Featured Articles

Volume 12 | June 2018

The role of genetic variation of human metabolism for BMI, mental traits and mental disorders A substantial amount of evidence links obesity with mental health. Genome-wide association studies (GWAS) and meta-analyses (GWAMA) have offered insights into the genetic contributors of BMI and of several categorically defined mental disorders as well as dimensional mental phenotypes. Hebebrand, Peters et al. have now studied loci associated with levels of blood or urine metabolites for their additional association with body mass index (BMI) and several mental traits or disorders. 19 SNPs located in nine independent loci appeared significant when strictly corrected for multiple testing.

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Targeting Hepatic PDKs Restores Insulin Signaling and Mitigates Lipogenesis The mitochondrial pyruvate dehydrogenase complex (PDC), which converts pyruvate to acetyl-CoA, is regulated by pyruvate dehydrogenase kinases (PDKs 1-4) and pyruvate dehydrogenase phosphatases (PDPs). PDKs play a pivotal role in maintaining energy homeostasis and contribute to metabolic flexibility. Wu et al. hypothesized that PDKs1-4 are a pharmacological target for obesity and type 2 diabetes. They tested recently developed novel pan-PDK inhibitors for improved glucose tolerance and reduced hepatic steatosis. Their results show that the liver-specific inhibitor PS10 lowers plasma glucose concentration via reduced hepatic gluconeogenesis.

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Phosphorylation of Beta-3 Adrenergic Receptor Drives Lipolysis Circulating free fatty acid (FFA) levels are predominantly derived from stored triglycerides that are actively broken down through enzymatic lipolysis in white adipose tissue. Signals that promote lipolysis involve activation of the β-adrenergic receptor (βAR). Hong et al. find that in vivo inhibition of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathway alters lipolysis in adipose tissue, by decreasing β3AR phosphorylation at serine 247 and subsequent downstream phosphorylation events that control release of FFA.

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Resveratrol improves ex vivo mitochondrial function in first degree relatives of T2D patientsResveratrol, a polyphenol present in various foods, has been proposed as a promising treatment in the prevention of type 2 diabetes (T2D). In a placebo-controlled, crossover study, de Ligt and colleagues investigated if 30 days of resveratrol supplementation can improve insulin sensitivity and muscle mitochondrial function in males at increased risk of developing T2D. Their results indicate that resveratrol supplementation does not affect insulin sensitivity, substrate utilization, energy expenditure, ectopic fat accumulation, or cardiac function and does not stimulate brown adipose tissue in these subjects. However, the data do support previous findings that low-dose resveratrol supplementation can improve muscle mitochondrial oxidative capacity.

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Antiretroviral therapy potentiates obesity and glucose intoleranceThe advent of antiretroviral therapy (ART) has significantly decreased mortality in HIV-infected patients. However, long-term administration of ART medications is associated with a disproportionate rise in non-AIDS-related mortality. HIV-1 patients often present with cardiovascular diseases, obesity, non-alcoholic fatty liver disease, and type-2 diabetes. Pepin et al. illustrate that ART worsens high-fat diet-induced metabolic derangements and exaggerates diet-induced adiposity. Combined transcriptomic and kinomic analyses of adipose tissue identified a diet-drug synergism that augments pro-inflammatory signaling within adipose tissue consistent with macrophage infiltration.

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Profiling of G Protein-Coupled Receptors in Vagal Afferents G protein-coupled receptors (GPCRs) act as transmembrane molecular sensors of neurotransmitters, hormones, nutrients, and metabolites. Because unmyelinated vagal afferents richly innervate the gastrointestinal mucosa, gut-derived molecules might directly modulate the activity of vagal afferents through GPCRs. However, the distribution of GPCR expression in vagal afferents is largely unknown. Egerod and colleagues determined the expression profile of all GPCRs in the vagal afferents of the mouse using a combination of quantitative PCR (qPCR), RNA sequencing, and double in situ hybridization studies.

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Neuraminidase 1 activates insulin receptor and reverses insulin resistance Neuraminidases catalyze the removal of sialic acid residues from glycan chains of glycoproteins. Mammalian neuraminidase 1 (NEU1) modulates cellular receptors involved in diverse signaling pathways, one of which is the insulin receptor (IR). Fougerat et al. reveal the molecular mechanism by which NEU1 desialylation activates the IR. They also show that acute pharmacological increase of NEU1 activity in insulin target tissues may reverse insulin resistance and glucose intolerance induced in mice by obesity. Thus, selective targeting of NEU1 may represent a novel therapeutic strategy for restoring insulin sensitivity and resolving hyperglycemia associated with type 2 diabetes.

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Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signalingInterleukin (IL)-18 is a cytokine that plays a crucial role in maintaining metabolic homeostasis. IL-18 is both necessary and sufficient for the maintenance of metabolic homeostasis. IL-18 levels are influenced by gender, age, and sex hormones. Lindegaard, Abildgaard and colleagues hypothesized that the presence of female sex hormones could preserve the metabolic phenotype of IL-18R-/- mice. They show that the combination of a lack of IL-18 signaling and female sex hormones, but not IL-18 or female sex hormone per se, leads to systemic insulin resistance and impaired insulin signaling in the liver.

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mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptinReactive oxygen species (ROS) modify the activity of proopiomelanocortin (POMC) expressing neurons of the hypothalamic arcuate nucleus (ARC), which control feeding behavior and peripheral metabolism. Haissaguerre et al. hypothesized that the mammalian target of rapamycin complex 1 (mTORC1) pathway mediates ROS-dependent responses in POMC neurons. Their study reveals that ROS require a functional mTORC1 pathway in POMC neurons to decrease food intake and that increased ROS and mTORC1 activity in POMC neurons are needed in order to observe the appetite suppressant action of leptin.

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The Role of IL-1 in Postprandial FatigueAfter ingesting a large meal, it is common to experience postprandial fatigue. Perception of fatigue has been linked to interleukin-1 (IL-1) - a family of 11 cytokines playing an important role in the initiation and regulation of the inflammatory response. The underlying mechanisms leading to postprandial fatigue are not well understood. Lehrskov et al. studied a cohort of both lean and obese individuals to investigate the role of IL-1 in postprandial fatigue. Their results indicate that IL-1 is at least partly driving postprandial fatigue in both lean and obese individuals.

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Regional differences in brain glucose metabolism Glucose is the main energy substrate for the brain, which accounts for about 20% of whole-body glucose utilization. Glucose is metabolized in cells either by glycolysis or the pentose phosphate pathway (PPP). Though each cell can use glucose for either glycolysis or the PPP, different cell populations favor distinct metabolic pathways. To investigate the regional fate of glucose, Kleinridders, Ferris, Reyzer et al. assessed multiple steps within the glycolytic pathway and PPP using a combination of gene and protein expression, protein activity assays, and imaging mass spectrometry (IMS). They demonstrate that IMS provides a direct measurement of the metabolites generated in these pathways in specific brain regions, including those which are otherwise difficult to assess.

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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
Referring article

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