Abstract

Obesity arises from disrupted energy homeostasis, yet the neural mechanisms linking transcriptional regulation to energy expenditure remain unclear. Here, we identify plant homeodomain finger protein 6 (Phf6), a gene mutated in Börjeson-Forssman-Lehmann syndrome (BFLS), as a pivotal regulator of energy balance. Phf6 is enriched in a subset of estrogen receptor 1 (Esr1)-expressing neurons within the hypothalamic medial preoptic area (MPOA). Knockout of Phf6 in the MPOA leads to obesity in a sex-dependent manner by reducing physical activity and energy expenditure, independent of food intake. In female mice, MPOA Phf6 neurons respond to physical activity. Activation and inhibition of MPOA Phf6 neurons increases and decreases physical activity and energy expenditure, respectively. Phf6 sustains the intrinsic excitability of MPOA Phf6 neurons and their responsiveness to estrogen. Circuit mapping identified an MPOA Phf6- VMHvl Esr1 pathway mediating Phf6’s effect on metabolism. These findings reveal a neurobiological basis for BFLS-associated obesity and highlight potential therapeutic targets.