Endurance exercise can lead to systemic improvements in insulin sensitivity and metabolic homeostasis, and is an effective approach to combat metabolic diseases. Pharmacological compounds that recapitulate the beneficial effects of exercise, also known as ‘exercise mimetics’, have the potential to improve disease symptoms of metabolic syndrome. These drugs, which can increase energy expenditure, suppress hepatic gluconeogenesis, and induce insulin sensitization, have accordingly been highly scrutinized for their utility in treating metabolic diseases including diabetes. Nevertheless, the identity of an efficacious exercise mimetic still remains elusive. In this review, we highlight several nuclear receptors and cofactors that are putative molecular targets for exercise mimetics, and review recent studies that provide advancements in our mechanistic understanding of how exercise mimetics exert their beneficial effects. We also discuss evidence from clinical trials using these compounds in human subjects to evaluate their efficacy in treating diabetes.
Lifestyle interventions such as improving diet and exercise habits can effectively combat many disease symptoms associated with metabolic syndrome, including obesity, hyperglycemia, insulin resistance, inflammation, hypercholesterolemia, and diabetes (Knowler et al. 2002, Shin et al. 2013). Even a small increase in daily physical activity can improve muscle fitness, promote resistance to diet-induced obesity, and reduce systemic inflammation (Warburton et al. 2006). Although the mechanisms through which exercise improves the symptoms of metabolic diseases are incompletely understood, adaptive changes in oxidative metabolism and mitochondrial function of skeletal muscle are believed to play a significant role (Fan et al. 2013). Endurance training in skeletal muscle can be mechanistically linked to activation of an AMP-sensitive gene expression program coordinated by 5′-adenosine monophosphate-activated protein kinase (AMPK) and the nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ) (Narkar et al. 2008). Two drugs that target these pathways, the AMP-analog 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR) and the PPARδ ligand GW501516, can greatly improve exercise performance in mice without training (Narkar et al. 2008). Subsequently, other drugs with exercise-mimetic effects have been identified as potential therapeutic avenues for metabolic diseases.
In this review, we discuss recent findings that address the efficacy of targeting AMPK and/or nuclear receptor-controlled pathways to mimic some of the benefits of exercise, and whether compounds that modulate AMPK and nuclear receptor activity might be useful for treating metabolic diseases such as type 2 diabetes (T2D). How might one specific exercise mimetic be used as a therapy for a complex disease such as T2D? One apparent mechanism is through the induction of glucose uptake in tissues such as skeletal muscle and fat, which removes excess glucose from circulation. As skeletal muscle is one of the major sites responsible for glucose clearance and utilization in the body, exercise-induced glucose uptake in skeletal muscle is a convenient and straightforward method to lower blood glucose level and improve insulin sensitivity (Baron et al. 1988). Hepatic gluconeogenesis is another major contributor for hyperglycemia, and interventions that inhibit gluconeogenesis could accordingly be antidiabetic (Magnusson et al. 1992). In addition, circulating fatty acids are negatively associated with insulin-dependent glucose uptake, providing one more target to develop antidiabetic therapies (Boden & Shulman 2002). Exercise is able to reduce hyperglycemia, suppress de novo glucose synthesis, and increase the uptake and metabolism of fatty acids, removing them from circulation. Accordingly, when evaluating exercise mimetics as potential therapies for T2D, we discuss three separate therapeutic strategies: reducing plasma glucose levels, suppressing gluconeogenesis, and sequestering/oxidizing fatty acids that promote insulin resistance. The safety, specificity, and strategies for therapeutic delivery for each exercise mimetic will also be considered.
