Featured Articles

Volume 6 | No. 1 | January 2017

A Critical Role for ChREBP-Mediated FGF21 Secretion in Hepatic Fructose MetabolismFructose, but not glucose, ingestion acutely and robustly activates hepatic Carbohydrate Responsive-Element Binding Protein (ChREBP), a key carbohydrate sensing transcription factor. Fibroblast growth factor 21 (FGF21) is a metabolic hormone synthesized by multiple tissues and released into circulation largely by the liver. Fisher and colleagues show that the acute FGF21 response to fructose ingestion observed in humans is conserved in mice. Furthermore, using ChREBP KO mice and FGF21 KO mice, they demonstrate that ChREBP is essential for fructose-induced increases in circulating FGF21. Moreover, they show that FGF21 is required for a normal hepatic metabolic response to fructose consumption and that the absence of FGF21 leads to liver disease in mice on high-fructose diets.

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Circulating FGF21 is potently induced by overfeeding of carbohydratesThe hormone fibroblast growth factor 21 (FGF21) has received increasing interest due to its role in the regulation of energy homeostasis and its potential antidiabetic and lipid-lowering properties. FGF21 holds promise as a therapeutic target. Lundsgaard et al. evaluate the role of dietary carbohydrates, without restricting protein intake, in the regulation of circulating FGF21. For this purpose, they performed a controlled randomized three-day cross-over dietary intervention study in healthy men. Short term overfeeding of carbohydrates revealed a paramount and remarkable stimulating effect on FGF21 secretion. In contrast, energy excess per se, induced by a hypercaloric fat-rich diet, did not induce a detectable increase in circulating FGF21. This suggests that FGF21 secretion provides a mechanism for peripheral disposal of the carbohydrate load.

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Deletion of Histone Deacetylase 3 in Beta Cells Improves Glucose ToleranceHistone deacetylase 3 (HDAC3) functions as part of multi-protein complexes that deacetylate histone tails, modifying chromatin structure and resulting in gene repression. Remsberg et al. deleted HDAC3 in beta cells of adult mice and demonstrated that HDAC3 in beta cells regulates insulin secretion and glucose metabolism. They identified several target genes that may in combination act to increase glucose-stimulated insulin secretion in vivo.

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Interaction of iron homeostasis with glucose metabolismDifferent iron phenotypes such as obesity-related iron deficiency and iron overload have been observed in association with obesity. A high serum ferritin concentration has been identified as a risk factor for the development of diabetes. Felder, Aigner, and colleagues confirm that high serum ferritin concentrations are linked to impaired glucose homeostasis. Their study identifies novel associations of iron excess with distinct subsets of phosphatidylcholines as well as a pathway involving sarcosine and citrulline. These metabolic pathways may be involved in iron-induced augmentation of insulin resistance.

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Fermentable carbohydrate to increase satietyThe resident intestinal microbiota plays an important role in determining susceptibility to obesity. This is partly due to the production of physiologically active metabolites during the process of microbial fermentation. To determine if the beneficial metabolic effects of fermentable carbohydrate are mediated by free fatty acid receptor 2 signaling, Brooks, Viardot et al. used mice with targeted deletion of this receptor. They demonstrate that this receptor is essential for mediating inulin’s ability to reduce food intake and protect against diet-induced obesity.

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Intestinal invalidation of GLUT2 delays tissue distribution of glucose The glucose transporter GLUT2 facilitates the passage of dietary sugars towards the bloodstream. Schmitt and colleagues generated an inducible model of GLUT2 invalidation in intestinal epithelial cells. They revealed unexpected functions for GLUT2 in regulating gut homeostasis such as modulating enteroendocrine L-cell density, microvillus length, gut permeability, and inflammation. Therefore, specifically blocking intestinal GLUT2 activity using drugs could be a strategy to protect against weight gain and metabolic perturbations.

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IP6K1 deletion enhances temperature modulated energy expenditure IP6 kinases (IP6Ks) regulate cell metabolism and survival. Mice with deletion of IP6K1 are protected from diet induced obesity (DIO). Zhu and colleagues determine effects of global IP6K1 deletion on body weight and energy expenditure at various diet and temperature conditions. Deletion of global IP6K1 dramatically protects mice from DIO and insulin resistance due to increased energy expenditure, which is not entirely dependent on environmental temperature condition.

