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Molecular and Cellular Biology, January 2004, p. 258-269, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.258-269.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Essential Role of STAT3 in Body Weight and Glucose Homeostasis

Yunxia Cui,1,2,{dagger} Lu Huang,1,2,{dagger},{ddagger} Florent Elefteriou,3 Guoqing Yang,1,2 John M. Shelton,4 Jerald E. Giles,1,2 Orhan K. Oz,5 Tiffany Pourbahrami,1,2 Christopher Y. H. Lu,6 James A. Richardson,4 Gerard Karsenty,3 and Cai Li1,2,6*

Touchstone Center for Diabetes Research,1 Department of Physiology,2 Department of Pathology,4 Department of Radiology,5 Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854,6 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 770303

Received 30 May 2003/ Returned for modification 5 August 2003/ Accepted 8 October 2003

STAT3 is a ubiquitous transcription factor that is indispensable during early embryogenesis. To study the functions of STAT3 postnatally, we generated conditional STAT3-deficient mice. To that end, STAT3lox/lox mice were crossed with mice expressing Cre under the control of rat insulin II gene promoter (RIP-Cre mice). Immunohistochemical and Western blot analyses showed that STAT3 is deleted from ß cells in the islets of Langerhans. Genomic DNA PCR revealed that STAT3 deletion also occurred in the hypothalamus. Hypothalamic Cre expression was further confirmed by crossing RIP-Cre/STAT3lox/lox mice with the ROSA26 Cre reporter strain and staining for lacZ activity. Double immunohistochemical staining confirmed that deletion of STAT3 occurred in leptin receptor (OB-Rb isoform)-positive neurons. RIP-Cre/STAT3lox/lox mice are mildly hyperglycemic and hyperinsulinemic at the time of weaning, become hyperphagic immediately after weaning, and exhibit impaired glucose tolerance. Body weight, body fat, and mRNA and protein levels of leptin are all significantly increased in RIP-Cre/STAT3lox/lox mice. Administration of recombinant leptin by intracerebroventricular infusion failed to cause complete loss of body fat in RIP-Cre/STAT3lox/lox mice. Transplantation of wild-type islets into RIP-Cre/STAT3lox/lox mice also failed to decrease adiposity or to correct other abnormalities in these mice. These data thus suggest that loss of STAT3 in the hypothalamus caused by RIP-Cre action likely interferes with normal body weight homeostasis and glucose metabolism.

* Corresponding author. Mailing address: Touchstone Center for Diabetes Research, Departments of Physiology and Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8854. Phone: (214) 648-3340. Fax: (214) 648-9191. E-mail: Cai.Li{at}UTSouthwestern.edu.

{dagger} Y.C. and L.H. contributed equally to this work.

{ddagger} Present address: Shanghai Haojia Technology Development Co., Ltd., Shanghai 200235, People’s Republic of China.

Molecular and Cellular Biology, January 2004, p. 258-269, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.258-269.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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