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PNAS 102 (50): 18011-18016

Copyright © 2005 by the National Academy of Sciences.

DEVELOPMENTAL BIOLOGY

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

May-yun Wang *, Lelio Orci {dagger}, Mariella Ravazzola {dagger}, and Roger H. Unger *, {ddagger}, §

*Gifford Laboratories, Touchstone Center for Diabetes Research and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8854; {ddagger}Veterans Affairs Medical Center, Dallas, TX 75216; and {dagger}Department of Cell Physiology and Metabolism, University Medical Center, CH-1211 Geneva 4, Switzerland

Contributed by Roger H. Unger, October 14, 2005

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-{gamma}-coactivator-1{alpha}, 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.

Key Words: autocrine/paracrine action • diet-induced obesity • hyperleptinemia • lepr-b • AMP-activated protein kinase

Author contributions: M.-y.W. and R.H.U. designed research; M.-y.W. and L.O. performed research; L.O. and M.R. contributed new reagents/analytic tools; M.-y.W., L.O., M.R., and R.H.U. analyzed data; and M.-y.W., L.O., and R.H.U. wrote the paper.

Conflict of interest statement: No conflicts declared.

Abbreviations: AMPK, AMP-activated protein kinase; DIO, diet-induced obesity; HFD, high fat diet; SD, Sprague–Dawley; SOCS, suppressor of cytokine signaling; TBST, TBS containing 0.1% Tween; TG, triglyceride; UCP, uncoupling protein; WAT, white adipose tissue; ZDF, Zucker diabetic fatty.

§ To whom correspondence should be addressed. E-mail: roger.unger{at}utsouthwestern.edu.

© 2005 by The National Academy of Sciences of the USA

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