Estrogen-receptor alpha (ERα) neurons in the ventrolateral region of the ventromedial hypothalamus (VMHVL) control an array of sex-specific responses to maximize reproductive success. In females, these VMHVL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERα VMHVL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMHVL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERα and Tac1 signaling. Disrupting development of Nkx2-1+ VMHVL neurons results in female-specific obesity, inactivity, and loss of VMHVL neurons co-expressing ERα and Tac1. Unexpectedly, two responses controlled by ERα neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMHVL neurons marked by ERα, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses.

Previous studies have shown reduced hypothalamo-pituitary-adrenal responses to both acute and chronic restraint stressors in rats allowed to ingest highly palatable foods (32% sucrose +/- lard) prior to restraint. In this study we tested the effects of prior access (7 d) to chow-only, sucrose/chow, lard/chow, or sucrose/lard/chow diets on central corticotropin-releasing factor (CRF) expression in rats studied in two experiments, 15 and 240 min after onset of restraint. Fat depot, particularly intraabdominal fat, weights were increased by prior access to palatable food, and circulating leptin concentrations were elevated in all groups. Metabolite concentrations were appropriate for values obtained after stressors. For unknown reasons, the 15-min experiment did not replicate previous results. In the 240-min experiment, ACTH and corticosterone responses were inhibited, as previously, and CRF mRNA in the hypothalamus and oval nucleus of the bed nuclei of the stria terminalis were reduced by palatable foods, suggesting strongly that both neuroendocrine and autonomic outflows are decreased by increased caloric deposition and palatable food. In the central nucleus of the amygdala, CRF was increased in the sucrose-drinking group and decreased in the sucrose/lard group, suggesting that the consequence of ingestion of sucrose uses different neural networks from the ingestion of lard. The results suggest strongly that ingestion of highly palatable foods reduces activity in the central stress response network, perhaps reducing the feeling of stressors.

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In addition to its established role in the immune system, tumour necrosis factor (TNF ) exerts complex regulatory actions on adipose tissue. TNF is produced in and secreted by the adipocyte and thus is in a position to exert a paracrine and/or autocrine role within adipose tissue. TNF affects many aspects of adipocyte function, from adipocyte development to lipid metabolism. Bringing together all of these diverse actions, TNF appears to play a general role in reducing adipose tissue mass. Dysregulation of TNF production and/or action could be one facet in the development of cachexia and obesity, as well as associated metabolic disorders such as insulin resistance.