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Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor

Department of Medicine and Bioregulatory Science (W.F., T.Y., T.O., M.N., R.T.), Graduate School of Medical Science (H.N.), Kyushu University, Fukuoka 812-8582, Japan; Department of Physiology (Y.N.), Kurume University School of Medicine, Kurume 830-0011, Japan; Department of Anatomy, Biology, and Medicine (S.C., H.Y.), Internal Medicine 1, Faculty of Medicine, Oita University, Oita-Shi 870-1192, Japan; and Institute of Molecular and Cellular Biosciences (S.K.), Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-0032, Japan

Address all correspondence and requests for reprints to: Toshihiko Yanase, M.D., Ph.D., Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yanase{at}intmed3.med.kyushu-u.ac.jp.

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 (AR^L-/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 AR^L-/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 AR^L-/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.