Estrogens and leptins act in the hypothalamus to maintain reproduction and energy homeostasis. Neurogenesis in the adult mammalian hypothalamus has been implicated in the regulation of energy homeostasis. Recently, high fat diet (HFD) and estradiol (E2) have been shown to alter cell proliferation and the number of newborn leptin-responsive neurons in the hypothalamus of adult female mice. The current study tested the hypothesis that new cells expressing estrogen receptor α (ERα) are generated in the arcuate nucleus (ARC) and the ventromedial nucleus (VMH) of the adult female mouse, hypothalamic regions that are critical in energy homeostasis. Adult mice were ovariectomized and implanted with capsules containing E2 or oil (Veh). Within each hormone group, mice were fed a HFD or standard chow for 6 weeks and treated with BrdU to label new cells. Newborn cells that respond to estrogens were identified in the ARC and VMH, of which a subpopulation were leptin-sensitive, indicating they are neurons. Moreover, there was an interaction between diet and hormone on the number of these newborn ERα expressing neurons that respond to leptin. Regardless of hormone treatment, HFD increased the number of ERα expressing cells in the ARC and VMH. E2 decreased hypothalamic fibroblast growth factor 10 (Fgf10) gene expression in HFD mice, suggesting a role for Fgf10 in E2 effects on neurogenesis. These findings of newly created estrogen-responsive neurons in the adult brain provide a novel mechanism by which estrogens can act in the hypothalamus to regulate energy homeostasis in females.
Significance Statement: Estrogens and leptin act in the hypothalamus to profoundly impact energy homeostasis in humans and rodents. For example, postmenopausal women gain weight, increasing their risk for heart disease and diabetes. Hypothalamic neurogenesis has been implicated in energy homeostasis in adult male and female rodents. In the present study, newborn neurons that respond to estrogens and leptins were identified in the adult female mouse hypothalamus. Moreover, the generation of these newborn hypothalamic neurons was regulated by estradiol and high fat diet. Estradiol decreased hypothalamic Fgf10 gene expression in HFD mice, suggesting a role for Fgf10 in estradiol effects on neurogenesis. These findings provide a novel mechanism by which estrogens can act in the female hypothalamus to regulate energy homeostasis.
Authors report no conflict of interest.
This work was funded by an NIH R01 DK61935 (MJT) and a Re-entry Award (EPB) from the National Institute of Diabetes and Digestive and Kidney Diseases.