Adipose differentiation-related protein regulates lipids and insulin in pancreatic islets

Abstract

The excess accumulation of lipids in islets is thought to contribute to the development of diabetes in obesity by impairing ␤-cell function. However, lipids also serve a nutrient function in islets, and fatty acids acutely increase insulin secretion. A better understanding of lipid metabolism in islets will shed light on complex effects of lipids on ␤-cells. Adipose differentiation-related protein (ADFP) is localized on the surface of lipid droplets in a wide range of cells and plays an important role in intracellular lipid metabolism. We found that ADFP was highly expressed in murine ␤-cells. Moreover, islet ADFP was increased in mice on a high-fat diet (3.5-fold of control) and after fasting (2.5-fold of control), revealing dynamic changes in ADFP in response to metabolic cues. ADFP expression was also increased by addition of fatty acids in human islets. The downregulation of ADFP in MIN6 cells by antisense oligonucleotide (ASO) suppressed the accumulation of triglycerides upon fatty acid loading (56% of control) along with a reduction in the mRNA levels of lipogenic genes such as diacylglycerol O-acyltransferase-2 and fatty acid synthase. Fatty acid uptake, oxidation, and lipolysis were also reduced by downregulation of ADFP. Moreover, the reduction of ADFP impaired the ability of palmitate to increase insulin secretion. These findings demonstrate that ADFP is important in regulation of lipid metabolism and insulin secretion in ␤-cells. MIN6 cells; oleic acid; palmitic acid; high-fat diet; fasting THE CURRENT EPIDEMIC OF OBESITY is feared to increase the prevalence of type 2 diabetes due to its contribution to insulin resistance (38). However, excess adiposity and dyslipidemia commonly seen in obesity may have an additional role in the development of diabetes by directly damaging ␤-cells (45). Indeed, prolonged exposure to elevated levels of fatty acids impairs insulin secretion in vivo and ex vivo, a phenomenon termed "lipotoxicity" (16,47,50,56). Ceramide generation, an increase in reactive oxygen species, 12/15-lipoxygenase activation, and atypical protein kinase C activation are some of the mechanisms proposed for islet dysfunction and lipid-induced apoptosis (5, 44, 51, 52). On the other hand, lipids serve a nutrient function and are the principal energy source in islets deprived of exogenous nutrients (34, 54). Not only does acute exposure to fatty acids augment insulin secretion ex vivo, but a rise in fatty acids also facilitates glucose-stimulated insulin secretion (GSIS) after fasting in vivo (10). The activation of cell surface fatty acid receptor G protein-coupled receptor 40 (GPR40) plays a significant role in the augmentation of insulin secretion by fatty acids. However, cellular uptake of fatty acids is also believed to contribute to the insulin secretion by provision of lipid metabolites, including long-chain acyl-CoA and diacylglycerides (25,43,65). Thus, fatty acids play complex and seemingly contradictory roles in ␤-cells, which calls for a better understanding of fatty acid uptake, storage...

Efficacy and Tolerability of an Herbal Formulation for Weight Management

“…These results suggest, respectively, that the herbal blend may attenuate fat accumulation by partially blocking adipogenesis and fat uptake, and by rendering lipid droplets more susceptible to lipases. [23][24][25][26][27][28] The ability of the herbal mix to promote significant weight loss may explain the higher levels of circulating adiponectin observed in the herbal supplemented group. These higher adiponectin levels, in turn, may increase fat metabolism, leading to a reduction in WHR, as adiponectin has been shown to facilitate fat oxidation in skeletal muscle and liver.…”

Signaling Molecules Involved in Lipid-Induced Pancreatic Beta-Cell Dysfunction

“…2). Furthermore, the downregulation of ADFP in MIN6 cells by ASO resulted in the suppression of the TG accumulation upon FFAs loading, indicating that ADFP may participate in the regulation of intracellular lipid metabolism in islet beta cells (Faleck et al, 2010) (Fig. 1).…”

“…Moreover, Imai et al reported that the reduction of ADFP via antisense oligonucleotide (ASO) could reverse fatty liver and alter lipid metabolism (Imai et al, 2007). More recently, it was found that the HFa diet could markedly increase the expression level of ADFP in murine islets along with the incremental expression of ADFP in human islets by addition of FFAs (Faleck et al, 2010). Effect of long-term lipotoxicity on the expression/activity of ADFP in beta cells remains to be identified (Fig.…”

Role of fatty acid transport protein 4 in oleic acid-induced glucagon-like peptide-1 secretion from murine intestinal L cells

“…However, somewhat unexpectedly, the effects of both phloretin treatment and FATP4 knockdown to reduce OA uptake by the GLUTag cells were relatively modest compared with their ability to prevent OA-induced GLP-1 release. A similar dissociation between OA uptake and insulin secretion has been noted in mouse insulinoma MIN6 cells such that knockdown of the adipose differentiation-related protein that coats lipid droplets decreases OA uptake by 17% but reduces insulin secretion by more than 50% (12). This discrepancy was attributed to impaired lipid metabolism, although the exact mechanisms were not investigated.…”