Featured Articles

Volume 5 | No. 11 | November 2016

Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivityThe SLC13A5 gene is the mammalian ortholog of the Drosophila melanogaster "I’m not dead, yet" (INDY) gene, in which its mutation is linked to a life-span extension. The data of Brachs and colleagues demonstrate that the mammalian homolog of INDY (mINDY) is involved in the regulation of liver fat metabolism. Its inhibition by a liver-specific siRNA is a reasonable approach to prevent fatty liver disease in C57BL/6J mice on a Western diet but has no effect on body weight. The data support that effects on hepatic lipid accumulation occur independent of body weight changes or whole-body fat content. The authors suggest that non-liver mINDY effects may mediate potential effects on body weight.

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Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptakeSkeletal muscle insulin resistance is an early metabolic defect that precedes hyperglycemia and marked weight gain in response to high-fat diet. Lee-Young and colleagues identify a novel and previously unidentified role for glucose-6-phosphate dehydrogenase (G6PDH) in skeletal muscle. Skeletal muscle G6PDH is defective across multiple disease states in animals and humans, with an underlying pathology of impaired glucose tolerance. G6PDH is directly regulated by skeletal muscle specific neuronal nitric oxide synthase (nNOSµ) activity, and this interaction appears to play a role in the regulation of insulin-independent glucose uptake.

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Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemiaCyclic AMP-responsive element-binding protein H (CREBH) is a basic leucine zipper domain transcriptional factor of the CREB/activating transcription factor family. The study of Kikuchi and colleagues suggests that intestinal CREBH functions as a metabolic regulator to attenuate diet-induced hypercholesterolemia and cholelithiasis by decreasing expression of the transporter gene Niemann-Pick C1-like 1 (Npc1l1). It is known that hepatic CREBH has the potential to ameliorate hypertriglyceridemia. This study identifies intestinal CREBH as a possible therapeutic target for the treatment of hypercholesterolemia and related metabolic diseases.

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Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetesMutation of the gene encoding leptin in mice (Lepob/ob) results in a deficiency of leptin and increases in hyperphagia and adiposity. The study of D’souza et al. indicates that reducing insulin gene dosage attenuates hyperinsulinemia and prevents obesity in Lepob/ob mice. However, curtailing hyperinsulinemia in Lepob/ob mice also resulted in the development of hyperglycemia. In the absence of leptin, sufficient insulin levels are required to prevent diabetes.

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Depot-specific differences in angiogenic capacity of adipose tissue in differential susceptibility to diet-induced obesityTo suppress the rapidly growing prevalence of obesity, several treatments have been suggested, including the modulation of angiogenesis in adipose tissue (AT). Here, Song et al. investigate whether angiogenic capacity is depot-specific by analyzing angiogenic sprouting of epididymal and inguinal fats from diet-induced obese and diet-resistant mice fed a high-fat diet (HFD). This study indicates that, compared to subcutaneous fat, visceral fat has higher angiogenic capability in response to HFD-induced over-nutrition.

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Modulation of ambient temperature promotes inflammation and initiates atherosclerosisThe molecular mechanisms that regulate atherosclerosis initiation and progression are not fully understood. The emergence of ambient temperature as a potential variable in disease modeling has already gained interest in the atherosclerosis field. Giles, Ramkhelawon and colleagues show, for the first time, that thermoneutral housing (at 29-32°C) in combination with obesogenic Western diet promotes mild induction of atherosclerosis in wild type mice. This report describes a novel, inflammatory murine model for atherosclerosis in the absence of previously utilized genetic manipulations. This approach represents a significant step forward in atherosclerosis modeling.

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Osteopontin is a key player for local adipose tissue macrophage proliferation in obesityAn increasing number of studies describe adipose tissue macrophage accumulation as the main driver of obesity-associated inflammation. Osteopontin (OPN) is a secreted glycoprotein involved in a wide variety of physiological and pathological conditions, including inflammatory processes. Tardelli et al. show that OPN-treated human monocytes outnumber controls while diminishing apoptosis. Furthermore, OPN enhances proliferation rates also in in vitro differentiated macrophages, thereby pointing to a novel mechanism that might trigger and maintain low-grade inflammation in obesity.

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Critical role for adenosine receptor A2a in beta-cell proliferationType 1 and type 2 diabetes are characterized by a shortage of functional beta-cells. One potentially curative strategy would be to stimulate remaining beta-cells to proliferate. Here, Schulz et al. show that adenosine signaling through the A2a receptor is required for compensatory beta-cell proliferation in mice during pregnancy and is sufficient to promote proliferation of mouse beta-cells in vitro. Their work suggests that adenosine signaling has an important role in generating beta-cell homeostasis, a feature that could be therapeutically exploited to increase the number of beta-cells in people with diabetes.

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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.



Flaminia Fanelli
University of Bologna, Italy
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