Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice.
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.
Lee
Young
Y
Gifford Laboratories, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8854, USA.
Naseem
R Haris
RH
Duplomb
Laurence
L
Park
Byung-Hyun
BH
Garry
Daniel J
DJ
Richardson
James A
JA
Schaffer
Jean E
JE
Unger
Roger H
RH
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
D020738:Leptin; D008055:Lipids; D012333:RNA, Messenger; D014280:Triglycerides; D003066:Coenzyme A Ligases