title: Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice.
abstract: The physiologic function of the progressive hyperleptinemia of diet-induced obesity is unknown. However, that lipotoxicity in nonadipose tissues of congenitally unleptinized obese rodents is far greater than in hyperleptinemic diet-induced obesity rodents has suggested an antilipotoxic role. To test this hypothesis, mice with severe lipotoxic cardiomyopathy, induced transgenically by cardiomyocyte-specific overexpression of the acyl CoA synthase (ACS) gene, were made hyperleptinemic by treatment with recombinant adenovirus containing the leptin cDNA. Normoleptinemic control ACS-transgenic mice developed severe dilated cardiomyopathy with thickened left ventricular walls and profound impairment of systolic function on echocardiogram; histologically, there was severe myofiber disorganization and interstitial fibrosis, with intracytoplasmic lipid vacuoles identifiable by electron microscope. By contrast, the hearts of hyperleptinemic ACS-transgenic mice appeared normal, with normal echocardiograms and cardiac triglyceride (TG) contents. Their lower myocardial TG content was ascribed primarily to profound lowering of plasma TG and free fatty acids; free fatty acids were 17% of normal at 8 weeks. Additionally, enhanced myocardial AMP-activated protein kinase phosphorylation may have increased fatty acid oxidation, thereby contributing to the lowering of lipid stores. We conclude that obesity-level hyperleptinemia protects the heart from lipotoxicity.
authors.affiliation: Gifford Laboratories, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8854, USA.
authors.forename: Young
authors.initials: Y
authors.lastname: Lee
authors.forename: R Haris
authors.initials: RH
authors.lastname: Naseem
authors.forename: Laurence
authors.initials: L
authors.lastname: Duplomb
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Garry
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.forename: Roger H
authors.initials: RH
authors.lastname: Unger
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D009202:Cardiomyopathies / Q000097:blood / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000097:blood*; D008055:Lipids / Q000097:blood*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D020738:Leptin; D008055:Lipids; D012333:RNA, Messenger; D014280:Triglycerides; D003066:Coenzyme A Ligases