Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice

Young H Lee, R. Haris Naseem, Laurence Duplomb, Byung Hyun Park, Daniel J. Carry, James A Richardson, Jean E. Schaffer, Roger H Unger

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

The physiologic function of the progressive hyperleptinemia of diet-induced obesity is unknown. However, that lipotoxicity in nonadipose tissues of congenially 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.

Original languageEnglish (US)
Pages (from-to)13624-13629
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number37
DOIs
StatePublished - Sep 14 2004

Keywords

  • AMP-activated protein kinase
  • Apoptosis
  • Leptin
  • SIRT1
  • Triglycerides

ASJC Scopus subject areas

  • General

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