Featured Articles

Volume 10 | April 2018

NAc inflammation mediates anxiodepressive behavior elicited by saturated dietary fatObesity considerably elevates the odds of developing depression. Obesity in humans and murine models is characterized by a state of chronic low-grade inflammation. Several lines of evidence implicate a neuroimmune etiology in a subset of depressed individuals; thus, persistent immune activation in obesity may give rise to mood impairments. Décarie-Spain, Sharma et al. sought to identify neuroinflammatory responses in the nucleus accumbens (NAc) and determine if they underlie anxiodepressive behavior provoked by diet-induced obesity. They found that a saturated, high fat diet (HFD) enhances systemic inflammation and anxiety-like and despair responses in behavioral tests. Concurrently, the saturated HFD was found to increase the expression of several immune markers in the NAc.

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Rapid sensing of leucine by hypothalamic neuronsDietary proteins strongly influence metabolic health via their effect on appetite, weight gain, and adiposity. Levels of the branched-chain amino acid leucine are likely to represent a physiological signal of protein availability in the control of appetite and metabolism. Appetite-regulating neurons in the arcuate nucleus of the hypothalamus (ARH) are well positioned to sense changes in leucine levels. However, the molecular, neurophysiological, and neurochemical mechanisms involved remain poorly understood. Heeley et al. show that a specialized group of mediobasal hypothalamus (MBH) neurons rapidly respond to physiological changes in extracellular leucine concentrations. This requires the modulation of plasma membrane calcium channels.

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Prolyl carboxypeptidase in AgRP neurons modulates food intake and body weightThe anorectic peptide α-melanocyte stimulating hormone (α-MSH) is a product of the proopiomelanocortin (POMC) gene. Peripheral administration of α-MSH does not reduce food intake, suggesting that α-MSH is rapidly degraded. Prolyl carboxypeptidase (PRCP) is a key enzyme responsible for the degradation of α-MSH. Bruschetta and colleagues provide evidence that PRCP in Neuropeptide Y/Agouti-related peptide neurons modulate melanocortin signaling in the hypothalamic paraventricular nucleus via control of α-MSH degradation.

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PPARα is dispensable for cold-induced adipose tissue browningCold exposure in mice causes specific white adipose tissue (WAT) depots to adopt features of brown adipose tissue (BAT), a process known as browning. One of the transcription factors that has been implicated in browning is Peroxisome Proliferator-Activated Receptor α (PPARα), mainly known as the master regulator of lipid metabolism in the liver during fasting. Defour and colleagues find that cold-induced changes in gene expression in inguinal WAT are unaltered in mice lacking PPARα, indicating that PPARα is dispensable for cold-induced browning.

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Disruption of seipin causes early-onset lipodystrophy and altered fuel utilisation Congenital generalized lipodystrophy (CGL) is a rare, autosomal recessive, genetic disorder characterized by dramatically reduced adipose tissue mass from birth. Individuals with CGL develop hepatic steatosis, hyperlipidaemia, and severe insulin resistance. One possible cause for CGL is a mutation of the gene BSCL2, which codes for the protein seipin. Mcilroy et al. used the non-inducible Adipoq-Cre model to investigate the consequences of ablating Bscl2 in developing and mature adipocytes. The data reveal that seipin deficiency in developing adipocytes is sufficient to cause severe generalized lipodystrophy early in life but that this does not induce all of the metabolic consequences of congenital seipin deficiency.

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Evidence against a role for NLRP3-driven islet inflammation in db/db miceType 2 diabetes (T2D) is now recognized as a chronic inflammatory disease. In particular, the pro-inflammatory cytokine interleukin-1β (IL-1β) has been highlighted as a potent driver of beta cell dysfunction. Mature IL-1β is mainly produced through the multi-protein inflammasome complexes such as NOD-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome. The orally available small molecule MCC950 potently and specifically inhibits NLRP3 activation and should prevent the decay of pancreatic islets. However, Kammoun et al. found that that MCC950 has no effect in db/db mice. Also, neither NLRP3 nor IL-1β mRNA expression were elevated in the islets from db/db mice. Their data caution the use of db/db mice as an appropriate pre-clinical model of T2D, particularly when testing the efficacy of drugs that target insulin secretory pathways and islet inflammation.

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Modeling pancreatic beta cell dedifferentiationType 2 diabetes develops as a consequence of a combination of insulin resistance and insufficient β cell mass. The decline in β cell mass has been attributed to a decrease in both β cell number and function. It has been suggested recently that β cell dedifferentiation represents a mechanism to explain loss of functioning β cells. Diedisheim et al. used EndoC-βH1, a recently developed functional human β cell line, to model β cell dedifferentiation in a human context. Their model implicates fibroblast growth factor signaling in the dedifferentiation process.

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Unique pharmacology of a novel insulin receptor antibodyA ubiquitous feature of type 2 diabetes (T2D) is decreased sensitivity to insulin. Insulin sensitizers such as thiazolidinediones can impact insulin resistance but have been associated with weight gain and cardiac events. There is a need for novel insulin-sensitizing agents that provide safer and more effective means to treat T2D. Hinke and colleagues characterize a novel monoclonal antibody against insulin receptor, IRAB-A. In vitro testing with IRAB-A indicates that it binds allosterically to the insulin receptor (IR) and has both sensitizer and agonist properties distinct from those of insulin.

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Galanin enhances glucose metabolism through enteric NOS neuronsGalanin is a neuropeptide largely expressed in the brain but also in enteric nervous system (ENS) neurons. Galanin is known to have beneficial effects on glucose metabolism. Aberrant duodenal hyper-contractility leads to an increase of glucose absorption that contributes to the chronic hyperglycemia observed in type 2 diabetes (T2D). Abot et al. show that oral galanin decreases duodenal contraction in mice by stimulating nitric oxide release from enteric neurons. This increases insulin sensitivity, which is associated with an improvement of several metabolic parameters.

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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.



Sandra Hummel
Helmholtz Zentrum München, Neuherberg, Germany
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