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Volume 31 | January 2020

Knockout of p85α in BAT induces resistance to HFD-induced obesityThe protein p85α is a regulatory subunit of phosphoinositide 3-kinases (PI3Ks). Some class I PI3K isoforms are involved in different levels of metabolic control as well as in systemic dysfunctions associated with obesity. The lack of p85α induces an increased insulin sensitivity in mice. Gomez-Hernandez and colleagues generated a mouse model lacking p85α in brown adipose tissue (BAT). Their data strongly suggest that under a high-fat diet, the loss of p85α in BAT improves thermogenic functionality and induces obesity resistance by increased insulin sensitivity and a nonfatty liver.

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Adipocyte-derived Periostin mediates glucocorticoid-induced hepatosteatosis Glucocorticoids (GCs) are widely used in the treatment of acute inflammatory, allergic, immunologic, and malignant disorders. However, long-term GC therapy is associated with many metabolic side effects, including hepatic steatosis. The molecular basis of GC-dependent development of fatty liver is poorly understood. Wan, Shan, et al. show that treatment with dexamethasone (DEX), a synthetic analog of GCs, results in triglyceride accumulation in the livers of healthy mice, but not in cultured hepatocytes. They further show that DEX can upregulate the expression levels of the adipokine Periostin in white adipose tissue, which in turn contributes to liver steatosis and hyperglycemia.

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Mechanisms underlying the metabolic effects of FGF21Fibroblast growth factor 21 (FGF21) is a member of the FGF superfamily that regulates metabolic homeostasis and is a potential therapeutic target for the treatment of metabolic syndrome. It was recently shown in mice that adipose tissue (AT) is required for the acute insulin-sensitizing effects of FGF21. Lewis et al. sought to determine the relative importance of different AT depots in FGF21-mediated metabolic improvements using a combination of in vivo studies with quantitative PET-CT imaging of both glucose and lipid tracers to assess the location and magnitude of their uptake and ex vivo, metabolic, and molecular biology approaches. They demonstrate the AT-specific capacity for glucose and lipid uptake and metabolism and the importance of AT in governing FGF21 response.

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Alternative splicing of UCP1 by non-cell-autonomous action of PEMTMitochondrial thermogenesis in brown adipose tissue (BAT) is largely driven by uncoupling protein 1 (UCP1). Phosphatidylethanolamine methyltransferase (PEMT) is an enzyme that generates phosphatidylcholine. Mice with a whole-body deletion of PEMT become cold-intolerant when fed a high-fat diet. Johnson and colleagues report that PEMT plays a vital role in thermogenesis by regulating UCP1 protein expression via alternative splicing. Surprisingly, PEMT within BAT does not mediate this effect, nor does it substantially affect BAT function. Rather, PEMT’s action occurs in a non-cell-autonomous manner.

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Deletion of iRhom2 protects against diet-induced obesityiRhom2 is a polytopic membrane protein that is highly expressed in immune cells, particularly macrophages. iRhom2 is required for the release of tumor necrosis factor (TNF) from myeloid cells. TNF, in turn, regulates the pathobiology of metabolic syndrome in several important ways. Badenes et al. evaluated the contribution of iRhom2 to metabolic syndrome. They report that iRhom2 knockout mice are protected from a range of deleterious metabolic phenotypes including obesity, adipose tissue inflammation, hepatic steatosis, and insulin resistance. Moreover, loss of iRhom2 enhances the capacity of the animals to dissipate excess energy via increased thermogenesis.

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Purβ promotes hepatic glucose production Patients with obesity and type 2 diabetes display elevated hepatic glucose production (HGP). Purine-rich element binding protein β (Purβ) is able to bind to purine-rich single- or double-stranded DNA or RNA, where it can act as a transcription factor or a repressor of transcription or translation. Jia et al. identify Purβ as a positive regulator of HGP. Purβ, induced by fasting or glucagon, promotes HGP by increasing Adcy6 transcription. Purβ/ADCY6 may be a promising drug target for the treatment of hyperglycemia in patients with obesity.

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FDG uptake tracks the oxidative damage in diabetic skeletal muscle Muscular glucose metabolism (MRGlu) is usually studied by analysis of 18F-fluoro-deoxyglucose (FDG) kinetics with positron emission tomography. However, conflicting results suggest that MRGlu and FDG uptake might reflect at least partially different mechanisms. Bauckneht, Cossu, et al. link FDG uptake and reactive oxygen species (ROS) generation. Their data indicate that fasting FDG uptake at least partially reflects hexose-6-phosphate dehydrogenase activity and is thus enhanced under the redox stress induced by hyperglycemia.

