Featured Articles

Volume 29 | Novemer 2019

Roux-en-Y gastric bypass enhances insulin secretion via TRPA1 expressionRoux-en-Y gastric bypass (RYGB) surgery quickly alleviates type 2 diabetes, but the mechanisms for this are only partly known. Kong, Tu, et al. found that RYGB restores the expression of transient receptor potential ankyrin 1 (TRPA1) in β-cells from diabetic rats, via increasing bile acids that activate farnesoid X receptor. This recruits the histone acetyltransferase steroid receptor coactivator-1 (SRC1) and promotes the acetylation of histone H3 at the promoter of TRPA1.

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Metformin prevents the pathological browning of subcutaneous white adipose tissueHypermetabolism is a chronic physiological response to severe trauma such as burns. Trademarks of this phenomenon include increases in resting energy expenditure, supraphysiological nutritional requirements, and the systemic wasting of adipose tissue reserves and muscle tissue. In this context, the preservation of white adipose tissue is seen as a valuable strategy to improve patient outcomes. Auger and colleagues demonstrate that metformin directly affects adipose tissue, independently of systemic effects, and that activation of protein phosphatase 2A in burns, owing to the anti-lipolytic action of this enzyme, appears to be a viable strategy for adipose preservation.

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Rfx6 promotes the differentiation of enteroendocrine cells while repressing serotonin productionEnteroendocrine cells (EECs) sense gut luminal factors that trigger the secretion of peptide hormones or amines, regulating food intake, digestion, and glucose metabolism. Piccand, Vagne, Blot, et al. studied the role of role of the transcription factor Regulatory Factor X 6 (Rfx6) in EEC development and show that enteroendocrine progenitors differentiate in two main cell trajectories, the enterochromaffin cells and the peptidergic enteroendocrine cells, the differentiation programs of which are differentially regulated by Rfx6.

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miR-873-5p targets GNMT-Complex II interface contributing to NAFLDNon-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Glycine N-methyltransferase (GNMT) is the most important and abundant S-adenosylmethionine-dependent methyltransferase in the liver. Fernández-Tussy, Fernández-Ramos, and colleagues describe a new essential role of GNMT in the mitochondria and demonstrate that the recovery of hepatic GNMT levels by targeting the microRNA miR-873-5p emerges as a new therapeutic approach for NAFLD.

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Genetically encoded sensors to detect fatty acid production and trafficking Fatty acids (FAs) are a significant energy source and substrates for membrane synthesis, and they serve as signaling molecules in regulating lipid homeostasis. However, our understanding of FA metabolism has been hampered by the lack of methods to detect their production and trafficking in a temporal and spatial manner in live cells. Mottillo et al. have developed genetically encoded sensors based upon the ligand-dependent interaction between peroxisome proliferator-activated receptor α (PPARα) and steroid receptor coactivator-1 (SRC-1) to image the production and trafficking of FAs.

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Temporal patterns of lipolytic regulators in adipose tissue after growth hormone exposure Lipolysis is the process in which triglycerides are hydrolyzed to free fatty acids and glycerol. Lipolysis can be stimulated by growth hormone (GH), but the exact mechanisms are unclear. Hjelholt et al. examined the expression of lipolytic regulators in human adipose tissue in response to GH. They found suppression of G0/G1 switch gene 2 and fat-specific protein 27 in human, obese, male subjects. Furthermore, upregulation of phosphatase and tensin homolog (PTEN) mRNA expression was recorded.

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Clinical and lifestyle related factors influencing whole blood metabolite levels Proper identification of factors affecting metabolite levels across multiple studies is highly relevant for standardized translation of metabolite biomarkers into clinical applications and to understand possible confounders of disease associations. However, only limited data exist regarding kind, number, and relevance of possible influencing factors. Beuchel and colleagues investigated the effects of 29 clinical and lifestyle related factors on metabolite levels in dried whole blood derived from mass spectrometry in three large human studies with different designs comprising a total of 16,222 subjects. They developed a generic and adaptable workflow and interpreted the discovered associations biologically by applying pathway-based methods.

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miR-10a-5p regulates macrophage polarization and promotes therapeutic adipose tissue remodelingAdipose tissue macrophages (ATMs) are a major immune cell type in adipose tissue that are thought to play important roles in adipose tissue remodeling. Presently, little is known about the mechanisms that regulate different macrophage phenotypes – proinflammatory or anti-inflammatory – in this context. Cho, Son, Kim, et al. found that generation of miRNAs in macrophages is necessary for the antiinflammatory polarization of macrophages. They identified miR-10a-5p as a key miRNA that facilitates antiinflammatory polarization of macrophages.

