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Volume 11 | May 2018

Adipocyte Xbp1s Overexpression Drives Uridine Production and Reduces Obesity Xbp1s is a transcriptional factor that is elevated in subcutaneous fat tissue from obese human subjects. Under fasting conditions, when there are high levels of lipolysis, pyrimidine biosynthesis in adipocytes is elevated. As a result, plasma uridine concentrations double, which has major implications for temperature regulation and energy expenditure. Deng et al. find that adipocyte overexpression of Xbp1s leads to profound loss of fat mass, and this loss is associated with elevation of uridine in adipose tissue and blood circulation. They demonstrate that Xbp1s triggered fat mass loss relies on pyrimidine biosynthesis. Hence, the stimulation of the adipocyte uridine synthesis pathway is a potential therapeutic target area for the treatment of obesity.

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Epoxygenase inactivation exacerbates metabolic dysfunction resulting from impaired adipogenesisEpoxyeicosatrienoic acids (EET) are synthesized by epoxygenases. The biological effects of EETs are pleiotropic, ranging from anti-inflammatory and cardioprotective actions to a regulatory role in cancer, organ/tissue regeneration, and embryonic hematopoiesis. Olona, Terra et al. find that Cyp2j4, the rat orthologue of human CYP2J2, which codes for an expoxygenase, is essential for maintaining a healthy adipogenesis status. Knockout of Cyp2j4 combined with the metabolic challenges aging or cafeteria diet caused adipocyte dysfunction.

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Loss of GLP-1 signaling reduces BAT thermogenesis and increases adiposityThe intestine and brain both produce glucagon-like peptide-1 (GLP-1), which plays an important role in the control of food intake and glycemia. The dorsomedial nucleus of the hypothalamus (DMH), a key part of the sympathetic control network, expresses GLP-1 receptor (GLP-1R) and is densely innervated by GLP-1 fibers, suggesting a possible role of DMH GLP-1R signaling in sympathetic nervous system regulation. Lee et al. find an important link between hindbrain GLP-1 projections into the DMH and sympathetic regulation of brown adipose tissue thermogenesis and energy balance.

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The Neurochemical Signature of Beige Fat InnervationSubcutaneous white adipose tissue, particularly in the inguinal depot (iWAT) can undergo a process of “beiging” in which thermogenic, mitochondria-rich, UCP1-expressing multilocular cells develop within white adipocytes. However, the neurochemical signals from nerves targeting iWAT that induce this change are unknown. Stefanidis et al. find that there is a significant shift in the gene expression profile in neurons directly innervating iWAT, concomitant with the beiging process, to a signature which is more aligned with that of neurons innervating brown adipose tissue. The most likely candidate to mediate the beiging process is α-melanocyte stimulating hormone.

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BAT derived ANGPTL4 controls glucose and lipid metabolism and thermogenesisBrown adipose tissue (BAT) is fueled by fatty acids provided by lipoprotein lipase (LPL). One of the important modulators of LPL activity is angiopoietin-like 4 (ANGPTL4). Singh et al. generated a novel mouse model lacking ANGPTL4 specifically in BAT (BAT-KO). Their results demonstrate that BAT derived ANGPTL4 is an important regulator of lipoprotein metabolism, glucose homeostasis, and insulin sensitivity. ANGPTL4 deficiency in BAT improves oxidative metabolism and the thermogenic function of brown adipocytes.

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Enterochromaffin 5-HT Cells - a major Target for GLP-1 and Gut Microbial MetabolitesThe enterochromaffin (EC) cell is the most abundant cell type among the enteroendocrine cells and its main secretory product is the biogenic amine serotonin (5-HT). Lund and colleagues characterize the expression of receptors that function as sensors of luminal stimuli in EC cells from the small intestine and the colon. They find that the receptor for the gut hormone glucagon-like peptide-1 (GLP-1) is particularly highly expressed and enriched in EC cells and that GLP-1 efficiently stimulates 5-HT release. Also, they find the colonic EC cells to express a large repertoire of known and proposed sensors of microbial metabolites including several receptors for short chain fatty acids.

