Essential Role of STAT3 in Body Weight and Glucose Homeostasis

Author:

Cui Yunxia12,Huang Lu12,Elefteriou Florent3,Yang Guoqing12,Shelton John M.4,Giles Jerald E.12,Oz Orhan K.5,Pourbahrami Tiffany12,Lu Christopher Y. H.6,Richardson James A.4,Karsenty Gerard3,Li Cai126

Affiliation:

1. Touchstone Center for Diabetes Research

2. Department of Physiology

3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030

4. Department of Pathology

5. Department of Radiology

6. Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854

Abstract

ABSTRACT 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, STAT3 lox/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 β 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/STAT3 lox/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/STAT3 lox/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/STAT3 lox/lox mice. Administration of recombinant leptin by intracerebroventricular infusion failed to cause complete loss of body fat in RIP-Cre/STAT3 lox/lox mice. Transplantation of wild-type islets into RIP-Cre/STAT3 lox/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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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