Journal of Biological Chemistry2863803538042. (doi:10.1074/jbc.M111.250613)

KimDKRyuDKohMLeeMWLimDKimMJKimYHChoWJLeeCHParkSB2012a Orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) is key regulator of hepatic gluconeogenesis. Journal of Biological Chemistry2872162821639. (doi:10.1074/jbc.M111.315168)

KimJWSunCJeonSYYouYHShinJYLeeSHChoJHParkCGYoonKH2012bGlucocorticoid treatment independently affects expansion and transdifferentiation of porcine neonatal pancreas cell clusters. BMB Reports455156.

KimMYLimJHYounHHHongYAYangKSParkHSChungSKoSHShinSJChoiBS2013Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db/db mice. Diabetologia56204217. (doi:10.1007/s00125-012-2747-2)

KimJWParkSYYouYHHamDSParkHSLeeSHYangHKYoonKH2014Targeting PGC-1alpha to overcome the harmful effects of glucocorticoids in porcine neonatal pancreas cell clusters. Transplantation97273279. (doi:10.1097/01.TP.0000438627.68225.25)

KimHMLeeESLeeBRYadavDKimYMKoHJParkKSLeeEYChungCH2015C-C chemokine receptor 2 inhibitor ameliorates hepatic steatosis by improving ER stress and inflammation in a type 2 diabetic mouse model. PLoS ONE10e0120711. (doi:10.1371/journal.pone.0120711)

KnuttiDKaulAKralliA2000A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen. Molecular and Cellular Biology2024112422. (doi:10.1128/MCB.20.7.2411-2422.2000)

KramerHFWitczakCAFujiiNJessenNTaylorEBArnoldsDESakamotoKHirshmanMFGoodyearLJ2006Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes5520672076. (doi:10.2337/db06-0150)

LacquemantCChikriMBoutinPSamsonCFroguelP2002No association between the G482S polymorphism of the proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene and type II diabetes in French Caucasians. Diabetologia45602603. (doi:10.1007/s00125-002-0783-z)

LakshmananAPWatanabeKThandavarayanRASariFRHarimaMGiridharanVVSoetiknoVKodamaMAizawaY2011Telmisartan attenuates oxidative stress and renal fibrosis in streptozotocin induced diabetic mice with the alteration of angiotensin-(1-7) mas receptor expression associated with its PPAR-gamma agonist action. Free Radical Research45575584. (doi:10.3109/10715762.2011.560149)

LeickLFentzJBiensoRSKnudsenJGJeppesenJKiensBWojtaszewskiJFPilegaardH2010PGC-1{alpha} is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle. American Journal of Physiology: Endocrinology and Metabolism299E456E465. (doi:10.1152/ajpendo.00648.2009)

LiSLiuCLiNHaoTHanTHillDEVidalMLinJD2008Genome-wide coactivation analysis of PGC-1alpha identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metabolism8105117. (doi:10.1016/j.cmet.2008.06.013)

LiNBrunTCnopMCunhaDAEizirikDLMaechlerP2009Transient oxidative stress damages mitochondrial machinery inducing persistent beta-cell dysfunction. Journal of Biological Chemistry2842360223612. (doi:10.1074/jbc.M109.024323)

LiJLuYLiuRXiongXZhangZZhangXNingGLiX2011DAX1 suppresses FXR transactivity as a novel co-repressor. Biochemical and Biophysical Research Communications412660666. (doi:10.1016/j.bbrc.2011.08.020)

LiYTranVHKotaBPNammiSDukeCCRoufogalisBD2014Preventative effect of Zingiber officinale on insulin resistance in a high-fat high-carbohydrate diet-fed rat model and its mechanism of action. Basic & Clinical Pharmacology & Toxicology115209215. (doi:10.1111/bcpt.12196)

LiangJLiuCQiaoACuiYZhangHCuiAZhangSYangYXiaoXChenY2013MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis. Journal of Hepatology58535542. (doi:10.1016/j.jhep.2012.10.024)

LingCDel GuerraSLupiRRonnTGranhallCLuthmanHMasielloPMarchettiPGroopLDel PratoS2008Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia51615622. (doi:10.1007/s00125-007-0916-5)

LuWSYanXDLiuHYHuangZTanXYHuangQYangCLiYYanLChengH2007[The cSNPs analysis in whole extron-wide of PGC-1alpha gene in Chinese population and the domain MEF2C bioinformatics study]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi24409416.