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DNA promoter methylation and transcriptome analysis unravels novel candidate genes for obesityIn order to gain insight into adipose tissue specific principles of epigenetic gene regulation and to elucidate how the provoke the well-known physiological differences between subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT), Keller et al. studied DNA promoter methylation levels in SAT and OVAT. They confirmed obesity and fat distribution candidate genes and identified genes which have been previously unrecognized in the pathophysiology of obesity. Their data suggest that DNA promoter methylation of specific genes is directly associated with BMI and obesity and clearly demonstrates adipose tissue depot specific differences.

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Conserved Function of the Long Noncoding RNA Blnc1 in Brown Adipocyte Differentiation Brown fat is present in adult humans and appears highly responsive to physiological and environmental stimuli. Mi and colleagues previously identified Blnc1 as a highly inducible long noncoding RNA that promotes brown and beige adipocyte differentiation. In the present study, they demonstrate that Blnc1 is highly conserved and drives the induction of a thermogenic gene program during brown adipocyte differentiation. In addition, both mouse and human Blnc1 physically interact with the RNA-binding protein hnRNPU and the transcription factor EBF2 to form a ribonucleoprotein complex that regulates the transcription of genes involved in thermogenesis.

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Development of White Adipose Tissue is Dependent on Zfp423 Zfp423 is a multi zinc-finger transcription factor expressed in preadipocytes and mature adipocytes in vivo. Shao et al. reveal that the loss of adipose Zfp423 during fetal white adipose tissue development leads to arrested terminal differentiation of inguinal white adipocytes by the time of birth. Upon high-fat diet feeding as adults, Zfp423-deficient animals become obese but exhibit a metabolic phenotype similar to that of partial lipodystrophy. This developmental defect can be rescued by administering rosiglitazone. These data define Zfp423 as a critical regulator of adipose development and illustrate the systemic metabolic consequences of pathological subcutaneous adipose tissue expansion in obesity.

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Insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activationGPS2 plays an important anti-inflammatory role in adipose tissue and macrophages and is required for the expression of genes regulating cholesterol and triglyceride metabolism. Cederquist et al. demonstrate that GPS2 is required for restricting the activation of the insulin signaling pathway through inhibition of Ubc13-mediated ubiquitination of the kinase AKT. Insulin-mediated ubiquitination of AKT, via Ubc13-mediated synthesis of K63 ubiquitin chains, is an unexpected, critical step for the activation of downstream signaling events. GPS2 deletion in mice adipose tissue results in constitutive ubiquitination and activation of AKT, leading to disrupted lipid metabolism and increased adiposity but also to elevated adiponectin levels.

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Celastrol Ameliorates Liver Metabolic Damage through Sirt1 Celastrol was recently identified as a potential novel treatment for obesity. Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. In this study, Zhang et al. report that Celastrol ameliorates NAFLD by decreasing lipid synthesis and improving the anti-oxidative and anti-inflammatory status. Celastrol aggravates liver metabolic damage in liver specific Silent mating type information regulation 2 homolog 1 (Sirt1)-deficient mice fed a high fat diet through inhibiting the phosphorylation of AMP-activated protein kinase a and boosting the translocation of nuclear factor kappa B into the nucleus, thereby increasing expression of Srebp-1c and the mRNA levels of liver proinflammatory cytokines.

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The neuropeptide TLQP-21 opposes obesity Cero and colleagues identified a novel lipolytic and anti-obesity mechanism exerted by TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic). Their study significantly advances the mechanistic understanding of lipolysis by the identification of a calcium-regulated pathway mediated by TLQP-21 and C3aR1. This pathway could be targeted to safely treat obesity and reverse catecholamine resistance, bypassing the side effects associated with the use of Gs-coupled receptor agonists and other potent prolipolytic mechanisms, which often lead to the development of insulin resistance and other metabolic diseases.

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Endospanin 1 affects oppositely body weight regulation and glucose homeostasis Endospanin1 (Endo1), a small four-transmembrane protein, behaves as a negative regulator of leptin receptor function. Vauthier, Roujeau et al. investigated whether silencing Endo1 in the hypothalamic arcuate nucleus (ARC), associated with reduced body weight, could also ameliorate glucose homeostasis accordingly. They reveal that the depletion of Endo1 in the ARC surprisingly worsens glucose homeostasis under conditions of enriched food. Interestingly, at the cellular level, Endo1 silencing has differential effects on leptin signal transduction.

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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.



Marc Reitman
National Institutes of Health (NIH), Bethesda, USA
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