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, MPOAPhf6 neurons respond to physical activity. Activation and inhibition of MPOAPhf6 neurons increases and decreases physical activity and energy expenditure, respectively. Phf6 sustains the intrinsic excitability of MPOAPhf6 neurons and their responsiveness to estrogen. Circuit mapping identified an MPOAPhf6-VMHvlEsr1 pathway mediating Phf6’s effect on metabolism. These findings reveal a neurobiological basis for BFLS-associated obesity and highlight potential therapeutic targets. Neural mechanisms underlying energy metabolism are not fully understood. Here authors show that Phf6-expressing neurons in the medial preoptic area as key regulators of physical activity and energy expenditure, revealing a neural mechanism underlying obesity in Börjeson-Forssman-Lehmann syndrome.
Wang et al. (Tue,) studied this question.