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J Biol Chem, Vol. 275, Issue 15, 11348-11354, April 14, 2000
From the Departments of Although many effects of leptin are mediated
through the central nervous system, leptin can regulate metabolism
through a direct action on peripheral tissues, such as fat and liver.
We show here that leptin, at physiological concentrations, acts through an intracellular signaling pathway similar to that activated by insulin
in isolated primary rat hepatocytes. This pathway involves stimulation
of phosphatidylinositol 3-kinase (PI3K) binding to insulin receptor
substrate-1 and insulin receptor substrate-2, activation of PI3K and
protein kinase B (AKT), and PI3K-dependent activation of
cyclic nucleotide phosphodiesterase 3B, a cAMP-degrading enzyme. One
important function of this signaling pathway is to reduce levels of
cAMP, because leptin-mediated activation of both protein kinase B and
phosphodiesterase 3B is most marked following elevation of cAMP by
glucagon, and because leptin suppresses glucagon-induced cAMP elevation
in a PI3K-dependent manner. There is little or no
expression of the long form leptin receptor in primary rat hepatocytes,
and these signaling events are probably mediated through the short
forms of the leptin receptor. Thus, leptin, like insulin, induces an
intracellular signaling pathway in hepatocytes that culminates in cAMP
degradation and an antagonism of the actions of glucagon.
Leptin Induces Insulin-like Signaling That Antagonizes cAMP
Elevation by Glucagon in Hepatocytes*
§,,,,¶,,, and
**
Pharmacology and
Pathology, University of Washington,
Seattle, Washington 98195
*
This work was supported by National Institutes of Health
Grants DK-21723 (to J. A. B.) and DK-42528 (to E. G. K.), a Pilot and Feasibility Award from the Diabetes
Endocrinology Research Center at the University of Washington funded by
National Institutes of Health Project Grant P30 DK17047, a Career
Development Award from the American Diabetes Association, and the
Marian E. Smith Junior Faculty Research Award (to K. E. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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