Publication Type Academic Article
Authors Musatov S, Chen W, Pfaff D, Mobbs C, Yang X, Clegg D, Kaplitt M, Ogawa S
Journal Proc Natl Acad Sci U S A
Volume 104
Issue 7
Pagination 2501-6
Date Published 02/06/2007
ISSN 0027-8424
Keywords Estrogen Receptor alpha, Metabolic Syndrome, RNA Interference, Ventromedial Hypothalamic Nucleus
Abstract Estrogen receptor alpha (ERalpha) plays a pivotal role in the regulation of food intake and energy expenditure by estrogens. Although it is well documented that a disruption of ERalpha signaling in ERalpha knockout (ERKO) mice leads to an obese phenotype, the sites of estrogen action and mechanisms underlying this phenomenon are still largely unknown. In the present study, we exploited RNA interference mediated by adeno-associated viral vectors to achieve focused silencing of ERalpha in the ventromedial nucleus of the hypothalamus, a key center of energy homeostasis. After suppression of ERalpha expression in this nucleus, female mice and rats developed a phenotype characteristic for metabolic syndrome and marked by obesity, hyperphagia, impaired tolerance to glucose, and reduced energy expenditure. This phenotype persisted despite normal ERalpha levels elsewhere in the brain. Although an increase in food intake preceded weight gain, our data suggest that a leading factor of obesity in this model is likely a decline in energy expenditure with all three major constituents being affected, including voluntary activity, basal metabolic rate, and diet-induced thermogenesis. Together, these findings indicate that ERalpha in the ventromedial nucleus of the hypothalamus neurons plays an essential role in the control of energy balance and the maintenance of normal body weight.
DOI 10.1073/pnas.0610787104
PubMed ID 17284595
PubMed Central ID PMC1892990
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