Sex-specific thermoregulatory effects of estrogen signaling in Reprimo lineage cells

Menopause affects over a million individuals annually and is characterized by variable and declining ovarian hormones. Decreasing estrogen levels impact energy homeostasis and increases the risk of metabolic disorders. Energy expenditure is largely directed towards thermoregulation, which is modulated in part by estrogen receptor (ER) α expressing neurons in the hypothalamus. Whether specific sub-populations of ERα+ neurons control the effects of estrogens on thermogenesis remains poorly understood. This study investigates the function of ERα in neurons that express Rprm (Reprimo), a gene we previously linked to thermoregulation in females. Here, we use a novel ReprimoCre mouse to selectively knock out ERα in Rprm lineage neurons (Reprimo-specific estrogen receptor α KO; RERKO) and report changes in core temperature in female mice, with no changes in body weight, body composition, or food intake. RERKO females have elevated brown adipose tissue (BAT) temperature and lower tail temperature relative to controls, suggesting increased heat production and impaired heat dissipation, respectively. Developmental expression of Rprm was detected in the brain, but not in BAT or white adipose tissue suggesting temperature changes may be mediated by the nervous system. Thus, we next ablated Rprm expressing neurons in the ventrolateral area of the ventromedial nucleus of the hypothalamus (VMHvl) and observed a reduction in core temperature and increased fat mass in ablated female mice relative to controls. Taken together, these results show that estrogen signaling in Rprm expressing cells and VMHvl ^Rprm neurons are critical for thermoregulation, mainly through the modulation of brown adipose tissue thermogenesis in female, but not male mice.