PPARδ: using GW501516 to promote oxidative metabolism in muscle
The PPAR family of nuclear receptors has long been appreciated for its role in regulating lipid metabolism and energetic homeostasis by their direct control of metabolic gene expression (Schoonjans et al. 1996). Mechanistically, PPARs operate as ligand-inducible transcription factors constitutively bound to consensus response elements on chromatin in a heterodimer with the retinoid X receptors (RXRs) (Barish et al. 2006). PPARδ was one of the first nuclear receptors to garner attention as a potential mediator of exercise given its importance in mitochondrial energy metabolism in skeletal muscle (Barish et al. 2006). Transgenic mice overexpressing a constitutively active form of PPARδ were shown to have a pro-endurance oxidative fiber-type shift with induced mitochondrial biogenesis in skeletal muscle. Therefore, PPARδ ligands naturally surfaced as putative exercise mimetics (Wang et al. 2003). Originally developed as a drug to treat hyperlipidemia (Oliver et al. 2001), the PPARδ-specific ligand GW501516 has been studied and reviewed extensively as an exercise mimetic since it was first demonstrated to synergistically promote endurance with exercise training in mice (Dressel et al. 2003, Narkar et al. 2008). At present, GW501516 has demonstrated some promise in a handful of phase 1 and phase 2 clinical trials for metabolic disorders such as hypercholesterolemia and dyslipidemia with no known side effects in humans, but has yet to move past this stage of study (Olson et al. 2012, Ooi et al. 2011). However, GW501516 was almost immediately and widely used as a doping agent by athletes after its discovery as a potential exercise mimetic, and has subsequently been banned by the World Anti-Doping Agency (Thevis et al. 2009). This fact is somewhat disconcerting considering that GW501516, in a similar manner to compounds that activate PPARα, has been reported to promote carcinogenesis in some animal models (Wang et al. 2006). GW501516 has also been linked to a decrease in bone density in ovariectomized rats, similar to side effects observed with PPARγ agonists (Mosti et al. 2014). In addition, GW501516 can potentiate liver fibrosis in response to CCl4-induced injury through a pro-proliferative mechanism (Kostadinova et al. 2012). Despite the known side effects, GW501516 still presents as an attractive antidiabetic compound given its profound effects on promoting oxidative metabolism. While oral administration of GW501516 might not be desirable due to its aforementioned side effects, targeted administration of GW501516 to muscle or elsewhere could provide an interesting alternative. A recent example of this strategy used topical application of polymer-encapsulated GW501516 to successfully promote healing of diabetic wounds by reducing oxidative stress in the wound microenvironment (Wang et al. 2015). Future studies, including additional animal studies carefully focusing on the tissue-specific effects of GW501516, would be necessary to establish the utility of this compound as a potential efficacious treatment for diabetes. Alternatively, the development of other PPARδ ligands with more exercise-specific effects could circumvent the undesirable side effects of GW501516.
PPARα: targeting the liver to promote metabolic fitness through FGF21
In a way similar to PPARδ, PPARα also regulates the expression of genes that control oxidative metabolism and lipid homeostasis. PPARα has several known endogenous ligands, most of which are fatty acids that can originate from dietary sources, lipolysis of lipid storage in adipose tissues, or de novo lipogenesis (Dreyer et al. 1993). While PPARδ is responsible for regulating its target genes most critically in skeletal muscle, PPARα functions in the liver to adapt to fluctuations in metabolic homeostasis (Contreras et al. 2013). For example, caloric restriction can result in lipolysis of white adipose tissue, liberating fatty acids that activate PPARα in the liver. Consequently, ligand-activated PPARα can induce the expression of its endocrine hormone-target genes that regulate adaptive changes in other tissues (Kersten et al. 1999). As this fasting response closely resembles metabolic improvements observed with exercise training, could compounds that target PPARα be used as exercise mimetics to treat diabetes?
Given the strong link between PPARα activity and metabolic fitness, recent research efforts have also focused on PPARα-target genes that exert its beneficial effects. One such candidate is the endocrine hormone fibroblast growth factor 21 (FGF21), which is produced and secreted by the liver in response to metabolic stress such as fasting (Inagaki et al. 2007, Lundasen et al. 2007). Acute bouts of exercise are able to induce hepatic FGF21 expression and increase circulating FGF21 levels as well (Cuevas-Ramos et al. 2012). Peripherally, FGF21 promotes a starvation-like state, and can stimulate glucose uptake and fatty acid oxidation in metabolic tissues such as muscle and fat (Potthoff et al. 2009, Mashili et al. 2011). Transgenic mice overexpressing Fgf21 in the liver as well as mice administered with supra-physiologic doses of FGF21 have significantly improved insulin sensitivity and resistance to metabolic syndrome (Kharitonenkov & Larsen 2011, Zhang et al. 2012b). Accordingly, FGF21 has been pursued as a potential therapy for metabolic diseases, but off-target effects such as those resulting in bone loss (Wei et al. 2012) have presented an obstacle. Current research efforts are instead directed toward the development of modified FGF21 variants that lack deleterious side effects. Recent studies have used these variants to improve metabolic homeostasis in diabetic monkeys as well as in a clinical trial involving obese human patients (Adams et al. 2013, Gaich et al. 2013). Strategies aimed at inducing FGF21 natively through a physiological metabolic stress while simultaneously circumventing the undesirable side effects of PPARα activation could also be potentially effective antidiabetic therapies (Wu et al. 2011, Bookout et al. 2013).
