Differential Regulation of Cardiac Substrate Utilization in Response to Chronic Central Nervous System Administration of Leptin and Melanotan II in Rats with Myocardial Infarction

Abstract

The brain leptin‐melanocortin system pathway plays an important role in regulating many physiological functions including energy homeostasis. We found that chronic intracerebroventricular (ICV) infusion of leptin or the melanocortin 4 receptor (MC4R) agonist Melanotan II, MTII, markedly attenuated cardiac dysfunction in rats with myocardial infarction (MI) induced by permanent left anterior descending coronary artery (LAD) ligation. In the present study we examined if activation of leptin‐MC4R axis in the central nervous system (CNS) alters cardiac substrate utilization in rats with MI. Male Sprague‐Dawley rats at 15 weeks of age were implanted with an ICV cannula into the lateral ventricle. After 10 days of recovery, the LAD was permanently ligated and saline vehicle (0.5 μL/hr, n=5), leptin (15 μg/day, n=5) or MTII (240 ng/day, n=3) was infused ICV via osmotic minipump for 14 consecutive days. On day 14 of treatment the hearts were quickly excised and perfused ex vivo in the working mode with glucose (5.5 mmol/L) and the fatty acid oleate (0.4 mmol/L). After a 5‐min baseline equilibration period the hearts were perfused for an additional 20 min and coronary flow samples were collected every 5 min to determine rates of substrate oxidation by quantitative measurement of [14C]O2 and [3H]2O using [U‐14C]glucose (0.08 μCi/ml) and [9,10‐3H]oleate (0.1 μCi/ml) as the radiolabeled tracers. Compared to vehicle treatment, chronic ICV leptin infusion for 2 weeks markedly increased glucose oxidation (0.60±0.04 vs. 0.27±0.02 μmol/min/g dry heart weight) without altering oleate oxidation (0.95±0.01 vs. 0.90±0.02 μmol/min/g dry heart weight). Chronic central MTII infusion did not alter glucose oxidation (0.25±0.03 vs. 0.27±0.02 μmol/min/g dry heart weight) but increased fatty acid oxidation compared to vehicle treatment (1.13±0.01 vs. 0.90±0.02 μmol/min/g dry heart weight). These results suggest the CNSmechanisms by which leptin and MC4R activation improve cardiac function post MI may involve increased myocardial bioenergetics by differential modulation of glucose and fatty acid utilization.Support or Funding InformationNHLBI PO1HL51971, NIGMS P20GM104357 and NIGMS U54GM115428This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.