Uncoupling Protein 1 (UCP1) plays a central role in non-shivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice, as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by the activation of α1/β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism, and pyruvate dehydrogenase activity for ATP-dependent thermogenesis by the SERCA2b pathway; beige fat thereby functions as a “glucose-sink” and improves glucose tolerance independent of body-weight loss. Our study uncovers a non-canonical thermogenic mechanism by which beige fat controls whole-body energy homeostasis through Ca2+ cycling.

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Highlights d Beige fat progenitors are marked by cell surface proteins, PDGFRa, Sca1, and CD81 d Beige APC proliferation is regulated by temperature, genetic background, and aging d CD81 mediates integrin-FAK signaling in response to irisin d CD81 loss causes obesity, insulin resistance, and adipose tissue inflammation

To the best of our knowledge, this is the first report of heterotopic transplantation of a decellularized whole porcine heart with mesenchymal stem cells. The scaffolds endured surgical procedures. We detected short-term coronary artery perfusion in the transplanted scaffolds by angiography. Future studies should analyse the histological features of transplanted decellularized scaffolds and optimize the system for recellularization to apply this unique technology clinically.

Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice. Am J Physiol Endocrinol Metab 305: E987-

Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces ␤ cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged ␤ cell-specific glucokinase haploinsufficient (Gck ؉/؊ ) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed ␤ cell apoptosis. In Gck ؉/؊ but not wild-type mice, SL significantly decreased the ␤ cell mass and ␤ cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck ؉/؊ mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against ␤ cell apoptosis, restored the ␤ cell mass, and normalized islet morphology in Gck ؉/؊ mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced ␤ cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated ␤ cell apoptosis in diabetic Gck ؉/؊ mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.Decreased ␤ cell mass as a result of increased apoptosis is an important characteristic of type 2 diabetes (1). A physiological animal model of ␤ cell apoptosis is crucial for understanding the pathophysiology of diabetes and for developing new strategies for preventing the progression of diabetes. Dietary sugars and fat influence postprandial glucose and ␤ cell function, thereby deteriorating glucose tolerance (2). Palmitic acid, oleic acid, and linoleic acid are the most abundant fatty acids among the total plasma fatty acids, plasma non-esterified fatty acids, plasma triacylglycerol, phospholipids, and plasma cholesteryl esters (3). Palmitic acid is a well known inducer of ␤ cell lipotoxicity. However, the effects of oleic acid and linoleic acid, two major unsaturated fatty acids, on ␤ cells remain obscure. We therefore selected two diet protocols, namely SO 2 and SL, to examine the effects of oleic acid and linoleic acid on pancreatic islets (4). The main components of the SO diet are sucrose and oleic acid, whereas those of the SL diet are sucrose and linoleic acid. Both of these diets contain similar amounts of palmitic acids (4).Desfluorositagliptin (DFS), a dipeptidyl peptidase-4 (DPP-4) inhibitor, acts by inhibiting the breakdown of many regulatory peptides including glucagon-like peptide-1 (GLP-1) (5). The clinically beneficial effects of DPP-4 inhibition on ␤ cells cannot be fully explained by the increase in insulin release alone,...

The derangement of endoplasmic reticulum (ER) homeostasis triggers β-cell apoptosis, leading to diabetes. Glucokinase upregulates insulin receptor substrate 2 (IRS-2) expression in β-cells, but the role of glucokinase and IRS-2 in ER stress has been unclear. In this study, we investigated the impact of glucokinase activation by glucokinase activator (GKA) on ER stress in β-cells. GKA administration improved β-cell apoptosis in Akita mice, a model of ER stress–mediated diabetes. GKA increased the expression of IRS-2 in β-cells, even under ER stress. Both glucokinase-deficient Akita mice and IRS-2–deficient Akita mice exhibited an increase in β-cell apoptosis, compared with Akita mice. β-cell–specific IRS-2–overexpressing (βIRS-2-Tg) Akita mice showed less β-cell apoptosis than Akita mice. IRS-2–deficient islets were vulnerable, but βIRS-2-Tg islets were resistant to ER stress–induced apoptosis. Meanwhile, GKA regulated the expressions of C/EBP homologous protein (CHOP) and other ER stress–related genes in an IRS-2–independent fashion in islets. GKA suppressed the expressions of CHOP and Bcl2-associated X protein (Bax) and protected against β-cell apoptosis under ER stress in an ERK1/2-dependent, IRS-2–independent manner. Taken together, GKA ameliorated ER stress–mediated apoptosis by harmonizing IRS-2 upregulation and the IRS-2–independent control of apoptosis in β-cells.