MichaelLFWuZCheathamRBPuigserverPAdelmantGLehmanJJKellyDPSpiegelmanBM2001Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. PNAS9838203825. (doi:10.1073/pnas.061035098)

MinorRKBaurJAGomesAPWardTMCsiszarAMerckenEMAbdelmohsenKShinYKCantoCScheibye-KnudsenM2011SRT1720 improves survival and healthspan of obese mice.Science Reports170. (doi:10.1038/srep00070)

MoluskyMMLiSMaDYuLLinJD2012aUbiquitin-specific protease 2 regulates hepatic gluconeogenesis and diurnal glucose metabolism through 11beta-hydroxysteroid dehydrogenase 1.Diabetes6110251035. (doi:10.2337/db11-0970)

MoluskyMMMaDBuelowKYinLLinJD2012bPeroxisomal localization and circadian regulation of ubiquitin-specific protease 2. PLoS ONE7e47970. (doi:10.1371/journal.pone.0047970)

MoraSPessinJE2000The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. Journal of Biological Chemistry2751632316328. (doi:10.1074/jbc.M910259199)

MormeneoEJimenez-MallebreraCPalomerXDe NigrisVVazquez-CarreraMOrozcoANascimentoAColomerJLerinCGomez-FoixAM2012PGC-1alpha induces mitochondrial and myokine transcriptional programs and lipid droplet and glycogen accumulation in cultured human skeletal muscle cells. PLoS ONE7e29985. (doi:10.1371/journal.pone.0029985)

NedumaranBHongSXieYBKimYHSeoWYLeeMWLeeCHKooSHChoiHS2009DAX-1 acts as a novel corepressor of orphan nuclear receptor HNF4alpha and negatively regulates gluconeogenic enzyme gene expression. Journal of Biological Chemistry2842751127523. (doi:10.1074/jbc.M109.034660)

NegrinKARoth FlachRJDiStefanoMTMatevossianAFriedlineRHJungDKimJKCzechMP2014IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS ONE9e107265. (doi:10.1371/journal.pone.0107265)

NelsonTLFingerlinTEMossLBarmadaMMFerrellRENorrisJM2007The peroxisome proliferator-activated receptor gamma coactivator-1 alpha gene (PGC-1alpha) is not associated with type 2 diabetes mellitus or body mass index among Hispanic and non Hispanic Whites from Colorado. Experimental Clinical Endocrinology Diabetes115268275. (doi:10.1055/s-2007-960495)

OberkoflerHKleinKFelderTKKremplerFPatschW2006Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells. Endocrinology147966976. (doi:10.1210/en.2005-0817)

OhYSLeeYJParkKChoiHHYooSJunHS2014Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells. European Journal of Pharmaceutical Science51137145. (doi:10.1016/j.ejps.2013.09.005)

OkauchiYIwahashiHOkitaKYuanMMatsudaMTanakaTMiyagawaJFunahashiTHorikawaYShimomuraI2008PGC-1alpha Gly482Ser polymorphism is associated with the plasma adiponectin level in type 2 diabetic men. Endocrine Journal55991997. (doi:10.1507/endocrj.K08E-070)

Padmaja DivyaSPratheeshkumarPSonYOVinod RoyRAndrew HitronJKimDDaiJWangLAshaPHuangB2015Arsenic induces insulin resistance in mouse adipocytes and myotubes via oxidative stress-regulated mitochondrial Sirt3-FOXO3a signaling pathway. Toxicological Sciences146290300. (doi:10.1093/toxsci/kfv089)