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Bdnf-e1-expressing neurons in the lateral hypothalamus critical for thermogenesis control Brain-derived neurotrophic factor (BDNF) has long been known to play a key role in energy homeostasis and thermogenesis, but the responsible neural circuits remained unknown. You and colleagues show that disruption of Bdnf promoter I (Bdnf-e1-/-), but not promoter IV or VI results in severe deficits in thermogenesis. Furthermore, they identify a subset of neurons in the lateral hypothalamus that are both thermogenesis related and Bdnf-e1 deficient.

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Bmal1 and secretagogin are necessary for circadian secretion of GLP-1 Bmal1 is a core clock gene that regulates circadian rhythmicity of gene expression and metabolism. Secretagogin is a protein that regulates fusion of secretory granules to the cell membrane. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is secreted in a circadian manner. Biancolin, Martchenko, et al. report that Secretagogin exhibits circadian expression in L-cells under the transcriptional regulation of BMAL1. This drives a subsequent time-dependent recruitment of Secretagogin toward the L-cell membrane that in turn facilitates circadian secretion of GLP-1.

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Lack of resolution sensor drives age-related cardiac defects Formyl peptide receptor 2 (FPR2) is a resolution sensor that plays a pivotal role in inflammation. FPR2 enables activated immune cells to be mobilized from the bone marrow to the injured organ, facilitating transformation from physiological inflammation to resolution. Persistent inflammation is a hallmark of coronary heart disease. Tourki, Kain, et al. provide a comprehensive evaluation of the system-wide integrative role of FPR2, including its impact on survival, structure, and function of cardiometabolic and renal syndromes. They find that FPR2 serves as a key resolution sensor for heart function, renal homeostasis, and lipid metabolism in cardiovascular physiology.

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MiR-132 controls pancreatic beta cell proliferation and survival The miRNA miR-132 plays a key role in beta cell function. However, in pancreatic islets, the downstream targets of miR-132 remain unknown and its involvement in beta cell regeneration in vivo has not been investigated. Mziaut and colleagues have found that miR-132 is a critical factor for control of beta cell replication after partial pancreatectomy. Targeted therapies for the expansion of beta cell mass in diabetes are actively sought, and in this context, miR-132 appears to be a worthy candidate.

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Targeted delivery of a PPARα/γ agonist to adipocytes enhances adipogenesis and prevents diabetes progression Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have an outstanding anti-diabetic potential as they promote adipogenesis and lead to the development of small, metabolically healthy adipocytes. However, these molecules also regulate a variety of processes in other cell types. Therefore, the clinical application of some PPARγ agonists is accompanied by serious side effects. To avoid this, Wittrisch et al. developed a peptide drug conjugate with the dual PPARα/γ agonist tesaglitazar (tesa) and a form of neuropeptide Y. This construct binds to NPY1-receptor on adipocytes for cell-type specific uptake. The authors show that the peptide conjugate prevents diabetes progression as efficiently as systemically administered tesa.

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Metabolic benefits of gastric bypass surgery: The role of fecal losses The Roux-en-Y gastric bypass (RYGB) procedure is one of the most efficient bariatric surgeries, inducing rapid weight loss and improvements in comorbidities of obesity. Barataud et al. performed duodenal-jejunal bypass (DJB), which is equivalent to RYGB without size restriction of the stomach, in mice and found that DJB induces dramatic loss of fecal matter in obese mice fed a high fat, high sugar diet. In obese mice, this could be sufficient to explain the lasting weight loss and associated improvements in glucose control associated with DJB. Fecal energy loss should no longer be underestimated in bypass surgery studies in the mouse.

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Glycerol not lactate is the major net carbon source for gluconeogenesis During fasting, the major glucose source switches to gluconeogenesis (GNG) which produces glucose from small metabolites such as lactate, glycerol and amino acids. It is believed that lactate is the major substrate contributing to GNG. However, lactate is largely generated from glucose and resynthesized to glucose, making lactate the largest direct contributor to glucose carbon but not necessarily a good source for new carbon entering GNG. Wang et al. fasted mice for 6, 12, and 18 hours to study the relative contribution of different GNG substrates. They demonstrate that lactate is the dominant direct contributor but a minor overall net carbon contributor to GNG. Instead, glycerol is the dominant net carbon source for GNG during short and prolonged fasting.

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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.



Marina Badenes
Instituto Gulbenkian de Ciência (IGC), Oeiras, Portugal
Referring article

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