Hypothalamic ERK Mediates the Anorectic and Thermogenic Sympathetic Effects of Leptin

Kamal Rahmouni; Curt D Sigmund; William G Haynes; Allyn L Mark

doi:10.2337/db08-0822

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Hypothalamic ERK Mediates the Anorectic and Thermogenic Sympathetic Effects of Leptin

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Hypothalamic ERK Mediates the Anorectic and Thermogenic Sympathetic Effects of Leptin

Kamal Rahmouni, Curt D Sigmund, William G Haynes and Allyn L Mark

Diabetes (New York, N.Y.), Vol.58(3), pp.536-542

03/2009

DOI: 10.2337/db08-0822

PMCID: PMC2646051

PMID: 19066310

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Abstract

OBJECTIVE— Leptin is an adipocyte hormone that plays a major role in energy balance. Leptin receptors in the hypothalamus are known to signal via distinct mechanisms, including signal transducer and activator of transcription-3 (STAT3) and phosphoinositol-3 kinase (PI 3-kinase). Here, we tested the hypothesis that extracellular signal–regulated kinase (ERK) is mediating leptin action in the hypothalamus. RESEARCH DESIGN AND METHODS— Biochemical, pharmacological, and physiological approaches were combined to characterize leptin activation of ERK in the hypothalamus in rats. RESULTS— Leptin activates ERK1/2 in a receptor-mediated manner that involves JAK2. Leptin-induced ERK1/2 activation was restricted to the hypothalamic arcuate nucleus. Pharmacological blockade of hypothalamic ERK1/2 reverses the anorectic and weight-reducing effects of leptin. The pharmacological antagonists of ERK1/2 did not attenuate leptin-induced activation of STAT3 or PI 3-kinase. Blockade of ERK1/2 abolishes leptin-induced increases in sympathetic nerve traffic to thermogenic brown adipose tissue (BAT) but does not alter the stimulatory effects of leptin on sympathetic nerve activity to kidney, hindlimb, or adrenal gland. In contrast, blockade of PI 3-kinase prevents leptin-induced sympathetic activation to kidney but not to BAT, hindlimb, or adrenal gland. CONCLUSIONS— Our findings indicate that hypothalamic ERK plays a key role in the control of food intake, body weight, and thermogenic sympathetic outflow by leptin but does not participate in the cardiovascular and renal sympathetic actions of leptin.

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Title: Subtitle: Hypothalamic ERK Mediates the Anorectic and Thermogenic Sympathetic Effects of Leptin
Creators: Kamal Rahmouni - Center on Functional Genomics of Hypertension, Department of Internal Medicine, University of Iowa, Iowa City, Iowa
Curt D Sigmund - Center on Functional Genomics of Hypertension, Department of Internal Medicine, University of Iowa, Iowa City, Iowa
William G Haynes - Cardiovascular Research Center, Department of Internal Medicine, University of Iowa, Iowa City, Iowa
Allyn L Mark - Center on Functional Genomics of Hypertension, Department of Internal Medicine, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: Diabetes (New York, N.Y.), Vol.58(3), pp.536-542
DOI: 10.2337/db08-0822
PMID: 19066310
PMCID: PMC2646051
NLM abbreviation: Diabetes
ISSN: 0012-1797
eISSN: 1939-327X
Publisher: American Diabetes Association
Language: English
Date published: 03/2009
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040393602771

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