ParvaizFManzoorSIqbalJMcRaeSJavedFAhmedQLWarisG2014Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome. Archives of Virology15910171025. (doi:10.1007/s00705-013-1892-3)

PeetersAFraislPvan den BergSVer Loren van ThemaatEVan KampenATakemoriHCarmelietP2011Carbohydrate metabolism is perturbed in peroxisome-deficient hepatocytes due to mitochondrial dysfunction, AMP-activated protein kinase (AMPK) activation, and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) suppression. Journal of Biological Chemistry2864216242179. (doi:10.1074/jbc.M111.299727)

PhilpABelewMYEvansAPhamDSiviaIChenASchenkSBaarK2011The PGC-1alpha-related coactivator promotes mitochondrial and myogenic adaptations in C2C12 myotubes. AJP Regulatory Integrative and Comparative Physiology301R864R872. (doi:10.1152/ajpregu.00232.2011)

PratleyREThompsonDBProchazkaMBaierLMottDRavussinESakulHEhmMGBurnsDKForoudT1998An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. Journal of Clinical Investigation10117571764. (doi:10.1172/JCI1850)

PuigserverPWuZParkCWGravesRWrightMSpiegelmanBM1998A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell92829839. (doi:10.1016/S0092-8674(00)81410-5)

PuigserverPRheeJLinJWuZYoonJCZhangCYKraussSMoothaVKLowellBBSpiegelmanBM2001Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Molecular Cell8971982. (doi:10.1016/S1097-2765(01)00390-2)

PurushothamASchugTTXuQSurapureddiSGuoXLiX2009Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metabolism9327338. (doi:10.1016/j.cmet.2009.02.006)

QadriIChoudhuryMRahmanSMKnottsTAJanssenRCSchaackJIwahashiMPuljakLSimonFRKilicG2012Increased phosphoenolpyruvate carboxykinase gene expression and steatosis during hepatitis C virus subgenome replication: role of nonstructural component 5A and CCAAT/enhancer-binding protein beta. Journal of Biological Chemistry2873734037351. (doi:10.1074/jbc.M112.384743)

RacitiGAIadiciccoCUlianichLVindBFGasterMAndreozziFLongoMTeperinoRUngaroPDi JesoB2010Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia53955965. (doi:10.1007/s00125-010-1676-1)

RamachandranBYuGGulickT2008Nuclear respiratory factor 1 controls myocyte enhancer factor 2A transcription to provide a mechanism for coordinate expression of respiratory chain subunits. Journal of Biological Chemistry2831193511946. (doi:10.1074/jbc.M707389200)

RhaGBWuGShoelsonSEChiYI2009Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation. Journal of Biological Chemistry2843516535176. (doi:10.1074/jbc.M109.052506)

RheeJInoueYYoonJCPuigserverPFanMGonzalezFJSpiegelmanBM2003Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. PNAS10040124017. (doi:10.1073/pnas.0730870100)

RodgersJTPuigserverP2007Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. PNAS1041286112866. (doi:10.1073/pnas.0702509104)

Rodrigue-WayACaronVBilodeauSKeilSHassanMLevyEMitchellGATremblayA2014Scavenger receptor CD36 mediates inhibition of cholesterol synthesis via activation of the PPARgamma/PGC-1alpha pathway and Insig1/2 expression in hepatocytes. FASEB Journal2819101923. (doi:10.1096/fj.13-240168)

RoweGCRaghuramSJangCNagyJAPattenISGoyalAChanMCLiuLXJiangASpokesKC2014PGC-1alpha induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circulation Research115504517. (doi:10.1161/CIRCRESAHA.115.303829)

RuanHBHanXLiMDSinghJPQianKAzarhoushSZhaoLBennettAMSamuelVTWuJ2012O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1alpha stability. Cell Metabolism16226237. (doi:10.1016/j.cmet.2012.07.006)

