Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin.
Leptin acts on the brain to regulate body weight and neuroendocrine function. Proopiomelanocortin (POMC) neurons in the hypothalamus are important targets of leptin. These cells express the leptin receptor ObRb, and leptin can regulate POMC mRNA levels, but the cellular mechanisms by which this occurs is unknown. Here we show evidence that leptin stimulates pomc gene transcription via activation of intracellular signal transducer and activator of transcription 3 (STAT3) proteins. In pomc-promoter assays using transfected cells, leptin induces pomc promoter activity. Expression of dominant negative STAT3 strongly suppresses this effect. Furthermore, maximal activation requires the presence of the STAT3-binding site, tyrosine 1138, of ObRb. Mutational analysis identifies a 30-bp promoter element that is required for regulation by leptin. In rats, robust leptin-dependent induction of STAT3 phosphorylation is demonstrated in hypothalamic POMC neurons using double immunohistochemistry. In total, approximately 37% of POMC cells are positive for phospho-STAT3 after leptin treatment. Furthermore, leptin-responsive POMC neurons are concentrated in the rostral region of the hypothalamus. Combined, our data show that a subpopulation of POMC neurons is leptin-responsive and suggest that stimulation of hypothalamic pomc gene expression in these cells requires STAT3 activation. We speculate that STAT3 is critical for leptin-dependent effects on energy homeostasis that are mediated by the central melanocortin system.
Münzberg
Heike
H
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Huo
Lihong
L
Nillni
Eduardo A
EA
Hollenberg
Anthony N
AN
Bjørbaek
Christian
C
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007031:Hypothalamus / Q000502:physiology*; D007033:Hypothalamus, Middle / Q000166:cytology / Q000502:physiology; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000502:physiology; D054411:Receptors, Leptin; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D020738:Leptin; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; C515447:leptin receptor, mouse; D011333:Pro-Opiomelanocortin