PPARγ: new mechanisms for generating insulin-sensitizing adipokines
PPARγ has long been a target for developing therapies for metabolic diseases, and the PPARγ-activating thiazolidinedione (TZD) class of drugs have been prolific antidiabetics since the early 1990s (Spiegelman 1998). PPARγ is essential for the development of adipose tissue, and regulates the expression of lipid metabolism genes as well as adipokines with critical metabolic functions such as adiponectin (Berger et al. 2005). Indeed, energetic stressors such as exercise and fasting can modulate PPARγ activity and the expression of its target genes in adipose tissue, highlighting PPARγ as a potential target for developing novel exercise mimetics (Vidal-Puig et al. 1996, Butcher et al. 2008). Even though the efficacy of PPARγ ligands in treating T2D has been firmly established, the precise mechanisms through which they function are still under investigation. Activation of PPARγ by TZDs is generally believed to enhance adipocyte development and lipid handling which results in increased absorption of circulating fatty acids into adipose tissue and promotes insulin resistance (Lehrke & Lazar 2005). Recently, TZDs were found to inhibit phosphorylation on the S273 residue of PPARγ by cyclin-dependent kinase 5 (CDK5), causing a dysregulated expression pattern of PPARγ-target genes in white adipose tissue indicative of obesity (Choi et al. 2010). The phosphorylated S273 can be bound by thyroid hormone receptor-associated protein 3 (THRAP3), which is essential for mediating PPARγ activity in obesogenic states (Choi et al. 2014a). This paradigm has already been explored as a potential therapeutic target for T2D using the nonagonist PPARγ ligand UHC1, which exclusively prevents the phosphorylation of S273 on PPARγ. As a result, UHC1 treatment not only improved insulin sensitivity but also reduced diet-induced obesity, which is quite different from the TZDs (Choi et al. 2014b). In addition to providing mechanistic insight into how TZDs and PPARγ are involved in the progression of diabetes, these studies also implicate THRAP3 and CDK5 as prospective antidiabetic targets as well.
In addition to its role in sequestering lipids that promote insulin resistance, PPARγ also controls the expression of key adipokines that regulate metabolic homeostasis. For example, adiponectin, a PPARγ-target gene produced and released from white adipose tissue, is able to suppress hepatic gluconeogenesis, activate glucose uptake in peripheral tissues, increase lipid catabolism, and promote weight loss (Yamauchi et al. 2001). Interestingly, adipose-derived adiponectin was recently shown to relay the FGF21-mediated systemic improvements in metabolic fitness, proposing a coordinated mechanism by which activation of PPARα in liver and PPARδ in fat produce an exercise-like metabolic improvement (Holland et al. 2013, Lin et al. 2013). Another adipokine, fibroblast growth factor 1 (FGF1), has also been identified as an adipose-specific PPARδ-target gene important for adipocyte remodeling and differentiation (Jonker et al. 2012). Accordingly, Fgf1-knockout mice are unable to maintain the plasticity of adipose tissues when challenged with a high-fat dietary stress (Jonker et al. 2012). Although physiological FGF1 functions predominantly in an autocrine manner due to its high affinity for cell surface heparan sulfate proteoglycans, ectopic injection of recombinant FGF1 rapidly lowered glucose levels by 50%, suppressed hepatic glucose production, and improved insulin sensitivity in obese diabetic mice, with the effects sustained for approximately 2 weeks (Suh et al. 2014). Such metabolic effects of FGF1 are independent of its mitogenic growth hormone-like effects since a nonmitogenic form of FGF1 can still induce similar effects (Suh et al. 2014). Comprehensively, these studies propose the therapeutic use of PPARδ-regulated adipokines to improve systemic metabolic homeostasis.
