Abstract 17402: Hypothalamic Leptin Resistance Contributes to Increased Myocardial Fatty Acid Oxidation Rates in Obesity
Obesity is associated with hypothalamic leptin-resistance and increased myocardial FA oxidation (FAO). Caloric restriction (CR) in leptin-deficient ob/ob mice and leptin-resistant db/db mice, normalized body weight and reversed diabetes, but myocardial FAO remained persistently increased in conjunction with hyperinsulinemia and persistently increased circulating concentrations of free fatty acids (FFA). To test the hypothesis that impaired hypothalamic leptin signaling contributes to elevated rates of myocardial FAO, caloric-restricted ob/ob mice were treated for 1-week, either with systemic leptin (3mg/kg/day – study 1) or with intracerebroventricular (ICV) leptin via a cannula that was chronically implanted into the lateral ventricle (15ng/hr – study 2). FAO (nmol/mg/g) was determined in isolated working hearts perfused with 5mM glucose, 0.4mM palmitate and 1 nM insulin. Food intake was kept constant (2.5 g/day) but body weight was reduced by ICV leptin in CR- ob/ob mice (from 26±0.9 to 23.7±0.7 g, p<0.05). In study 1: FAO was elevated in CR-ob/ob mice (513±50) and was reduced to 367±31 by systemic leptin (p<0.05), which was not different from that of lean CR-wildtype mice (337 ±34). In study 2: FAO in CR-ob/ob mice was also increased relative to CR- wildtype mice (334±14 vs. 179±17, p<0.05). ICV leptin normalized FAO to wildtype levels (214±32, p <0.05 vs. CR-ob/ob). ICV leptin restored circulating insulin to wildtype levels (from 0.8±0.2 ng/mL to 0.3 ng/mL, p<0.05) and reduced FFA concentrations in CR-ob/ob from 1.6±0.3 mM to levels that were equivalent to wildtype controls (0.6±0.1 mM, p<0.05). In parallel, expression levels of the PPAR-α targets MCAD, LCAD and HADH-a/b, which were increased in CR-ob/ob mice were normalized to wildtype levels after ICV leptin repletion. In conclusion, hypothalamic leptin resistance contributes to elevated FAO in obesity by regulating insulin sensitivity and the circulating concentrations of FFA, which are PPAR-α ligands.
- © 2010 by American Heart Association, Inc.