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Bile acids are important regulators of appetite- and metabolism-regulating hormones Recent studies have indicated that bile acids (BA), in addition to their well-known role in fat absorption, may stimulate the secretion of a number of appetite- and metabolism-regulating peptide hormones from the gut and pancreas. Kuhre et al. sought to evaluate the rat as a model for BA effects by examining the effects of BAs on the secretion of the most important appetite- and metabolism-regulating hormones. Their study shows that BAs have marked effects on the secretion of these hormones and, therefore, in addition to their role as fat emulsifiers, should be regarded as important regulators of blood glucose and metabolism.

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FGF21 increases after acute alcohol ingestion and sustained binge drinking at OktoberfestIn mice, alcohol increases circulating fibroblast growth factor 21 (FGF21) levels and FGF21 overexpression or continuous infusion reduces alcohol and sweet intake. Søberg, Andersen et al. tested the hypothesis that in humans, alcohol ingestion increases hepatic secretion of FGF21, which then suppresses further alcohol intake. To do this, they assessed plasma FGF21 levels in fasted humans after acute and sub-chronic alcohol ingestion and measured the effects of bolus human FGF21 administration on alcohol preference in mice. They further correlated fasting FGF21 levels with self-reported alcohol-related behaviors, emotional responses, and problems in a cohort of 49 healthy human subjects. Their findings support the notion that FGF21 may be a liver-derived inhibitor of alcohol intake.

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E2F1 promotes gluconeogenesis and contributes to hyperglycemia during diabetesAberrant regulation of hepatic glucose production is a major contributor to the hyperglycemia observed in type 2 diabetes (T2D). The transcription factor E2F1 is essential for controlling liver metabolism, regulating cholesterol uptake and promoting lipid synthesis through transcriptional regulation of key lipogenic enzymes. Giralt, Denechaud et al. demonstrate that E2F1 also contributes to mammalian glucose homeostasis through the control of hepatic glucose production. Their results indicate that E2F1 is critical for inducing hyperglycemia in T2D. This suggests that reducing E2F1 activity could protect against obesity-induced hyperglycemia.

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GHR-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered liver signalingLaron syndrome (LS) is a rare, autosomal recessive, hereditary disorder caused by loss-of-function mutations in the growth hormone receptor (GHR) gene. Although mechanistic studies have been performed in cell lines derived from LS patients and healthy controls, animal models are of pivotal importance for understanding the pathophysiology of LS in vivo. Hinrichs and colleagues developed a GHR-deficient (GHR-KO) pig model and show that it resembles important aspects of LS pathophysiology and features altered activation of signaling cascades in the liver.

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VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat Cognitive function is affected by macronutrient intake, with high fat diets and obesity being particularly deleterious. The central nervous system depends on glucose as its energy substrate, and brain glucose uptake is mediated by the glucose transporter GLUT1. A high fat diet in mice was shown to reduce GLUT1 expression in brain endothelia, leading to cognitive impairment. This reaction was counterbalanced by an increased production of vascular endothelial growth factor (VEGF), which increased GLUT1 expression again. Schüler et al. investigated the response of 92 human mono- and dizygous twins to an acute shift from low fat to high fat diet with respect to serum levels of VEGF and the expression of GLUT1. Their data indicate VEGF as a determining factor linking dietary fat intake to cognitive function in humans.

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Statin Dose Reduction With Complementary Diet Therapy: A Pilot Study Of Personalized MedicineThe first line treatment for cardiovascular disease (CVD) prevention is LDL-cholesterol lowering by statins. A critical issue that undermines CVD prevention is the high prevalence of statin undertreatment due to real or perceived adverse effects. The combination of nutraceuticals with statin treatment could help overcome these limitations. Scolaro and colleagues evaluated the effects of daily consumption of a combined supplementation of omega-3 fatty acids, plant sterols, and polyphenols on biomarkers of inflammation, lipidemia, and oxidative stress in type 2 diabetic patients treated with statins. They then conducted a pilot study to evaluate the effects of statin dose reduction. The results suggest a potential for adding nutraceuticals to statin therapy for primary prevention.

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Computational genome-wide screen connects miRNAs to obesity and type 2 diabetesMiRNAs are small non-coding RNAs which are known to bind to the 3’UTR region of specific mRNAs leading to an altered expression or translation of the corresponding target gene(s). Most miRNAs have hundreds of targets involved in different signaling cascades. Thus, they are potent regulators and suitable candidates in polygenic diseases like obesity or type 2 diabetes (T2D). Gottmann et al. introduce a computational framework miR-QTL-Scan that integrates miRNAs located in quantitative trait loci (QTL), target-prediction tools and databases of experimentally validated targets, transcriptome profiles, and pathway enrichment analysis to identify miRNAs that can be related to obesity and T2D.