PGC1α: promoting thermogenic metabolism in brown and beige fat
PPARδ is also essential for the development and function of brown adipose tissue (BAT), a mitochondrially dense and highly metabolic fat tissue responsible for adaptive thermogenesis (Cannon & Nedergaard 2004). When stimulated by cold challenge and adrenergic signaling, BAT can rapidly uptake and burn glucose to generate heat through uncoupled mitochondrial oxidative phosphorylation. Induction of thermogenesis in BAT is directly mediated by PPAR gamma coactivator 1 alpha (PGC1α) (Wu et al. 1999). PGC1α is also highly induced in skeletal muscle by exercise, where it activates nuclear receptors such as the PPARs and estrogen-related receptors (ERRs) to induce genes that are involved in mitochondrial energy expenditure, fatty acid oxidation, and glucose uptake (Baar et al. 2002, Finck & Kelly 2006). Therefore, PGC1α has been an attractive target for antidiabetic therapies aiming to improve metabolic fitness by inducing energy expenditure, and has been extensively studied and reviewed as a putative target for exercise mimetics in fat and muscle (Lin et al. 2005).
In the last few years, several studies have highlighted the potential to use PGC1α-dependent pathways to ‘brown’ subcutaneous white fat pads to create ‘beige’ fat that expresses genes specific for brown fat function and has increased mitochondrial energy expenditure and increased uptake of glucose and lipids (Harms & Seale 2013). Mechanistically, how can browning of white fat be achieved? TZD treatment has been linked to browning, and TZD binding to PPARγ facilitates the direct interaction between PPARγ and the deacetylase sirtuin 1 (SIRT1). When deacetylated by SIRT1, PPARγ induces the expression of genes that mediate thermogenesis in white fat (Qiang et al. 2012). Accordingly, a SIRT1 gain-of-function model resulted in a similar browning effect as observed in TZD treatment, which significantly improved insulin sensitivity (Qiang et al. 2012). Browning has also been recently associated with inflammation, with macrophages recruited to white fat during cold challenge facilitating its transition to the beige state (Qiu et al. 2014). IL4 treatment alone was also sufficient to increase the amount of beige fat and subsequently reduce the symptoms of obesity in mice (Qiu et al. 2014). Metabolic endocrine hormones, including FGF21, have also been closely associated with browning in mice and humans, but conflicting evidence exists as to their actual specific contribution to the development of beige fat (Lee et al. 2014). One such hormone that has been hotly contested recently in the browning field is irisin, a myokine that is secreted from skeletal muscle by the cleavage of fibronectin type III domain-containing protein 5 (FNDC5). The expression of FNDC5 and secretion of irisin are induced by exercise in skeletal muscle in a PGC1α-dependent manner. In mouse, irisin acts on white adipose tissues and turns on its browning program, which induces energy expenditure and protects against diet-induced obesity and diabetes (Bostrom et al. 2012). Given these findings, recombinant irisin certainly seems like an attractive exercise-mimetic candidate useful for the treatment of T2D. However, mixed findings have been recently published regarding the relevance of irisin to browning in humans. For example, irisin levels in circulation as well as in muscle and fat have been inversely correlated with obesity in human subjects, and human white adipose cell lines have yet to show sensitivity to irisin-mediated browning (Elsen et al. 2014). In addition, emerging evidence suggests that irisin may originate from adipose tissue in addition to muscle (Crujeiras et al. 2014). Further investigation into the molecular mechanisms that govern browning in human and animal models will be required to determine if this process can be efficaciously targeted by exercise mimetics.
AMPK: targeting the central regulator of energy homeostasis
Long considered to be at the nexus of metabolic signaling pathways, AMP-activated protein kinase (AMPK) relays fluctuations in intracellular energy supply to functional cellular energetics by simultaneously activating catabolic and repressing anabolic processes (Hardie 2011). Mechanistically, AMP interacts with AMPK’s gamma subunit, facilitating an activating phosphorylation of the alpha subunit by upstream regulatory kinases such as LKB1. This allows AMPK to phosphorylate its downstream targets, many of which are key participants or regulators of energy metabolism pathways including nuclear receptor cofactors such as PGC1α (Shaw et al. 2005, Jager et al. 2007, Gwinn et al. 2008). Accumulating evidence has established a ‘global’ role for AMPK in relaying energetic stress to physiological changes from a wide array of environmental stimuli such as caloric restriction, exercise, and disease conditions such as T2D (Narkar et al. 2008, Canto & Auwerx 2009). As such, pharmacological modulation of AMPK activity has developed into an attractive and widely studied therapeutic avenue for metabolic disorders.
