Insulin and leptin have overlapping effects in the control of energy homeos
tasis, but the molecular basis of this synergism is unknown, Insulin signal
s through a receptor tyrosine kinase that phosphorylates and activates the
docking proteins IRSs (insulin receptor substrates), whereas the leptin rec
eptor and its associated protein tyrosine kinase JAK2 (Janus kinase 2) medi
ate phosphorylation and activation of the transcription factor STAT3 (signa
l transducer and activator of transcription). Here, we present evidence for
the integration of leptin and insulin signals in the hypothalamus. Insulin
induced JAK2 tyrosine phosphorylation, leptin receptor phosphorylation whi
ch, in the presence of leptin, augmented the interaction between STAT3 and
this receptor. Insulin also increased the leptin-induced phosphorylation of
STAT3 and its activation. These results indicate that insulin modulates th
e leptin signal transduction pathway, and may provide a molecular basis for
the coordinated effects of insulin and leptin in feeding behavior and weig
ht control. (C) 2001 Published by Elsevier Science B.V. on behalf of the Fe
deration of European Biochemical Societies.