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PAR2 controls cholesterol homeostasis and lipid metabolism in NAFLDThe cell surface receptor Protease-activated receptor 2 (PAR2) has recently been postulated to be involved in several critical pathways in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) progression where it triggers inflammation, fibrosis, and hepatocellular necrosis. Rana et al. found that PAR2 expression levels in hepatocytes significantly increase with disease progression in patients diagnosed with NAFLD and/or NASH. Mechanistic studies identified downstream effectors of cholesterol homeostasis and lipid metabolism. Together, these data indicate that blocking the activity of PAR2 may have broad salutary effects on cholesterol and lipid metabolism in NAFLD and NASH.

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Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects Dietary restriction (DR) without malnutrition extends lifespan across species from yeast to primates but is not feasible as a long-term intervention in humans. Dietary methionine restriction (MR) has emerged as a promising alternative to calorie restriction. The type III endoribonuclease DICER seems to play a role in the beneficial effects of DR. Guerra et al. show that DICER is upregulated in DR as well as MR, and that MR is both sufficient and necessary for DICER upregulation. They also provide evidence that DICER is important for several beneficial health effects of DR.

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Interaction of GLP-1 and the response of the dorsolateral prefrontal cortex to food-cues predicts body weight development Weight reduction by lifestyle interventions is possible, but often followed by weight regain. Maurer and colleagues sought to determine predictors of successful maintenance of weight loss. They analyzed the interaction of dorsolateral prefrontal cortex (DLPFC) activity after presentation of food cues and the response of GLP-1 after oral glucose intake in individuals taking part in a weight loss-weight maintenance intervention study over 27 months. The interaction of GLP-1 and DLPFC activity was a predictor for successful body weight regulation. Biomarkers for body weight regulation may be improved by considering neuronal and hormonal processes together since their interaction might be superordinate to each phenotype alone.

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FGF21 is required for the therapeutic effects of L. rhamnosus GG against fructose-induced fatty liverFructose consumption, largely in the form of high-fructose corn syrup, is particularly associated with non-alcoholic fatty liver disease (NAFLD). The probiotic Lactobacillus rhamnosus GG (LGG) has been proven beneficial in NAFLD. Zhao, Liu, Liu, et al. found that prolonged fructose feeding decreased upregulation of fibroblast growth factor 21 (FGF21). LGG supplementation rescued FGF21 expression. Using FGF21 KO mice, they found that FGF21 is required for the beneficial effects of LGG in fructose-induced NAFLD.

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Single cell transcriptomic profiling of large intestinal enteroendocrine cells Enteroendocrine cells (EECs) are gastrointestinal epithelial cells that produce more than twenty different hormones. The physiological role of the large number of EECs in the large intestine is not clear. Billing, Larraufie, et al. studied EECs of the large intestine using single cell RNA-sequencing. They identified different subpopulations and showed that these likely represent cellular gradients mapping along the proximal-distal and crypt-surface gut axes. Their data suggests that these cells can contribute to circulating gut hormone concentrations despite their distal location.

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New roles for prokineticin 2 in feeding behavior, insulin resistance and T2DProkineticin 2 (PROK2) is expressed in discrete regions of the brain, including the hypothalamus and the main olfactory bulb (MOB). Odor detection is one of the most important triggers to initiate food intake for most animals including humans. Mortreux and colleagues found that PROK2 in the MOB is a new link between olfaction, eating behavior, and energy homeostasis. In humans, plasma PROK2 correlated negatively with type 2 diabetes, body mass index, and energy intake.

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Deletion of melanin-concentrating hormone receptor 1 from GABAergic neurons increases locomotor activityMelanin-concentrating hormone (MCH) plays a critical role in the regulation of central energy balance. MCH knockout mice are lean and have increased energy expenditure and locomotor activity. Chee et al. sought the place of action of MCH and found that MCH regulates locomotor activity via GABAergic neurons in the nucleus accumbens, and that it does so in part by inhibiting dopamine release.

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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.



Emilio Mottillo
Wayne State University School of Medicine, Detroit, MI, USA
Referring article

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December
6 − 8
2019
Cachexia, Sarcopenia and Muscle Wasting
Berlin, Germany
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