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(Received for publication, October 2, 1996, and in revised form, February 3, 1997)
From the Hoechst AG, HMR, Research Area Frankfurt,
D-65926 Frankfurt, Federal Republic of Germany
Leptin is an adipocyte hormone involved in the
regulation of energy homeostasis. Generally accepted biological effects
of leptin are inhibition of food intake and stimulation of metabolic rate in ob/ob mice that are defective in the
leptin gene. In contrast to these centrally mediated effects of leptin,
we are reporting here on leptin effects on isolated rat adipocytes.
Leptin impairs several metabolic actions of insulin, i.e.
stimulation of glucose transport, glycogen synthase, lipogenesis,
inhibition of isoproterenol-induced lipolysis, and protein kinase A
activation, as well as stimulation of protein synthesis. Insulin
effects were reduced by leptin (2 nM) with a half-life of
about 8 h. At low leptin concentrations (<1 nM), the
insulin sensitivity was reduced leading to a shift to the right in the
dose-response curve. At higher concentrations the responsiveness was
diminished, resulting in nearly complete inhibition of insulin effects
at >30 nM leptin. The IC50 value of leptin was
3.1 ± 1 nM after 15 h of preincubation of
adipocytes in primary culture. The natural splice variant
des-Gln49-leptin exhibited a significantly lower potency.
Adipocytes regained full insulin sensitivity within a few hours after
leptin removal. The stimulation of glucose transport by vanadate was
not affected by leptin. These data show specific and potent impairment
of insulin action by leptin in the physiological concentration range of
both leptin and insulin, which may be related to the pathophysiology of
insulin resistance in both non-insulin-dependent diabetes mellitus and obesity.
Volume 272, Number 16,
Issue of April 18, 1997
pp. 10585-10593
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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