A hypothalamic circuit links high-fat diet exposure to anxiety-like behavior and anxiety-associated hyperphagia

Obesity and anxiety disorders are frequently comorbid, yet the neural circuit mechanisms linking metabolic and affective states remain incompletely understood. Here, in male mice exposed to long-term high-fat diet, we identify a hypothalamic circuit comprising arcuate nucleus agouti-related protein neurons and paraventricular nucleus corticotropin-releasing hormone neurons that regulates anxiety-like behavior under metabolic stress, with downstream recruitment of lateral hypothalamic area glutamatergic neurons to modulate feeding in a state-dependent manner. In vivo fiber photometry and ex vivo electrophysiology show that high-fat diet enhances activity and feeding-locked recruitment of this circuit, associated with increased anxiety-like behavior and feeding. Circuit-specific inhibition attenuates both phenotypes, whereas corticotropin-releasing hormone receptor 2 signaling in the lateral hypothalamic area selectively mediates high-fat diet-associated hyperphagia without affecting anxiety-like behavior. In this work, we show a disease-state-dependent hypothalamic circuit differentially recruited under chronic high-fat diet to coordinate anxiety-related behavior and feeding output, providing a framework for metabolic-affective interactions.