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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:The current study has investigated the hypothalamic gene expressions regulated by glucocorticoid (GC), key hormones in energy homeostasis. Using serial analysis of gene expression (SAGE) method, we have studied the effects of adrenalectomy (ADX) and GC on the transcriptomes of mouse hypothalamus. Approximately, 180 000 SAGE tags, which correspond to 50 000 tag species, were isolated from each group of intact or adrenalectomized mice, as well as 1, 3 and 24 hours after GC injection. ADX has upregulated diazepam binding inhibitor gene expression, while downregulating vomeronasal 1 receptor D4, genes involved in mitochondrial phosphorylation (cytochrome c oxidase 1 and NADH dehydrogenase 3), 3b-hydroxysteroid dehydrogenase-1, and prostaglandin D2 synthase. GC has increased the gene expression levels of dehydrogenase/reductase member 3, prostaglandin D2 synthase, solute carrier family 4 member 4, and five cytoskeletal proteins including myosin light chain phosphorylatable fast and troponin C2 fast. On the other hand, GC has reduced the mRNA levels of calmodilin 1 and expressed sequence tag similar to (EST) calmodilin 2, ATP synthase F0 subunit 6, and solute carrier family 4 member 3. Moreover, seven uncharacterized and 43 novel transcripts were modulated by ADX and GC. The current study has identified genes that may regulate hypothalamic systems governing energy balance in response to ADX and GC. Keywords: Hormone effect analysis Male C57BL6 mice were obtained from Charles River Laboratories (St. Constant, QC, Canada), at 12-14 weeks of age. Mice were housed in an air-conditioned room (19-25 degree) with controlled lighting from 07:15 to 19:15 h and were given free access to food (Lab Rodent Diet No. 5002) and water. One week prior to sampling of hypothalamus, adrenalectomy was performed in mice of all experimental groups (n = 12 per group). ADX mice received sodium chloride (0.9g/dl) in their drinking water after the surgery. GC (corticosterone, 0.1 mg per mouse) was subcutaneously injected to ADX mice and the hypothalamus was harvested at 1 hour (ADX + GC 1 h), 3 hours (ADX + GC 3 h) and 24 hours (ADX + GC 24 h) after the GC injection. ADX received an injection of vehicle solution (5% ethanol with 0.4% methocel A15LV premium) at 24 hours prior to sacrifice. All mice were killed between 08:30 and 12:30 by decapitation under isoflurane anesthesia. Brain was removed from the skull and the hypothalamus was immediately dissected, frozen in liquid nitrogen, pooled together for each group, and stored at -80 degree until RNA extraction.

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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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