1529-P: Medial Preoptic Area FoxO1 Controls Thermogenesis in a Sexually Dimorphic Manner

The medial preoptic area (MPOA) is a thermointegrative center that mediates metabolic adaptation to temperature change, contributing to body weight homeostasis. The Forkhead transcription factor O1 (FoxO1) plays a crucial role in mediating the effects of leptin and insulin on metabolic homeostasis in the hypothalamus. However, the metabolic function of FoxO1 in the MPOA has not been explored. In our study, we observed that the mRNA and protein expression of FoxO1 in the MPOA decreased in female mice after a 2-week high-fat diet (HFD) challenge, but not in male mice. Specific deletion of FoxO1 in MPOA neurons (FoxO1^MPOA-KO) did not affect body weight in animals fed a chow diet at room temperature. However, it prevented HFD-induced obesity (DIO) in female mice, but not in male mice. This female-specific protection was associated with increased lean mass, decreased fat mass, enhanced thermogenic activity in adipose tissues, increased energy expenditure, and unchanged food intake compared to control mice with DIO. Female FoxO1^MPOA-KO mice also showed increased temperature-dependent changes in energy expenditure, specifically when exposed to cold (6 °C), but not when exposed to thermoneutrality (30 °C) or at a room temperature (22 °C). Furthermore, the protection against DIO in females induced by FoxO1^MPOA-KO was diminished by ovariectomy (OVX), and supplementation with 17β-estradiol after OVX failed to restore this protection, suggesting an estrogen-independent mechanism. Finally, mice with constitutively activated FoxO1 in MPOA neurons (FoxO1^MPOA-CA) showed significantly increased DIO and poor glucose tolerance in both sexes, further supporting the essential metabolic role of FoxO1^MPOA. These findings indicate that FoxO1^MPOA plays a crucial role in directing and coordinating the metabolic adaptation to nutritional or environmental temperature challenges in female mice.