Plasma concentrations of triglycerides, total cholesterol, and serum-free fatty acids were measured by enzymatic methods using commercially available kits. in WAT explants fromob/obmice also increased expression of above -ARs. In contrast, induction of PGC-1 and UCP-1 expression in brown adipose tissue of DBKO mice was not accompanied by changes in the expression of these -ARs. Collectively, these findings suggest that PKC deficiency may prevent genetic obesity, in part, by remodeling the catabolic function of adipose tissues through -ARs dependent and impartial mechanisms. Keywords:protein kinase C, adipose tissue remodeling, -adrenergic receptors, thermogenesis Leptin is an adipocyte-derived hormone that is required for normal energy homeostasis (13). It plays a key role in the control of body weight by suppressing food intake through actions on hypothalamic receptors and by increasing energy expenditure via activation of sympathetic activity and brown adipose tissue (BAT) thermogenesis. This is best illustrated by loss of function mutations in genes encoding leptin or the leptin receptor, which result in severe obesity in rodents and humans. Leptin is also known to play a dual role in glucose metabolism and insulin signaling, acting as an insulin sensitizer and as an antagonizer. In vivo, leptin has been reported to enhance insulin action in inhibiting hepatic glucose output while antagonizing insulin action on the expression of metabolic ZNF538 genes (4). The insulin and leptin signaling pathways are known to share downstream targets such as Janus kinase-2, insulin receptor substrates, phosphatidyl-inositol 3-kinase, protein kinase B, mitogen-activated protein kinase, and protein kinase C (PKC). Recent data provide evidence that PKC is usually activated by leptin via increasing calcium concentration and stimulating inositol triphosphate (IP-3) production (5). PKC-dependent phosphorylation of Ser-318 in insulin receptor substrate-1 has been implicated in mediating the inhibitory signal of leptin around the insulin-signaling cascade (6). Several other interactions in different physiological systems have been described between PKC and leptin (710). PKCs comprise a large family of serine/threonine protein kinases that plays a key role in signal transduction and regulation of gene expression (1114). Twelve distinct members have been discovered in mammalian cells, and these have been subdivided into three distinct subfamilies as follows: conventional PKCs (, I, II, and ), novel Banoxantrone D12 PKCs (, , , and ), and atypical PKCs ( and /). These PKC isoforms are unique not only with respect to their primary structures but also in their expression patterns, subcellular localization, in vitro activation, and responsiveness to extracellular signals. Most importantly, these isoforms show differences in cofactor dependence and responsiveness to calcium and phospholipid metabolites. Conventional PKCs bind to and are activated by sn-1,2-diacylglycerol, which increases the specificity of the enzyme for phosphatidylserine and its affinity for Banoxantrone D12 calcium. Novel PKCs are also activated by DAG and require phosphatidylserine as a cofactor but have lost the requirement for calcium. Atypical PKCs do not respond to DAG or calcium but apparently still require phosphatidylserine as a cofactor. Recent studies have shown that DAG-PKC signaling is usually activated in diabetic conditions, and the induction appears to be restricted to a few diabetic-related isoforms (15,16). PKC is usually one isoform that has been most directly linked to important aspects of hyperglycemia in in vivo and in vitro. PKC was also one of the earliest isoforms acknowledged in insulin signaling and appears to play dual functions in insulin signaling pathways (1722). PKC does not Banoxantrone D12 appear to regulate glucose-induced insulin secretion in vivo (23), even though it has been reported to undergo translocation to the plasma membrane subsequent to stimulation by glucose in primary islet cells (24). We recently showed that PKC is usually markedly elevated in white adipose tissue (WAT) of leptin-deficient (ob/ob) mice and is significantly induced by intake of high-fat diet (HFD) (25,26). We also assessed the impact of PKC deficiency on glucose and lipid homeostasis in vivo and found that deficiency of PKC signaling resulted in adipose atrophy, hypoleptinemia, hyperphagia, and altered expression of genes involved in energy homeostasis in the adipose tissue. The lean phenotype of PKC/mice was associated with reduced serum leptin and compensatory increased food intake (26). Furthermore, adiposity is not increased when PKC-deficient (PKC/) mice are challenged with a HFD. These studies identified the PKC signaling pathway as a novel modulator of adipose tissue homeostasis. Unlike PKC/mice, ob/obmice exhibit marked obesity, hyperphagia, insulin.