To date, several AMPK-targeted exercise-mimetic compounds have been designed and exhaustively tested with this aim in mind. At the forefront is AICAR, an adenosine analog whose intracellular metabolite directly interacts with and activates AMPK (Sullivan et al. 1994). AICAR has been shown to induce glucose uptake in skeletal muscle via AMPK-dependent stimulation of the translocation of the cellular glucose transporter GLUT4 onto cell membranes (Russell et al. 1999). When administered to sedentary mice, AICAR alone can significantly enhance exercise performance without training through facilitating an oxidative fiber-type switch and mitochondrial biogenesis in skeletal muscle (Narkar et al. 2008). More recently, AICAR has also been used to recapitulate exercise’s mood-improving effects while simultaneously improving insulin sensitivity in a mouse model of depression and diet-induced obesity (Liu et al. 2014). Despite the known benefits, AICAR has yet to demonstrate its antidiabetic efficacy in humans, due to it being rapidly metabolized once administered, and its marginal oral activity (Musi & Goodyear 2002). In addition, AICAR administration in humans has been linked to lactic acidosis, an undesirable side effect which has shelved other antidiabetic compounds in the past (Musi & Goodyear 2002). Even though these issues have not been resolved to date, AICAR still has potential and continues to be pursued as a possible antidiabetic agent.
Metformin, a drug of the biguanide class known to function in an AMPK-dependent manner, is one of the most widely used antidiabetic drugs on the market today (Zhou et al. 2001, Knowler et al. 2002). Despite the broad usage of metformin to this end due to its efficacious, if transient, ability to improve insulin sensitivity, the precise mechanism by which metformin exerts its effects is imperfectly understood (Luengo et al. 2014). One proposed mechanism for metformin is as an inhibitor of the mitochondrial electron transport chain (ETC): by interacting with the ETC directly, metformin disrupts the normal process of cellular ATP generation, creating cellular energy deficit (Andrzejewski et al. 2014), which in turn induces mitochondrial energy metabolism by activating AMPK and its subsequent downstream targets (Zhou et al. 2001). Recently metformin has also been linked to bile acid homeostasis in liver through its activation of AMPK. Upon activation, AMPK directly phosphorylates and activates the nuclear receptor farnesoid X receptor (FXR) in the liver, promoting metabolic homeostasis (Lien et al. 2014). Interestingly, structural studies have also suggested that metformin might interact directly with AMPK’s gamma subunit in a manner similar to AMP (Zhang et al. 2012a). Recent evidence, however, has proposed alternative mechanisms for metformin’s action. For example, metformin was found to directly inhibit the mitochondrial enzyme glycerophosphate dehydrogenase, which is involved in the gluconeogenic pathway in liver (Madiraju et al. 2014). This inhibition disrupted the redox-sensitive lactate-to-pyruvate ratio, resulting in suppressed hepatic gluconeogenesis (Madiraju et al. 2014). Similar phenotypes were also observed in mice deficient for glycerophosphate dehydrogenase (Madiraju et al. 2014). These findings are supported by independent studies demonstrating the ability of metformin to inhibit hepatic gluconeogenesis in an AMPK-independent manner (Foretz et al. 2010). While precise mechanism of action of metformin remains muddled, the compound is still highly relevant for treating metabolic disorders such as T2D, which is likely linked to some interaction with an AMPK-dependent pathway.
