The study investigates the mechanism by which short-chain fatty acids (SCFAs), specifically acetate, reduce appetite through central homeostatic mechanisms. Using in vivo 11C-acetate and PET-CT scanning, the researchers show that colonic acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal administration of acetate suppresses appetite and activates hypothalamic neurons. Acetate administration also activates acetyl-CoA carboxylase and changes the expression profiles of regulatory neuropeptides that favor appetite suppression. Additionally, 13C high-resolution magic-angle-spinning (HR-MAS) reveals that 13C acetate from colonally fermented carbohydrate increases hypothalamic 13C acetate levels, which in turn increases the 13C labeling of the glutamate-glutamine and GABA neuroglial cycles. These findings suggest that acetate has a direct role in central appetite regulation, potentially opening new avenues for therapeutic strategies to combat obesity.The study investigates the mechanism by which short-chain fatty acids (SCFAs), specifically acetate, reduce appetite through central homeostatic mechanisms. Using in vivo 11C-acetate and PET-CT scanning, the researchers show that colonic acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal administration of acetate suppresses appetite and activates hypothalamic neurons. Acetate administration also activates acetyl-CoA carboxylase and changes the expression profiles of regulatory neuropeptides that favor appetite suppression. Additionally, 13C high-resolution magic-angle-spinning (HR-MAS) reveals that 13C acetate from colonally fermented carbohydrate increases hypothalamic 13C acetate levels, which in turn increases the 13C labeling of the glutamate-glutamine and GABA neuroglial cycles. These findings suggest that acetate has a direct role in central appetite regulation, potentially opening new avenues for therapeutic strategies to combat obesity.