Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons

•Generation of 5-HT2CRYFP mouse line revealed 40% of hypothalamic POMC neurons co-express 5-HT2CRs in male and female mice.•Pomc expressed exclusively within 5-HT2CR cells modulates energy intake and insulin sensitivity in male and female mice.•An unexpected sex difference in physical activity and energy expenditure is modulated by hypothalamic Pomc.•Pomc expressed exclusively within 5-HT2CR cells differentially impacts body weight accumulation in male and female mice.