SIRT1: relaying mitochondrial redox states to metabolic improvements
Cellular energetic state is highly associated with its oxidation–reduction (redox) state through the coupling of multiple redox nodes with mitochondrial energy metabolism. One of the key redox nodes is that of NAD+/NADH, which are critical cofactors that transport electrons during mitochondrial oxidative phosphorylation and function as coenzymes in key metabolic reactions. NAD+ has also been proposed to function as a cofactor for the deacetylase sirtuin 1 (SIRT1), which deacetylates and activates PGC1a, promoting mitochondrial biogenesis and energy metabolism in a way similar to exercise (Rodgers et al. 2005). Moreover, AMPK activation elevates the intracellular NAD+/NADH ratio and induces the activity of SIRT1 to activate PGC1a, which mediates the energetic functions of AMPK on top of its direct phosphorylation of PGC1a (Canto et al. 2009). Accordingly, drugs that impact the NAD+/NADH ratio or target SIRT1 directly have the potential to create exercise-like effects. Recent studies have explored these strategies, using compounds in this manner to increase oxidative metabolism and combat diet-induced obesity in mice. For example, supplementing mice with the NAD+ precursor nicotinamide riboside increased intracellular NAD+ levels and enhanced mitochondrial function in skeletal muscle and BAT, comprehensively resulting in improved exercise performance (Canto et al. 2012). Similarly, inhibition of the NAD+-consuming DNA repair enzyme poly (ADP-ribose) polymerase 1 (PARP1) conferred resistance to diet-induced metabolic defects through improvements in mitochondrial function and oxidative metabolism in skeletal muscle (Pirinen et al. 2014). Interestingly, genetic deletion of PARP1 or treatment with PARP inhibitors was able to correct the phenotype of mice with dysfunctional synthesis of cytochrome c, a model of mitochondrial disease (Cerutti et al. 2014). Analogously, the administration of nicotinamide riboside to the Twinkle mitochondrial DNA deletor mouse model of mitochondrial disease increased mitochondrial biogenesis in skeletal muscle and blunted the progression of mitochondrial myopathy (Khan et al. 2014). Collectively, compounds that can be used to modulate the cellular redox state by increasing the NAD+/NADH ratio can create an exercise-like, PGC1a-dependent induction of mitochondrial and metabolic fitness, which might be useful for combating obesity and T2D.
How else might the SIRT1–PGC1a pathway be exploited to create exercise-like effects? Resveratrol, a naturally occurring polyphenol produced by grapes, is a well-established activator of SIRT1 that can promote mitochondrial function in muscle, increase exercise endurance, and is also linked to longevity (Lagouge et al. 2006). Subsequently, resveratrol has been proposed to combat diseases ranging from cardiac dysfunction to cancer through activation of SIRT1, although its exact mechanism of action is not known (Baur & Sinclair 2006). Does resveratrol have potential to be used as an exercise mimetic to efficaciously treat diabetes? Resveratrol has undergone a few recent clinical trials to address this question. One trial revealed that administering resveratrol to 10 obese type 2 diabetic males induced the expression of both AMPK and SIRT1 in skeletal muscle, coupled with an increase in resting metabolic rate (Goh et al. 2014). Another trial demonstrated that after 6 months of resveratrol treatment, patients receiving the compound had approximately 10% higher levels of circulating adiponectin, coupled with reduced expression of inflammatory markers (Tome-Carneiro et al. 2013). These results suggest that resveratrol treatment might exert beneficial effects on white adipose tissue, potentially mediated through PPARγ. Unfortunately, another recent clinical trial administering high doses of resveratrol to 24 obese male subjects for 4weeks did not show any improvements in insulin sensitivity, glucose homeostasis, or oxidative metabolism (Poulsen et al. 2013). Resveratrol treatment also appeared to suppress exercise-dependent improvements in aerobic respiration in a trial of 27 inactive aged men (Gliemann et al. 2013). Although conflicting clinical evidence exists as to the efficacy of resveratrol to treat diabetes, the compound unquestionably highlights the promise of SIRT1 as a putative antidiabetic target.
Conclusions and perspectives
The push to develop novel drugs to treat diabetes has never been stronger in the metabolism field, and AMPK/nuclear receptor-regulated pathways continue to remain in the limelight with regard to artificially recapitulating the benefits of exercise. The specific molecular mechanisms dictating how these exercise mimetics work are just beginning to emerge, despite many of these compounds being used to combat diabetes for more than a decade (Fig. 1). Future studies aimed at fleshing out a concrete link between exercise, AMPK, and nuclear receptors, and improvements in metabolic homeostasis will facilitate the development of new exercise mimetics with improved tissue specificity, increased stability, and minimal side effects. Given the amount of recent findings that critically advance our understanding of these drugs, we believe that an exercise mimetic capable of efficaciously treating T2D should be in our near future.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
M E is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology. This work was supported by U.S. National Institutes of Health grants (DK057978, DK090962, HL088093, HL105278, CA014195 and ES010337), the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust (#2012-PG-MED002), Ipsen/Biomeasure, and the Ellison Medical Foundation.
The authors thank L Ong and C Brondos for administrative assistance.
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