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Skeletal muscle O-GlcNAc transferase is important for energy homeostasis and insulin sensitivityProtein modification by O-linked β-D-N-acetylglucosamine (O-GlcNAc) is a post-translational event that has been suggested to serve as an integrated cellular nutrient sensor. Dysregulated O-GlcNAc signaling in skeletal muscle is associated with the development of several metabolic diseases. Shi, Munk and colleagues show that skeletal muscle from type 2 diabetic humans has elevated O-GlcNAcylation levels compared with matched controls. Moreover, they show that knockout of O-GlcNAc transferase (OGT) in skeletal muscle in mice improves whole-body insulin sensitivity and increases energy expenditure.

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NAMPT-mediated NAD+ biosynthesis is indispensable for adipose tissue plasticity and development of obesityThe expression of nicotinamide phosphoribosyltransferase (NAMPT) is associated with obesity in humans. However, divergent patterns of NAMPT association suggest differing depot-specific NAMPT contributions in human fat and make it difficult to assign a positive or negative role of NAMPT in metabolic syndrome. Nørgaard Nielsen, Peics, Ma et al. sought to determine whether NAMPT plays a causal role in adipose tissue dynamics and the development of obesity. Their findings indicate that adipose NAMPT plays an essential role in handling dietary lipid to modulate fat tissue plasticity, food intake, and systemic glucose homeostasis.

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Vertical Sleeve Gastrectomy Corrects Metabolic Perturbations in a Rat Model Bariatric surgery is currently the most effective strategy for weight loss. Vertical sleeve gastrectomy (VSG) is a procedure in which about 80% of the stomach along the greater curvature is removed. It results in sustained weight loss and rapid improvements in glucose and lipid metabolism. However, the mechanism underlying this success is unclear. Wood et al. tested the effects of VSG in a rat model selectively bred for low running capacity. They found that VSG caused weight loss and some metabolic improvements independent of any changes in exercise capacity. However, it seems that basal energy expenditure and fat and carbohydrate oxidation was reduced by VSG making these animals more efficient at storing energy, an effect that would limit weight loss.

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Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2Fibroblast growth factor 23 (FGF23) is a bone-derived hormone which regulates the serum inorganic phosphate (Pi) concentration and vitamin D metabolism. The presence of regulatory feedback loops operating between FGF23 and Pi/vitamin D has been suggested. However, no Pi-receptor or sensor has yet been identified in mammals. Bon and colleagues provide experimental evidence that the Pi transporter PiT2 regulates synthesis and secretion of FGF23 in response to high Pi load. These findings may identify PiT2 as a target for novel therapies to improve the excessive FGF23 secretion in hyperphosphatemic disorders such as chronic kidney disease.

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GPR142 Prompts GLP-1 Release to Improve β Cell FunctionGPR142 is a tryptophan-activated Gαq-coupled receptor with enriched expression in pancreatic islets. Both natural and synthetic ligands for this receptor were shown to enhance glucose-dependent insulin secretion and improve in vivo glucose homeostasis in animals. However, which specific cell types in the pancreatic islet express this receptor and what mechanisms mediate augmented insulin release remains poorly understood. Lin et al. show that in addition to its localization in β cells, GPR142 is measurably expressed in α cells in both human and mouse pancreas. They demonstrate that GPR142 activation stimulates glucagon secretion as well as glucagon-like peptide-1 production and release from the islet. The latter determines GPR142’s insulinotropic, β cell proliferative, and pro-survival effects.

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Overexpression of ST5 has no effect on β-cell proliferation Identifying methods to promote β-cell proliferation, especially in adults, has been an attractive therapeutic strategy for the treatment of diabetes. Suppression of Tumorigenicity 5 (ST5) plays a role in one of the pathways thought to promote cell proliferation. Ou and colleagues tested the hypothesis that overexpression of the long isoform of ST5, an activator of the Ras/ERK pathway, is able to promote adult β-cell proliferation. However, they found that that overexpressing ST5 under both basal metabolic or challenged states is not sufficient to enhance β-cell proliferation.

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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.



Susan Burke
Pennington Biomedical Research Center, Baton Rouge, LA, USA
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