Liporegulation in Diet-induced Obesity: The antisteatotic role of hyperleptinemia

Young H Lee, May-Yun Wang, Tetsuya Kakuma, Zhuo Wei Wang, Evelyn E Babcock, Kay McCorkle, Moritake Higa, Yan Ting Zhou, Roger H Unger

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

To test the hypothesis that the physiologic liporegulatory role of hyperleptinemia is to prevent steatosis during caloric excess, we induced obesity by feeding normal Harlan Sprague-Dawley rats a 60% fat diet. Hyperleptinemia began within 24 h and increased progressively to 26 ng/ml after 10 weeks, correlating with an ∼150-fold increase in body fat (r = 0.91, p < 0.0001). During this time, the triacylglycerol (TG) content of nonadipose tissues rose only 1-2.7-fold implying antisteatotic activity. In rodents without leptin action (fa/fa rats and ob/ob and db/db mice) receiving a 6% fat diet, nonadipose tissue TG was 4-100 times normal. In normal rats on a 60% fat diet, peroxisome proliferator-activated receptor α protein and liver-carnitine palmitoyltransferase-1 (L-CPT-1) mRNA increased in liver. In their pancreatic islets, fatty-acid oxidation increased 30% without detectable increase in the expression of peroxisome proliferator-activated receptor-α or oxidative enzymes, whereas lipogenesis from [ 14C]glucose was slightly below that of the 4% fat-fed rats (p < 0.05). Tissue-specific overexpression of wild-type leptin receptors in the livers of fa/fa rats, in which marked steatosis is uniformly present, reduced TG accumulation in liver but nowhere else. We conclude that a physiologic role of the hyperleptinemia of caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing the up-regulation of lipogenesis and increasing fatty-acid oxidation.

Original languageEnglish (US)
Pages (from-to)5629-5635
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number8
DOIs
StatePublished - Feb 23 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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