High-fat diet feeding rapidly induces sex-specific neuronal plasticity in lateral hypothalamic glutamatergic neurons

Hypothalamic circuits play a central role in coordinating feeding and energy balance, yet how these circuits adapt to dietary excess to regulate body weight remains poorly understood. Lateral hypothalamic area glutamatergic (LHA Vglut2 ) neurons critically mediate food intake and body weight, but how they adapt their function to acute overfeeding and whether such adaptation is sexually dimorphic are unknown. Here, we examined the impact of high-fat diet (HFD) on LHA Vglut2 neurons in mice. Whole-cell recordings revealed baseline sex differences in neuronal properties: female LHA Vglut2 neurons exhibited higher basal excitability and differential synaptic input compared to males. HFD feeding produced distinct forms of neuronal plasticity between sexes within 1 day. In males, HFD increased intrinsic excitability while excitatory synaptic input was decreased. In contrast, excitability of female LHA Vglut2 neurons remained unchanged, but inhibitory synaptic strength was selectively reduced. To test the causal relationship between enhanced LHA Vglut2 neuron excitability and weight gain during overfeeding, we expressed the depolarizing sodium channel NaChBac to chronically increase LHA Vglut2 neuron excitability. Chronic elevation of LHA Vglut2 neuron excitability suppressed body weight gain during acute HFD exposure in males, whereas females displayed significant weight loss during HFD exposure. Together, these results suggest that female mice may be protected from diet-induced obesity via sexually dimorphic LHA Vglut2 neurons. In males, overfeeding rapidly induces compensatory changes in LHA Vglut2 neuron excitability that may act to limit body weight gain. Further enhancement of LHA Vglut2 neuron excitability can suppress weight gain in an obesogenic environment for both males and females. Significance Statement Chronic overeating alters hypothalamic circuits that regulate feeding, but the time course of these adaptations and whether they differ between sexes is poorly understood. Here we show that overeating engages lateral hypothalamic glutamatergic neurons, which negatively regulate food intake and body weight, through sexually dimorphic mechanisms. In males but not females, overfeeding rapidly enhances excitability of lateral hypothalamic glutamatergic neurons. These sex-specific adaptations lead to distinct behavioral outcomes following chronic neuronal activation. Our findings reveal that hypothalamic circuits employ fundamentally different strategies across sexes to respond to dietary excess, providing insight into sex-dependent vulnerability to metabolic disorders.