Featured Articles

Volume 6 | No. 6 | June 2017

Four new genes contributing to human insulin secretionType 2 diabetes (T2D) is a complex, multifactorial disorder with an estimated heritability ranging between 40% and 70%. Genome-wide association studies (GWAS) have shown that common T2D is highly polygenic. Ndiaye, Ortalli, Canouil et al. performed a comprehensive expression study of candidate T2D susceptibility genes closest to all GWAS-identified T2D single nucleotide polymorphisms (SNPs) in a large panel of human organs, tissues, and cells, followed by the functional analysis of the knockdown of these genes in human pancreatic beta-cell lines. They found that the expression of tested candidate T2D susceptibility genes was significantly and specifically enriched in pancreatic beta cells, and they report functional evidence for a role in insulin secretion of four T2D susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6).

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FGF21 does not require AMPK or the phosphorylation of ACC to mediate improvements in glucose homeostasisFibroblast growth factor 21 (FGF21) is an endocrine factor that exerts potent anti-obesity and anti-diabetic effects. FGF21 administration activates the energy sensor AMP-activated protein kinase (AMPK) to promote mitochondrial biogenesis and greater mitochondrial oxidative function. Mottillo, Desjardin et al. demonstrate that unlike metformin, the beneficial metabolic effects of pharmacological administration of FGF21 on energy metabolism, fuel selection, body weight, insulin tolerance, and liver lipids are not mediated through adipocyte AMPK or the AMPK/ACC pathway.

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Vaspin expression is increased after obesogenic diets and cold exposureVisceral adipose tissue-derived serine protease inhibitor (vaspin) has anti-diabetic and anti-obesogenic properties. Weiner et al. investigated the effects of brown adipose tissue (BAT) activating physiological stimuli, such as high caloric diets or cold exposure, on vaspin gene expression and secretion in mice. They report a novel BAT-specific regulation of vaspin gene expression upon BAT activating physiological stimuli in vivo with epigenetic changes. Their data suggest that vaspin gene expression is specifically increased in activated BAT, indicating functional relevance and potentially beneficial effects of vaspin on BAT function.

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Rasal2 deficiency reduces adipogenesis and obesity-related disordersRas proteins are known to play fundamental roles in cell growth and proliferation. Rasal2 (Ras protein activator like 2) is a Ras-GTPase-activating protein (Ras-GAP). A single nucleotide polymorphism of its gene is associated with increased body mass index. Zhu et al. demonstrate that Rasal2 deficiency leads to lower adiposity and an increase in resistance to HFD-induced obesity. In addition, Rasal2 deficiency ameliorates numerous obesity-related metabolic disorders, including glucose intolerance, insulin resistance, and hepatic steatosis. These findings implicate Rasal2 as a potential therapeutic target to combat obesity-related disorders.

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Glucagon-like peptide-2 promotes gallbladder refillingThe physiological cycle of gallbladder (GB) filling and emptying dictates the flow of the bile into the intestine, enabling the enterohepatic circulation of bile acids (BA). Unexpectedly, reports of gallbladder disease have been associated with the use of both glucagon-like peptide-1 receptor (GLP-1R) and GLP-2R agonists and after bariatric surgery. To explore whether GLP-1 and/or GLP-2 influence GB physiology, Yusta et al. have studied the acute actions of these peptides on GB activity in mice. They delineate a Tgr5-independent, GLP-2R-dependent pathway that counteracts the actions of cholecystokinin and promotes GB filling.

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Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant miceEndogenous circadian clocks are based on transcriptional-translational feedback loops built from a set of clock genes/proteins including the transcription factor circadian locomotor output cycles kaput (CLOCK). Mice carrying a dominant negative mutation in the gene encoding CLOCK are overweight and, under high-fat diet (HFD) conditions, develop symptoms of the metabolic syndrome. Meyer-Kovac, Kolbe, et al. show that liver gene therapy may partially restore metabolic responses to HFD in circadian Clock mutant mice, indicating an important role of liver clock function in energy homeostasis and appetite regulation.

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Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cellsThe transcription factors (TFs) forkhead box protein A2 (Foxa2) and pancreatic and duodenal homeobox 1 (Pdx1) share several important functions, such as regulation of insulin production and modulation of the function of other transcription factors. In diabetic models, the levels of both TFs appear to be reduced in dedifferentiated β-cells, suggesting that these TFs act alone or in combination to induce or maintain β-cell identity. Bastidas-Ponce and colleagues generated a reporter mouse line expressing TF fusion proteins that develops hyperglycemia postnatally. This phenotype occurs due to the failure to generate and preserve mature β-cells. The reduction in Pdx1 levels along with the possible destruction of the cooperative function of this TF with Foxa2 are the responsible mechanisms underlying loss of β-cell maturation, identity, and function.

