Leptin and Insulin Sensitivity
Leptin-induced increases in skeletal muscle (SkM) insulin sensitivity (IS) are associated with decreases in SkM lipid levels (Buettner et al. Am J Physiol, 278: E563-E569,2000). However, the role of altered lipid metabolism in the beneficial effects of leptin on SkM IS is poorly understood. The current study addressed the effects of hyperleptinemia (HLEP) on acute hyperlipidemia-induced insulin resistance. Control (CONT) male Wistar rats were infused with either saline (CONT-SAL) or lipid (CONT-LIP) for 5h (5ml/kg/h) followed by a hyperinsulinemic-euglycemic clamp (15mU/kg/min insulin). Gucose infusion rates (GIR) were significantly lower in CONT-LIP vs. CONT-SAL (31.9±1.1 vs. 38.5±0.8 mg/kg/min, P=0.004, n=6/group). As previously reported the lipid metabolites diacylglycerol (DAG, 2.8±0.2 vs 2.1±0.3nMol/mg protein) and ceramide (CER, 0.8±0.1 vs 0.5±0.01nMol/mg protein) were elevated, and triglyceride (TG, 27.5±3.4 vs 41.0±5.7mg/mg protein) decreased (all P<0.05), in soleus muscle (SOL) in LIP vs SAL. In contrast to control animals a lipid infusion in HLEP (plasma leptin=57.8 ng/ml for 5 days) had no effect on GIR compared to saline-infused HLEP (43.0±4.1 vs. 43.8±5.1 mg/kg/min, P=0.40, n=6/group). Furthermore, DAG (2.8±0.2 vs 2.3±0.2), CER (1.1±0.1 vs 1.0±0.1), and TG (17.1±4.9 vs 16.0±2.6) levels in SOL were similar in HLEP-LIP and HLEP-SAL (all P>0.10). Fatty acid oxidation in the isolated SOL, acetyl CoA carboxylase phosphorylation (ACC-P), and the expression of the putative fatty acid transporters FAT/CD36 and FABPpm were similar in HLEP vs CONT. However, membrane-associated PKCtheta was decreased in HLEP-LIP compared to CONT-LIP. We conclude that (1) HLEP prevents IR induced by a lipid infusion, (2) HLEP SkM does not accumulate DAG or CER or deplete TG in response to a lipid infusion, (3) altered FAox or FABPpm, FAT/CD36 expression are not likely sufficient to explain the effects of HLEP, and (4) membrane-associated PKCtheta is suppressed following acute hyperlipidemia in hyperleptinemic animals.
Advisor:Allan Z. Zhao, PhD; Adolfo Garcia-Ocana, PhD; Fredric L. Goss, PhD; Bret H. Goodpaster, PhD
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Keywords:health physical and recreation education
Date of Publication:04/20/2005