Acetate, a short-chain fatty acid produced by colonic fermentation of dietary fibre, reduces appetite through central mechanisms in the brain. This study used in vivo 11C-acetate and PET-CT to show that acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal acetate administration suppressed appetite and activated hypothalamic neurons. Acetate also activated acetyl-CoA carboxylase and altered the expression of neuropeptides that favor appetite suppression. Using 13C high-resolution magic-angle-spinning, the study found that 13C acetate from colonically fermented 13C-labeled carbohydrate increased hypothalamic 13C acetate above baseline levels, enhancing glutamate-glutamine and GABA neuroglial cycles. These findings suggest that acetate directly regulates central appetite. The study also showed that acetate reduces food intake in mice, with acute i.p. injection of acetate (500 mg kg-1) leading to a significant reduction in food intake at 1 and 2 hours post-injection. Acetate did not affect blood glucose or circulating levels of PYY and GLP-1. Central administration of acetate into the third ventricle of rats also reduced food intake, though less potently than in mice. Acetate increased the expression of POMC and suppressed AgRP, favoring appetite suppression. Acetate also reduced AMPK activity, leading to increased ACC activity, which elevated malonyl-CoA and stimulated POMC expression, reducing food intake. The study further demonstrated that acetate preferentially accumulates in the hypothalamus, where it is metabolized in astrocytes, leading to increased glutamate-glutamine and GABA cycles. 13C acetate from colonically fermented carbohydrate showed higher incorporation into hypothalamic metabolism than in other brain regions. These findings suggest that acetate, derived from colonic fermentation of dietary fibre, plays a direct role in central appetite regulation. The study highlights the potential of acetate as a therapeutic agent for obesity prevention and treatment.Acetate, a short-chain fatty acid produced by colonic fermentation of dietary fibre, reduces appetite through central mechanisms in the brain. This study used in vivo 11C-acetate and PET-CT to show that acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal acetate administration suppressed appetite and activated hypothalamic neurons. Acetate also activated acetyl-CoA carboxylase and altered the expression of neuropeptides that favor appetite suppression. Using 13C high-resolution magic-angle-spinning, the study found that 13C acetate from colonically fermented 13C-labeled carbohydrate increased hypothalamic 13C acetate above baseline levels, enhancing glutamate-glutamine and GABA neuroglial cycles. These findings suggest that acetate directly regulates central appetite. The study also showed that acetate reduces food intake in mice, with acute i.p. injection of acetate (500 mg kg-1) leading to a significant reduction in food intake at 1 and 2 hours post-injection. Acetate did not affect blood glucose or circulating levels of PYY and GLP-1. Central administration of acetate into the third ventricle of rats also reduced food intake, though less potently than in mice. Acetate increased the expression of POMC and suppressed AgRP, favoring appetite suppression. Acetate also reduced AMPK activity, leading to increased ACC activity, which elevated malonyl-CoA and stimulated POMC expression, reducing food intake. The study further demonstrated that acetate preferentially accumulates in the hypothalamus, where it is metabolized in astrocytes, leading to increased glutamate-glutamine and GABA cycles. 13C acetate from colonically fermented carbohydrate showed higher incorporation into hypothalamic metabolism than in other brain regions. These findings suggest that acetate, derived from colonic fermentation of dietary fibre, plays a direct role in central appetite regulation. The study highlights the potential of acetate as a therapeutic agent for obesity prevention and treatment.