Fat storage in adipocytes requires inactivation of leptin's paracrine activity: Implications for treatment of human obesity

May-Yun Wang, Lelio Orci, Mariella Ravazzola, Roger H Unger

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despite a 10-fold higher plasma leptin. In 6 days of a HFD, mRNA of the postreceptor leptin inhibitor, suppressor of cytokine signaling-3, increased 22-fold in WAT, while leptin receptor (Lepr-b) mRNA gradually disappeared, implying leptinergic blockade at both postreceptor and receptor levels. Adipocyte-specific Lepr-b overexpression of a Lepr-b transgene completely prevented the adipocyte hypertrophy and hyperplasia and the increase in body fat induced in wild-type mice by HFD. Activated STAT-3 and AMP-activated protein kinase (AMPK), and the mRNA of lipooxidative enzymes, peroxisome proliferator-activated receptor-γ-coactivator-1α, and uncoupling protein-1 and -2 were increased in WAT. Body temperature was elevated in the transgenic mice, suggesting uncoupled fatty acid oxidation of surplus fatty acids. In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes.

Original languageEnglish (US)
Pages (from-to)18011-18016
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number50
DOIs
StatePublished - Dec 13 2005

Keywords

  • AMP-activated protein kinase
  • Autocrine/paracrine action
  • Diet-induced obesity
  • Hyperleptinemia
  • Lepr-b

ASJC Scopus subject areas

  • General

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