We also detected decreased density of active mitochondria without changes in total mitochondrial density, and lower citrate synthase activity

We also detected decreased density of active mitochondria without changes in total mitochondrial density, and lower citrate synthase activity. Desnutrin (also called ATGL/iPLA2/ PNPLA2) (Duncan et al., 2010), a patatin-domain containing protein, was identified by us and others as the Rabbit polyclonal to AMHR2 major triacylglycerol (TAG) hydrolase. Although desnutrin is highly Bevirimat expressed in adipose tissue, the main energy storage Bevirimat organ, it is also found in other tissues (Jenkins et al., 2004; Villena et al., 2004; Zimmermann et al., 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 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 circulation to be taken up by other tissues. In contrast, FAs generated from lipolysis in other tissues where TAG is found in greatly lesser amount, are metabolized primarily within the cell. HFD feeding can cause TAG accumulation not only in adipose tissue, but various other tissues (Matsui et al., 2004) and lower desnutrin level or activity can contribute to TAG accumulation. Ectopic TAG accumulation in various tissues, such as liver and muscle, has been linked to metabolic syndrome and insulin resistance. Although molecular details are not known, increased intracellular lipid metabolites as well as mitochondrial dysfunction Bevirimat have been implicated in this process. Excessive caloric or fat intake leading to obesity has not only been associated with insulin resistance and type 2 diabetes but also cell dysfunction. In rodents, feeding of a high fat diet (HFD) has been reported to result in islet cell dysfunction 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 in response to catabolism of metabolic fuels involving 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) resulting in plasma membrane depolarization to allow Ca2+ influx, triggering insulin secretion from cells (Detimary et al., 1998). Maintaining mitochondrial function is essential to preserve levels of cellular ATP and insulin secretion. Thus, impairments in mitochondrial morphology and function 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 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 brown adipose Bevirimat tissue and desnutrin-catalyzed lipolysis provides endogenous ligands for PPAR to promote mitochondrial function.