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Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction.

ABSTRACT: Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-? (ER?). However, ER?-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ER? in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ER? in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ER? in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ER? from both SF1 and POMC neurons causes hypometabolism, hyperphagia, and increased visceral adiposity. Additionally, female mice lacking ER? in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ER? inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ER? neurons to regulate different aspects of energy homeostasis and reproduction.

SUBMITTER: Xu Y

PROVIDER: S-EPMC3235745 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction.

Xu Yong Y Nedungadi Thekkethil P TP Zhu Liangru L Sobhani Nasim N Irani Boman G BG Davis Kathryn E KE Zhang Xiaorui X Zou Fang F Gent Lana M LM Hahner Lisa D LD Khan Sohaib A SA Elias Carol F CF Elmquist Joel K JK Clegg Deborah J DJ

Cell metabolism 20111001 4

Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-α (ERα). However, ERα-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ERα in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ERα in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion ...[more]

PMID: 21982706

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Project description:OBJECTIVE:The cocaine- and amphetamine-regulated transcript (CART) codes for a pivotal neuropeptide important in the control of appetite and energy homeostasis. However, limited understanding exists for the defined effector sites underlying CART function, as discrepant effects of central CART administration have been reported. METHODS:By combining Cart-cre knock-in mice with a Cart adeno-associated viral vector designed using the flip-excision switch (AAV-FLEX) technology, specific reintroduction or overexpression of CART selectively in CART neurons in the arcuate nucleus (Arc) and lateral hypothalamic area (LHA), respectively, was achieved. The effects on energy homeostasis control were investigated. RESULTS:Here we show that CART neuron-specific reintroduction of CART into the Arc and LHA leads to distinct effects on energy homeostasis control. Specifically, CART reintroduction into the Arc of otherwise CART-deficient Cartcre/cre mice markedly decreased fat mass and body weight, whereas CART reintroduction into the LHA caused significant fat mass gain and lean mass loss, but overall unaltered body weight. The reduced adiposity in ArcCART;Cartcre/cre mice was associated with an increase in both energy expenditure and physical activity, along with significantly decreased Npy mRNA levels in the Arc but with no change in food consumption. Distinctively, the elevated fat mass in LHACART;Cartcre/cre mice was accompanied by diminished insulin responsiveness and glucose tolerance, greater spontaneous food intake, and reduced energy expenditure, which is consistent with the observed decrease of brown adipose tissue temperature. This is also in line with significantly reduced tyrosine hydroxylase (Th) and notably increased corticotropin-releasing hormone (Crh) mRNA expressions in the paraventricular nucleus (PVN). CONCLUSIONS:Taken together, these results identify catabolic and anabolic effects of CART in the Arc and LHA, respectively, demonstrating for the first time the distinct and region-specific functions of CART in controlling feeding and energy homeostasis.

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Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction.

Publications

Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction.

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