STAT3 signalling is required for leptin regulation of energy balance but not reproduction.
Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.
Bates
Sarah H
SH
Research Division, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, Massachusetts 02215, USA.
Stearns
Walter H
WH
Dundon
Trevor A
TA
Schubert
Markus
M
Tso
Annette W K
AW
Wang
Yongping
Y
Banks
Alexander S
AS
Lavery
Hugh J
HJ
Haq
Asma K
AK
Maratos-Flier
Eleftheria
E
Neel
Benjamin G
BG
Schwartz
Michael W
MW
Myers
Martin G
MG
D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics; D004734:Energy Metabolism; D030762:Estrous Cycle / Q000502:physiology; D005260:Female; D006706:Homeostasis; D006801:Humans; D007246:Infertility / Q000235:genetics; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D009478:Neuropeptide Y / Q000235:genetics; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin; D012098:Reproduction / Q000502:physiology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D000521:alpha-MSH / Q000235:genetics
D001786:Blood Glucose; D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D020738:Leptin; D009478:Neuropeptide Y; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C515447:leptin receptor, mouse; D000521:alpha-MSH