FoxO1 inhibits leptin regulation of pro-opiomelanocortin promoter activity by blocking STAT3 interaction with specificity protein 1.
Leptin controls food intake and energy expenditure by regulating hypothalamic neuron activities. Leptin exerts its actions through complex signaling pathways including STAT3 phosphorylation, nuclear translocation, and binding to target gene promoter/cofactor complexes. Deficient or defective leptin signaling leads to obesity, which may be caused by insufficient leptin levels and/or resistance to leptin signaling. To understand the molecular mechanisms of leptin resistance, we studied the regulation of pro-opiomelanocortin (POMC) gene expression by leptin. We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter. Furthermore, FoxO1 binds to STAT3 and prevents STAT3 from interacting with the SP1.POMC promoter complex, and consequently, inhibits STAT3-mediated leptin action. Our study suggests that leptin action could be inhibited at a step downstream of STAT3 phosphorylation and nuclear translocation, and provides a potential mechanism of leptin resistance in which an increased FoxO1 antagonizes STAT3-mediated leptin signaling.
Yang
Guoqing
G
Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667.
Lim
Chun-Yan
CY
Li
Chao
C
Xiao
Xiaoqiu
X
Radda
George K
GK
Li
Cai
C
Cao
Xinmin
X
Han
Weiping
W
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D020738:Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016329:Sp1 Transcription Factor; C494087:Stat3 protein, mouse; D011333:Pro-Opiomelanocortin