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Central Leptin Signaling Is Required to Normalize Myocardial Fatty Acid Oxidation Rates in Caloric-Restricted ob/ob Mice.

Authors Sloan C, Tuinei J, Nemetz K, Frandsen J, Soto J, Wride N, Sempokuya T, Alegria L, Bugger H, Abel ED Submitted By E. Dale Abel on 5/2/2011 Status Published Journal Diabetes Year 2011 Date Published 5/1/2011 Volume : Pages 60 : 1424 - 1434 PubMed Reference 21441440 Abstract OBJECTIVE ob/ob and db/db mice manifest myocardial hypertrophy, insulin resistance, altered substrate utilization, mitochondrial dysfunction, and lipid accumulation. This study was designed to determine the contribution of central and peripheral leptin signaling to myocardial metabolism and function in ob/ob and db/db mice in the absence of diabetes and morbid obesity. RESEARCH DESIGN AND METHODS Male ob/ob mice (aged 4 weeks) were caloric restricted by pairfeeding to a leptin-treated ob/ob group. In addition to determining glucose tolerance and circulating lipid concentrations, myocardial substrate metabolism and mitochondrial function were determined in saponin-permeabilized cardiac fibers. Second, experiments were performed to determine whether leptin treatment by intraperitoneal injection or intracerebroventricular infusion could normalize myocardial palmitate oxidation in caloric-restricted ob/ob mouse hearts. RESULTS Despite normalizing body weight and glucose tolerance, fat mass and circulating lipid levels remained increased in caloric-restricted ob/ob animals. Palmitate oxidation remained elevated in caloric-restricted ob/ob hearts and was normalized by intraperitoneal or intracerebroventricular leptin. Intraperitoneal and intracerebroventricular treatment also normalized circulating free fatty acid levels, myocardial fatty acid oxidation gene expression, and myocardial insulin sensitivity. CONCLUSIONS These data suggest that impaired hypothalamic leptin signaling is sufficient to increase myocardial fatty acid oxidation by increasing delivery of free fatty acid substrates and peroxisome proliferator-activated receptor-a ligands to the heart.

Investigators with authorship
Name Institution E. Dale Abel University of Iowa

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