Functional potentiation of leptin-signal transducer and activator of transcription 3 signaling by the androgen receptor.
Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice.
Fan
WuQiang
W
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan.
Yanase
Toshihiko
T
Nishi
Yoshihiro
Y
Chiba
Seiichi
S
Okabe
Taijiro
T
Nomura
Masatoshi
M
Yoshimatsu
Hironobu
H
Kato
Shigeaki
S
Takayanagi
Ryoichi
R
Nawata
Hajime
H
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004435:Eating / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D020738:Leptin; D011944:Receptors, Androgen; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011333:Pro-Opiomelanocortin