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NNT reverse mode of operation mediates glucose control of mitochondrial redox state The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells depends on the increased flux of glucose metabolism through glycolysis and the mitochondrial Krebs cycle. The mitochondrial NAD(P)H and glutathione redox state may play a role in GSIS. Mitochondrial NADPH is typically produced by Nicotinamide nucleotide transhydrogenase (NNT) and some other enzymes. Santos, Muller et al. show that NNT mediates the effects of glucose on islet NADPH and mitochondrial glutathione redox state, but, contrary to current views on NNT in β-cells, it does so by reducing its reverse mode of operation, which consumes NADPH, from non-stimulating to stimulating glucose concentrations.

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Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation The receptors for the endogenous lipid signaling molecule prostaglandin E2 (PGE2), called E-Prostanoid Receptor 1-4 (EP1-4), are expressed in rodent and human islets. Little is known about the role of PGE2 and the EP receptors in regulating β-cell proliferation and survival, which can affect β-cell mass dynamics. Carboneau and colleagues identify EP3 and EP4 as novel regulators of β-cell proliferation and survival in mouse and human islets ex vivo. Their data suggest that inhibition of EP3 and/or activation of EP4 may improve outcomes in the settings of obesity and T2D by enhancing β-cell proliferation, survival and glucose stimulation of insulin secretion.

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Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors developmentThe “thrifty phenotype hypothesis” proposes that poor fetal and infant growth increases the risk of type 2 diabetes and metabolic syndrome. Although the mechanisms are not completely clear, nutrient availability is essential for proper cell growth and survival, and nutritional insults early in life are believed to have a deleterious effect on the developmental program of the pancreas and ultimately impair islet function. Elghazi et al. determine the effect of different nutrients and growth factors on the control of embryonic pancreatic growth and development. In addition, they identify an important role of mTOR signaling on these processes.

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Insulin controls food intake and energy balance via NPY neurons Insulin plays a critical role in the short- and long-term control of glucose and energy homeostasis. While the functions of insulin signaling in peripheral tissues have been studied extensively, its actions in the central nervous system are far less understood. Loh et al. generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and tested the consequences on energy homeostasis. Their results suggest that insulin signaling in NPY neurons is required for maintaining normal energy homeostasis and that an impaired insulin-NPY signaling pathway may contribute to the development of metabolic diseases.

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Restoration of Lepr in β cells does not prevent hyperinsulinemia and hyperglycemiaIn vitro studies have demonstrated that Leptin receptor (Lepr) is expressed in murine and human pancreatic β cells, as well as in β cell lines. Previous studies have attempted to assess whether leptin has a direct action on β cell function, but the results are contradictory. D’souza and Kieffer selectively restored Lepr in pancreatic β cells of Lepr knockout mice. This did not prevent the development of hyperinsulinemia and β cell expansion. These findings suggest that leptin receptor signaling directly in β cells does not regulate β cell function. The authors propose that actions of leptin on β cells are secondary to action of leptin signaling in other tissues.

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Endocannabinoid-dependent disinhibition of orexinergic neuronsOrexin (OX) neurons have been implicated in a variety of functions, including energy balance and food seeking and intake. It was recently demonstrated that chronic leptin deficiency or resistance in ob/ob and in high-fat diet (HFD) fed mice, respectively, causes a morphological switch from predominantly excitatory to predominantly inhibitory innervation of OX neurons. As a consequence, OX neurons of ob/ob and HFD animals are disinhibited and release more OX in target brain area. Becker and colleagues show that the functional excitatory innervation is reduced, although modestly, in ob/ob compared to wild type mice. In ob/ob mice, chronic absence of leptin induces a 2-arachidonoylglycerol (2-AG) mediated functional disinhibition of OX neurons. This helps explain the increase of OX production and, consequently, the excessive food intake of ob/ob mice.

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FGF21 resistance is not mediated by downregulation of beta-klotho expressionFibroblast growth factor 21 (FGF21) is an important regulator of nutrient and energy homeostasis. FGF21 signals to target cells through a receptor complex consisting of the FGF receptor (FGFR), FGFR1c, and a co-receptor termed β-klotho. Elevated FGF21 levels during obesity have led to the postulation that obesity is a “FGF21-resistant state”. Markan and colleagues show that while β-klotho expression in white adipose tissue is markedly reduced during diet-induced obesity, maintenance of β-klotho expression in adipose tissue does not increase FGF21 sensitivity or significantly improve metabolic parameters during obesity.

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β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 Brown adipose tissue (BAT) can combust (surplus) energy through uncoupled respiration mediated by uncoupling protein 1 (UCP1). A strong pattern of BAT glucose uptake is seen in positron emission scanning tomography (PET) scans after activation of β3-adrenergic receptors. Olsen, Csikasz, and colleagues found that acute β3-adrenergic stimulation induces glucose uptake in BAT independently of the presence and activation of UCP1 and thus independently of thermogenesis. These results demonstrate that acute glucose uptake is a mechanism separate from thermogenesis.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

Watch the most recent interview by clicking the video still. The link "referring article" directs you to this author's publication.



Marjoleine F. Broekema
University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
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