The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism

TLDR

Dietary carbohydrate fermented by gut microbiota has been linked to weight loss, yet the mechanism remains unknown. In vivo 11C‑acetate PET‑CT demonstrates that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate suppresses appetite, activates hypothalamic neurons, upregulates acetyl‑CoA carboxylase, shifts neuropeptide expression toward appetite suppression, and increases hypothalamic 13C acetate and related neurotransmitter cycle labeling, indicating a direct central role in appetite regulation.

Abstract

Abstract Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo 11 C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13 C high-resolution magic-angle-spinning that 13 C acetate from fermentation of 13 C-labelled carbohydrate in the colon increases hypothalamic 13 C acetate above baseline levels. Hypothalamic 13 C acetate regionally increases the 13 C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13 C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation.