Abstract 1129: Hypothalamic Leptin Action Normalizes Fatty Acid Oxidation in the Heart of Obese Mice via Cardiac AMP-Activated Protein Kinase Inhibition
Obese individuals have high rates of cardiac fatty acid oxidation and low glucose oxidation, which contributes to cardiac insulin-resistance and contractile dysfunction. The anorexic hormone, leptin, can regulate cardiac fatty acid oxidation both directly via cardiac leptin receptors, as well as indirectly via hypothalamic leptin receptors. However, what effect hypothalamic leptin administraton has on cardiac energy metabolism in obesity is not known. To address this, diet-induced obesity was produced in mice by feeding them a 60% fat diet for 8-weeks. Control mice were fed a 10% fat diet for 8-weeks. Mice were then centrally administered leptin (5 μg/day icv) or vehicle (ACSF) for a 7-day period. At the end of the 8-week period the high fat fed mice had a greater body weight in comparison to low fat fed mice (45.5±0.8 vs. 33.4±0.6 g, p±0.05). Central administration of leptin for 7-days decreased body weight in both low and high fat fed mice (high fat: −4.0±0.5 vs −1.2± 0.2 g; low fat: −3.1±0.5 vs −0.03±0.44 g, p±0.05). Fatty acid oxidation and glucose oxidation were then measured in isolated working hearts perfused with 0.8 mM [9,10-3H] palmitate, 5 mM [5-3H/U-14C]glucose, 2.5 mM Ca2+, 3% albumin and 50 μU/ml insulin. In high fat fed mice hearts administered vehicle, hearts obtained 86.3% of cardiac ATP production from fatty acid oxidation, compared to 53.2% in low fat fed mice. Leptin treatment decreased fatty acid oxidation to 81.7% of ATP production in high fat fed mice and 46.6% in low fat fed mice. The leptin-induced decrease in fatty acid oxidation was accompanied by a decrease in cardiac AMP-activated protein kinase (AMPK) activity, a fuel sensing kinase that activates fatty acid oxidation. This was accompanied by an increase in cardiac malonyl-CoA levels, an endogenous inhibitor of mitochondrial fatty acid uptake (high fat: 6.6±0.4 vs 8.5±0.3 nmol/g dry wt; low fat: 6.5±0.3 vs 8.8 ± 0.5 nmol/g dry wt, p<0.05). We conclude that leptin acting at the level of hypothalamus can inhibit cardiac fatty acid oxidation and increase glucose oxidation in obese mice. The effects of leptin are mediated by an increase in malonyl CoA, probably due to a decrease in AMPK inhibition of acetyl CoA carboxylase (which synthesizes malonyl CoA).