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Becn1/Beclin-1 is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although Becn1 has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of Becn1 in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific Becn1 knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of Becn1 in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that Becn1 depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte Becn1 would serve as a crucial player for adipocyte survival and adipose tissue homeostasis. [ABSTRACT FROM AUTHOR]

SREBP1c is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic β-cells are largely unknown. In this study, we demonstrate that SREBP1c regulates β-cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic β-cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated β-cell proliferation through its novel target gene, PAX4 Compared with SREBP1c+/+ mice, SREBP1c-/- mice showed glucose intolerance with low insulin levels. Moreover, β-cells from SREBP1c-/- mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c-overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating β-cell compensatory responses in obesity. [ABSTRACT FROM AUTHOR]

Beige adipocytes can dissipate energy as heat. Elaborate communication between metabolism and gene expression is important in the regulation of beige adipocytes. Although lipid droplet (LD) binding proteins play important roles in adipose tissue biology, it remains unknown whether perilipin 3 (Plin3) is involved in the regulation of beige adipocyte formation and thermogenic activities. In this study, we demonstrate that Plin3 ablation stimulates beige adipocytes and thermogenic gene expression in inguinal white adipose tissue (iWAT). Compared with wild-type mice, Plin3 knockout mice were cold tolerant and displayed enhanced basal and stimulated lipolysis in iWAT, inducing peroxisome proliferator-activated receptor α (PPARα) activation. In adipocytes, Plin3 deficiency promoted PPARα target gene and uncoupling protein 1 expression and multilocular LD formation upon cold stimulus. Moreover, fibroblast growth factor 21 expression and secretion were upregulated, which was attributable to activated PPARα in Plin3-deficient adipocytes. These data suggest that Plin3 acts as an intrinsic protective factor preventing futile beige adipocyte formation by limiting lipid metabolism and thermogenic gene expression. [ABSTRACT FROM AUTHOR]

Adipose tissue inflammation is an important factor in obesity that promotes insulin resistance. Among various cell types in adipose tissue, immune cells actively regulate inflammatory responses and affect whole-body energy metabolism. In particular, invariant natural killer T (iNKT) cells contribute to mitigating dysregulation of systemic energy homeostasis by counteracting obesity-induced inflammation in adipose tissue. However, the molecular mechanisms by which adipose iNKT cells become activated and mediate anti-inflammatory roles in obese adipose tissue have not been thoroughly understood yet. In the current study, we demonstrate that adipocyte CD1d plays a key role in the stimulation of adipose iNKT cells, leading to anti-inflammatory responses in high-fat diet (HFD)-fed mice. Accordingly, adipocyte-specific CD1d-knockout (CD1dADKO) mice showed reduced numbers of iNKT cells in adipose tissues and decreased responses to α-galactosylceramide-induced iNKT cell activation. Additionally, HFD-fed CD1dADKO mice revealed reduced interleukin-4 expression in adipose iNKT cells and aggravated adipose tissue inflammation and insulin resistance. Collectively, these data suggest that adipocytes could selectively stimulate adipose iNKT cells to mediate anti-inflammatory responses and attenuate excess proinflammatory responses in obese adipose tissue. [ABSTRACT FROM AUTHOR]

Liver X receptor (LXR)alpha and LXRbeta play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic beta-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced beta-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in beta-cells as a possible cause of beta-cell lipotoxicity, a key step in the development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Liver X receptor (LXR)α and LXRβ play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the fiver, intestine, fat, and macrophages are well established, its role in pancreatic β-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced β-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in β-cells as a possible cause of β-cell lipotoxicity, a key step in the development of type 2 diabetes. Diabetes 56:1534-1543, 2007 [ABSTRACT FROM AUTHOR]

Becn1 / Beclin-1 is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although Becn1 has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of Becn1 in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific Becn1 knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of Becn1 in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that Becn1 depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte Becn1 would serve as a crucial player for adipocyte survival and adipose tissue homeostasis., (© 2020 by the American Diabetes Association.)

Adipose tissue is the key organ coordinating whole-body energy homeostasis. Although it has been reported that ring finger protein 20 (RNF20) regulates lipid metabolism in the liver and kidney, the roles of RNF20 in adipose tissue have not been explored. Here, we demonstrate that RNF20 promotes adipogenesis by potentiating the transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ). Under normal chow diet feeding, Rnf20 defective ( Rnf20 +/- ) mice exhibited reduced fat mass with smaller adipocytes compared with wild-type littermates. In addition, high-fat diet-fed Rnf20 +/- mice alleviated systemic insulin resistance accompanied by a reduced expansion of fat tissue. Quantitative proteomic analyses revealed significantly decreased levels of PPARγ target proteins in adipose tissue of Rnf20 +/- mice. Mechanistically, RNF20 promoted proteasomal degradation of nuclear corepressor 1 (NCoR1), which led to stimulation of the transcriptional activity of PPARγ. Collectively, these data suggest that RNF20-NCoR1 is a novel axis in adipocyte biology through fine-tuning the transcriptional activity of PPARγ., (© 2019 by the American Diabetes Association.)

SREBP1c is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic β-cells are largely unknown. In this study, we demonstrate that SREBP1c regulates β-cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic β-cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated β-cell proliferation through its novel target gene, PAX4 Compared with SREBP1c +/+ mice, SREBP1c -/- mice showed glucose intolerance with low insulin levels. Moreover, β-cells from SREBP1c -/- mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c-overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating β-cell compensatory responses in obesity., (© 2018 by the American Diabetes Association.)

Objective: Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo., Research Design and Methods: Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR., Results: CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain., Conclusions: We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.

Adiponectin has recently received a great deal of attention due to its beneficial effects on insulin resistance and metabolic disorders. One of the mechanisms through which adiponectin exerts such effects involves an increase in fatty acid oxidation in muscle and liver. In the present study, we demonstrate that 5'-AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) are involved in the activation of peroxisome proliferator-activated receptor (PPAR)alpha by adiponectin in muscle cells. Adiponectin increases the transcriptional activity of PPARalpha and the expression of its target genes, including ACO, CPT1, and FABP3 in C2C12 myotubes. These effects were suppressed by the overexpression of a dominant-negative form of AMPK. Moreover, chemical inhibitors of AMPK and p38 MAPK potently repressed fatty acid oxidation and the induction of PPARalpha target gene expression by adiponectin. Interestingly, araA, an AMPK inhibitor, prevented the activation of p38 MAPK, whereas SB203580, a p38 MAPK inhibitor, did not affect AMPK activation, suggesting that p38 MAPK is a downstream signaling factor of AMPK. Taken together, these results suggest that adiponectin stimulates fatty acid oxidation in muscle cells by the sequential activation of AMPK, p38 MAPK, and PPARalpha.