Sex-Specific Thermoregulatory Effects of Estrogen Signaling in Reprimo Lineage Cells

Abstract Estrogens have considerable effects on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor α (ERα) alters energy intake and expenditure, effects that may be mediated by specific regions or cellular subpopulations of the hypothalamus. This study investigates the function of ERα signaling in the lineage that expresses Rprm (reprimo), a gene we previously linked to thermoregulation in females. Here, we engineered a novel ReprimoCre mouse to selectively knock out ERα in Rprm lineage cells (Reprimo-specific ERα knockout [KO]; RERKO). We report modest changes in core temperature, higher brown adipose tissue (BAT) mass, elevated BAT temperature during the light phase, and lower tail temperature during the light phase in RERKO females relative to controls. RERKO females also exhibited a subtle difference in locomotion and no differences in feeding or body mass. These phenotypes suggest sex-specific effects on the patterns of body temperature instead of overall increases or decreases in heat generation or dissipation. Labeling of the Rprm lineage was detected in the brain, but not in BAT or white adipose, suggesting that temperature changes may be mediated by the nervous system. To test for centrally mediated effects on temperature, we ablated Rprm-expressing cells in the mediobasal hypothalamus. Although this approach eliminates the cells entirely instead of selectively eliminating ERα in Rprm-expressing cells, we observed a phenotype similar to RERKO mice, with effects on core temperature and BAT mass. Together, these results indicate that estrogen signaling in the Rprm lineage is important for thermoregulation in female, but not male, mice.