Critical role of STAT3 in leptin's metabolic actions.
Leptin has pleiotropic effects on glucose homeostasis and feeding behavior. Here, we validate the use of a cell-permeable phosphopeptide that blocks STAT3 activation in vivo. The combination of this biochemical approach with stereotaxic surgical techniques allowed us to pinpoint the contribution of hypothalamic STAT3 to the acute effects of leptin on food intake and glucose homeostasis. Leptin's ability to acutely reduce food intake critically depends on intact STAT3 signaling. Likewise, hypothalamic signaling of leptin through STAT3 is required for the acute effects of leptin on liver glucose fluxes. Lifelong obliteration of STAT3 signaling via the leptin receptor in mice (s/s mice) results in severe hepatic insulin resistance that is comparable to that observed in db/db mice, devoid of leptin receptor signaling. Our results demonstrate that the activation of the hypothalamic STAT3 pathway is an absolute requirement for the effects of leptin on food intake and hepatic glucose metabolism.
Buettner
Christoph
C
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Pocai
Alessandro
A
Muse
Evan D
ED
Etgen
Anne M
AM
Myers
Martin G
MG
Rossetti
Luciano
L
D000818:Animals; D001069:Appetite Regulation / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D007986:Luteinizing Hormone; D005947:Glucose