SatohT2014Molecular mechanisms for the regulation of insulin-stimulated glucose uptake by small guanosine triphosphatases in skeletal muscle and adipocytes. International Journal of Molecular Sciences151867718692. (doi:10.3390/ijms151018677)

SawadaNJiangATakizawaFSafdarAManikaATesmenitskyYKangKTBischoffJKalwaHSartorettoJL2014Endothelial PGC-1alpha mediates vascular dysfunction in diabetes. Cell Metabolism19246258. (doi:10.1016/j.cmet.2013.12.014)

SchillingMMOeserJKChandyJKFlemmingBPAllenSRO’BrienRM2008Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1alpha. Diabetologia5115051514. (doi:10.1007/s00125-008-1050-8)

ShlomaiARechtmanMMBurdelovaEOZilberbergAHoffmanSSolarIFishmanSHalpernZSklanEH2012The metabolic regulator PGC-1alpha links hepatitis C virus infection to hepatic insulin resistance. Journal of Hepatology57867873. (doi:10.1016/j.jhep.2012.06.021)

SilvestreMFViolletBCatonPWLeclercJSakakibaraIForetzMHolnessMCSugdenMC2014The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions. Life Sciences1005560. (doi:10.1016/j.lfs.2014.01.080)

StumvollMFritscheAt’HartLMMachannJThamerCTschritterOJacobSDekkerJMMaassenJA2004The Gly482Ser variant in the peroxisome proliferator-activated receptor gamma coactivator-1 is not associated with diabetes-related traits in non-diabetic German and Dutch populations. Experimental Clinical Endocrinology Diabetes112253257.

SugdenMCCatonPWHolnessMJ2010PPAR control: it’s SIRTainly as easy as PGC. Journal of Endocrinology20493104. (doi:10.1677/JOE-09-0359)

SuhJHSieglaffDHZhangAXiaXCvoroAWinnierGEWebbP2013SIRT1 is a direct coactivator of thyroid hormone receptor beta1 with gene-specific actions. PLoS ONE8e70097. (doi:10.1371/journal.pone.0070097)

SunLLJiangBGLiWTZouJJShiYQLiuZM2011MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes Research and Clinical Practice9194100. (doi:10.1016/j.diabres.2010.11.006)

SunWWangYMiaoXWangYZhangLXinYZhengSEpsteinPNFuYCaiL2014Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2. Free Radical Biology and Medicine682234. (doi:10.1016/j.freeradbiomed.2013.11.015)

SuwaMNakanoHRadakZKumagaiS2015A comparison of chronic AICAR treatment-induced metabolic adaptations in red and white muscles of rats. Journal of Physiological Sciences65121130. (doi:10.1007/s12576-014-0349-0)

TackCJStienstraRJoostenLANeteaMG2012Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunological Reviews249239252. (doi:10.1111/j.1600-065x.2012.01145.x)

TaheripakGBakhtiyariSRajabibazlMPasalarPMeshkaniR2013Protein tyrosine phosphatase 1B inhibition ameliorates palmitate-induced mitochondrial dysfunction and apoptosis in skeletal muscle cells. Free Radical Biology and Medicine6514351446. (doi:10.1016/j.freeradbiomed.2013.09.019)

TalukdarSBhatnagarSDridiSHillgartnerFB2007Chenodeoxycholic acid suppresses the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317. Journal of Lipid Research4826472663. (doi:10.1194/jlr.M700189-JLR200)

ThaiMVGuruswamySCaoKTPessinJEOlsonAL1998Myocyte enhancer factor 2 (MEF2)-binding site is required for GLUT4 gene expression in transgenic mice. Regulation of MEF2 DNA binding activity in insulin-deficient diabetes. Journal of Biological Chemistry2731428514292. (doi:10.1074/jbc.273.23.14285)

