Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin.
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.


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.
Rahmouni
Kamal
K
Center on Functional Genomics of Hypertension, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA. kamal-rahmouni@uiowa.edu
Sigmund
Curt D
CD
Haynes
William G
WG
Mark
Allyn L
AL
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002149:Energy Intake; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D054411:Receptors, Leptin / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology
D020738:Leptin; D054411:Receptors, Leptin; D048049:Extracellular Signal-Regulated MAP Kinases