Primary cilia in the hypothalamic AgRP neurons mediate metabolic effects of butyrate

The microbiota-derived short-chain fatty acid (SCFA), butyrate influences host metabolism beyond the gut, including central regulation of appetite and energy homeostasis. However, mechanistic insights into central butyrate metabolic actions are undetermined. Here, we demonstrated that primary cilia of agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus are essential for butyrate's anorexigenic effects and glucose homeostasis. Notably, peripheral or central butyrate administration to the mice significantly enhanced hypothalamic ciliogenesis, possibly through increased histone acetylation and activation of ciliogenic transcription factors, leading to suppressed food intake and improved metabolism. Disrupting cilia in the hypothalamus or specifically in AgRP neurons, but not in ventromedial hypothalamus neurons, abolished these effects. At the neuronal level, butyrate inhibited AgRP neuron activity, and this effect was markedly reduced following primary cilia deletion, indicating that cilia are crucial for butyrate's inhibitory action. These findings establish primary cilia in AgRP neurons as essential mediators of butyrate's metabolic effects.