ThakranSSharmaPAttiaRRHoriRTDengXElamMBParkEA2013Role of sirtuin 1 in the regulation of hepatic gene expression by thyroid hormone. Journal of Biological Chemistry288807818. (doi:10.1074/jbc.M112.437970)

TheysNAhnMTBouckenoogheTReusensBRemacleC2011Maternal malnutrition programs pancreatic islet mitochondrial dysfunction in the adult offspring. Journal of Nutritional Biochemistry22985994. (doi:10.1016/j.jnutbio.2010.08.015)

TianGSawashitaJKuboHNishioSYHashimotoSSuzukiNYoshimuraHTsuruokaMWangYLiuY2014Ubiquinol-10 supplementation activates mitochondria functions to decelerate senescence in senescence-accelerated mice. Antioxidants & Redox Signaling2026062620. (doi:10.1089/ars.2013.5406)

VimaleswaranKSRadhaVGhoshSMajumderPPDeepaRBabuHNRaoMRMohanV2005Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) gene polymorphisms and their relationship to Type 2 diabetes in Asian Indians. Diabetic Medicine2215161521. (doi:10.1111/j.1464-5491.2005.01709.x)

ViolletBGuigasBLeclercJHebrardSLantierLMounierRAndreelliFForetzM2009AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiologica1968198. (doi:10.1111/j.1748-1716.2009.01970.x)

WangYLiXGuoYChanLGuanX2010alpha-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling in the skeletal muscle of aged mice. Metabolism59967976. (doi:10.1016/j.metabol.2009.10.018)

WangXGuCHeWYeXChenHZhangXHaiC2012Glucose oxidase induces insulin resistance via influencing multiple targets in vitro and in vivo: the central role of oxidative stress. Biochimie9417051717. (doi:10.1016/j.biochi.2012.03.024)

WangLJiaYRogersHSuzukiNGassmannMWangQMcPherronACKoppJBYamamotoMNoguchiCT2013Erythropoietin contributes to slow oxidative muscle fiber specification via PGC-1alpha and AMPK activation. International Journal of Biochemistry and Cell Biology4511551164. (doi:10.1016/j.biocel.2013.03.007)

WangXYunJWLeiXG2014Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets. Antioxidants & Redox Signaling20191203. (doi:10.1089/ars.2013.5361)

WeickertMOPfeifferAF2006Signalling mechanisms linking hepatic glucose and lipid metabolism. Diabetologia4917321741. (doi:10.1007/s00125-006-0295-3)

WendeARSchaefferPJParkerGJZechnerCHanDHChenMMHancockCRLehmanJJHussJMMcClainDA2007A role for the transcriptional coactivator PGC-1alpha in muscle refueling. Journal of Biological Chemistry2823664236651. (doi:10.1074/jbc.M707006200)

WrightDC2007Mechanisms of calcium-induced mitochondrial biogenesis and GLUT4 synthesis. Applied Physiology, Nutrition, and Metabolism32840845. (doi:10.1139/H07-062)

XiaoLZhuXYangSLiuFZhouZZhanMXiePZhangDLiJSongP2014Rap1 ameliorates renal tubular injury in diabetic nephropathy. Diabetes6313661380. (doi:10.2337/db13-1412)

YamamotoTShimanoHNakagawaYIdeTYahagiNMatsuzakaTNakakukiMTakahashiASuzukiHSoneH2004SREBP-1 interacts with hepatocyte nuclear factor-4 alpha and interferes with PGC-1 recruitment to suppress hepatic gluconeogenic genes. Journal of Biological Chemistry2791202712035. (doi:10.1074/jbc.M310333200)

YanWZhangHLiuPWangHLiuJGaoCLiuYLianKYangLSunL2013Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1alpha signaling contributing to increased vulnerability in diabetic heart.Basic Research in Cardiology108329. (doi:10.1007/s00395-013-0329-1)

YangFStewartMYeJDeMetsD2015Type 2 diabetes mellitus development programs in the new regulatory environment with cardiovascular safety requirements. Diabetes, Metabolic Syndrome and Obesity8315325. (doi:10.2147/DMSO)

