Essential role of STAT3 in body weight and glucose homeostasis.
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 beta 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.
Cui
Yunxia
Y
Touchstone Center for Diabetes Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854, USA.
Huang
Lu
L
Elefteriou
Florent
F
Yang
Guoqing
G
Shelton
John M
JM
Giles
Jerald E
JE
Oz
Orhan K
OK
Pourbahrami
Tiffany
T
Lu
Christopher Y H
CY
Richardson
James A
JA
Karsenty
Gerard
G
Li
Cai
C
D000818:Animals; D001835:Body Weight / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D005947:Glucose