Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation.
Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3(N-/-)). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3(N-/-) mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db/db and ob/ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.
Gao
Qian
Q
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Wolfgang
Michael J
MJ
Neschen
Susanne
S
Morino
Katsutaro
K
Horvath
Tamas L
TL
Shulman
Gerald I
GI
Fu
Xin-Yuan
XY
D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics; D002001:Adipose Tissue, Brown / Q000473:pathology / Q000502:physiology; D000818:Animals; D001833:Body Temperature Regulation / Q000235:genetics*; D003345:Corticosterone / Q000097:blood; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D007247:Infertility, Female / Q000235:genetics*; D007248:Infertility, Male / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics; D007700:Kinetics; D020738:Leptin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009765:Obesity / Q000235:genetics*; D051381:Rats; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D007381:Intermediate Filament Proteins; D020738:Leptin; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D003345:Corticosterone