YaoWCaiHLiXLiTHuLPengT2014Endoplasmic reticulum stress links hepatitis C virus RNA replication to wild-type PGC-1alpha/liver-specific PGC-1alpha upregulation. Journal of Virology8883618374. (doi:10.1128/JVI.01202-14)

YoonJCPuigserverPChenGDonovanJWuZRheeJAdelmantGStaffordJKahnCRGrannerDK2001Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature413131138. (doi:10.1038/35093050)

YoonJCXuGDeeneyJTYangSNRheeJPuigserverPLevensARYangRZhangCYLowellBB2003Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. Developmental Cell57383. (doi:10.1016/S1534-5807(03)00170-9)

YuXLongYC2015Autophagy modulates amino acid signaling network in myotubes: differential effects on mTORC1 pathway and the integrated stress response. FASEB Journal29394407. (doi:10.1096/fj.14-252841)

YuAZhengYZhangRHuangJZhuZZhouRJinDYangZ2013Resistin impairs SIRT1 function and induces senescence-associated phenotype in hepatocytes. Molecular Cellular Endocrinology3772332. (doi:10.1016/j.mce.2013.06.028)

YuanHDPiaoGC2011An active part of Artemisia sacrorum Ledeb. suppresses gluconeogenesis through AMPK mediated GSK3beta and CREB phosphorylation in human HepG2 cells. Bioscience Biotechnology and Biochemistry7510791084. (doi:10.1271/bbb.100881)

YuanHDKim doYQuanHYKimSJJungMSChungSH2012Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3beta via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells. Chemico-Biological Interactions1953542. (doi:10.1016/j.cbi.2011.10.006)

ZengYGuPLiuKHuangP2013Maternal protein restriction in rats leads to reduced PGC-1alpha expression via altered DNA methylation in skeletal muscle. Molecular Medicine Reports7306312. (doi:10.3892/mmr.2012.1134)

ZhangPLiuCZhangCZhangYShenPZhangJZhangCY2005Free fatty acids increase PGC-1alpha expression in isolated rat islets. FEBS Letters57914461452. (doi:10.1016/j.febslet.2005.01.046)

ZhangSLLuWSYanLWuMCXuMTChenLHChengH2007Association between peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C. Chinese Medical Journal12018781885.

ZhangKHHuangQDaiXPYinJYZhangWZhouGZhouHHLiuZQ2010Effects of the peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha) Thr394Thr and Gly482Ser polymorphisms on rosiglitazone response in Chinese patients with type 2 diabetes mellitus. Journal of Clinical Pharmacology5010221030. (doi:10.1177/0091270009355159)

ZhangCMcFarlaneCLokireddySBonalaSGeXMasudaSGluckmanPDSharmaMKambadurR2011Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway. Diabetologia5414911501. (doi:10.1007/s00125-011-2079-7)

ZhangMLvXLiJMengZWangQChangWLiWChenLLiuY2012Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis. Molecular and Cellular Endocrinology363122130. (doi:10.1016/j.mce.2012.08.006)

ZhangZWangSZhouSYanXWangYChenJMellenNKongMGuJTanY2014Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway. Journal of Molecular and Cellular Cardiology774252. (doi:10.1016/j.yjmcc.2014.09.022)

ZhouXChenJWangFYangHYangRWangXWangY2014Selenium-enriched exopolysaccharides improve skeletal muscle glucose uptake of diabetic KKAy mice via AMPK pathway. Journal of Physiology and Biochemistry70547554. (doi:10.1007/s13105-014-0334-3)

ZhuLLLiuYCuiAFShaoDLiangJCLiuXJChenYGuptaNFangFDChangYS2010PGC-1alpha coactivates estrogen-related receptor-alpha to induce the expression of glucokinase. American Journal of Physiology: Endocrinology and Metabolism298E1210E1218. (doi:10.1152/ajpendo.00633.2009)

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