Excessive caloric intake leading to obesity is usually associated with insulin

Excessive caloric intake leading to obesity is usually associated with insulin resistance and dysfuntion of islet cells. Desnutrin (also called ATGL/iPLA2/ PNPLA2) (Duncan et al., 2010), a patatin-domain made up of protein, was recognized by us and others as the major triacylglycerol (TAG) hydrolase. Although desnutrin is usually highly expressed in adipose tissue, the main energy storage organ, it is usually also found in other tissues (Jenkins et al., 2004; Villena et al., 2004; Zimmermann et al., Rabbit polyclonal to AHR 2004). The product of desnutrin-catalyzed TAG lipolysis, diacylglycerol (DAG), undergoes further hydrolysis catalyzed by hormone sensitive lipase (HSL) to generate monoacylglycerol (MAG) which is usually finally hydrolyzed by MAG lipase to generate glycerol. Each step of TAG hydrolysis liberates a fatty acid (FA) (Duncan et al., 2007). FAs produced from TAG hydrolysis in adipose tissue are released into blood circulation to be taken up by other tissues. In contrast, FAs generated from lipolysis in other tissues where TAG is usually found in greatly smaller amount, are metabolized primarily within the cell. HFD feeding can cause TAG accumulation not only in adipose tissue, but numerous other tissues (Matsui et al., 2004) and lower desnutrin level or activity can contribute to TAG accumulation. Ectopic TAG accumulation in numerous tissues, such as liver and muscle mass, has been linked to metabolic syndrome and insulin resistance. Although molecular details are not known, increased intracellular lipid metabolites as well as mitochondrial disorder have been implicated in this process. Excessive caloric or excess fat intake leading to obesity has not only been associated with insulin resistance and type 2 diabetes but also cell disorder. In rodents, feeding of a high excess fat diet (HFD) has been reported to Catharanthine sulfate supplier result in islet cell disorder and impairment of insulin secretion (Ehses et al., 2010; Evans-Molina et al., 2009). It has been well documented that insulin secretion by cells is usually in response to catabolism of metabolic fuels including mitochondrial ATP production (Detimary et al., 1998; Lu et al., 2010). An increase in cytosolic ATP or ATP/ADP ratio induces closure of ATP-sensitive potassium channel (KATP) producing in plasma membrane depolarization to allow Ca2+ influx, causing insulin secretion from cells (Detimary et al., 1998). Maintaining mitochondrial function is usually essential to preserve levels of cellular ATP and insulin secretion. Thus, impairments in mitochondrial morphology and function Catharanthine sulfate supplier have been shown to decrease insulin secretion, presumably through blunted ATP production (Lu et al., 2010; Weiss et al., 2012). Yet, how mitochondrial function for insulin secretion may become perturbed in type 2 diabetes is not well understood. The peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors control expression of genes involved in energy homeostasis and lipid metabolism (Yessoufou and Wahli, 2010). Of the three PPAR family members, PPAR is Catharanthine sulfate supplier highly expressed in oxidative tissues to play a central role in FA oxidation, whereas PPAR is preferentially expressed in adipose tissue to promote adipogenesis and fat storage. In contrast, PPAR is widely expressed and implicated in both FA and glucose metabolism. Although PPARs can be activated by specific synthetic agonists, endogenous ligands are yet to be clearly defined. In this regard, FAs, in particular unsaturated FAs, may act as endogenous ligands, or serve as precursors to generate ligands, to transcriptionally activate target genes. However, the sources of intracellular FAs that activate PPARs directly, or indirectly by converting to endogenous ligands, have not been well understood. We previously reported that, among the PPAR family of transcription factors, PPAR is the most highly expressed in Catharanthine sulfate supplier brown adipose tissue and desnutrin-catalyzed lipolysis provides endogenous ligands for PPAR to promote mitochondrial function and to maintain brown adipose phenotype (Ahmadian et al., 2011). Similarly, Zechner and coworkers reported desnutrin-mediated promotion of FA oxidation through PPAR in cardiac muscle (Haemmerle et al., 2011). These studies suggest that activation of PPAR by FAs, or other metabolites, is a common feature for desnutrin-catalyzed TAG hydrolysis. Here, we report that ablation of desnutrin in islet cells impairs glucose-stimulated insulin secretion (GSIS). Desnutrin ablation using RIP-Cre or RIP-CreER in mice results in TAG accumulation in islets, leading to pronounced hyperglycemia. Adenovirus-mediated desnutrin expression in KO islets restores GSIS. Furthermore, we show that desnutrin-catalyzed lipolysis activates PPAR, rather than PPAR, Catharanthine sulfate supplier which in turn is critical for expression of genes involved in mitochondrial function and thus ATP production required for GSIS. RESULTS Desnutrin ablation in pancreatic cells causes glucose intolerance in mice Recent studies have shown that a high fat diet (HFD) can cause pancreatic cell dysfunction and impair insulin secretion in mice (Ehses et al., 2010; Evans-Molina et al., 2009). HFD can elevate.