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PNAS 102 (50): 18011-18016

Copyright © 2005 by the National Academy of Sciences.

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



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  		Fig. 1.. Effect of high fat feeding on body weight and plasma leptin levels. (A) Mean (±SEM) body weight of normal 5-week-old SD rats fed a 4% ({triangleup}) or 60% ({bullet}) fat diet for the times as indicated. (B) Mean (±SEM) plasma leptin level of 4% and 60% fat-fed rats. (C) Phosphorylated STAT-3 content of WAT of the rats 12 weeks after the start of the 4% or 60% fat feeding.

 


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  		Fig. 2.. Comparison of the effect of overnutrition on the response of adipose tissue to exogenous hyperleptinemia induced by i.v. administration of AdCMV-leptin (+) or AdCMV-{beta}-galactosidase as a control (–). (A) Mean (±SEM) plasma leptin levels. (B) Mean (±SEM) body fat, measured by magnetic nuclear resonance spectroscopy. (C) Phosphorylated and total STAT-3 content, measured by immunoblotting, of WAT in normal (+/+) ZDF rats fed either 6% or 60% fat.

 


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  		Fig. 3.. Effect of 20 weeks of overnutrition on the expression profiles of leptin, the leptin inhibitor, SOCS-3, and the leptin receptor, Lepr-b, in adipose tissue of normal rats. (A) The mRNA of leptin. (B) Lepr-b. (C) SOCS-3 in WAT of normal lean SD rats fed either a 4% ({triangleup}) or 60% ({bullet}) fat diet (*, P < 0.05).

 


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  		Fig. 4.. The adipocyte-specific Lepr-b transgene and its obesity-preventing phenotype. (A) Map of the aP2-Lepr-b transgene construct. (B) Immunoblot for Lepr-b in WAT from Lepr-b-transgenic mice and wild-type controls. (C) Mean (±SEM) body weight of Lepr-b-transgenic mice ({triangleup}) and wild-type controls ({bullet}) on a 60% fat diet. *, P < 0.001. (D) Gross appearance of a wild-type (Left) and a Lepr-b-transgenic (Right) mouse after 12 weeks on a 60% fat diet. (E) Comparison of WAT of a wild-type and a Lepr-b-transgenic mouse after 12 weeks on a 60% fat diet. (F) Activated STAT-3 (P-STAT-3) in WAT of wild-type and Lepr-b-transgenic mice on a 60% fat diet. (G) Activated AMP-activated protein kinase (P-AMPK) in WAT of the wild-type and Lepr-b-transgenic mice on a 60% fat diet.

 

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