This study investigates the role of acetate in the gut microbiota-brain-β cell axis and its impact on metabolic syndrome. The authors found that increased production of acetate by an altered gut microbiota leads to activation of the parasympathetic nervous system, which in turn promotes increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia, and obesity. The gut microbiota is identified as the primary source of increased acetate production, and the study demonstrates that this acetate drives GSIS through parasympathetic activation. Chronic increases in acetate turnover lead to obesity, hyperphagia, and metabolic syndrome, which can be mitigated by vagotomy. The gut microbiota's role in generating acetate and its subsequent effects on GSIS and metabolic health suggest potential therapeutic targets for obesity and related conditions.This study investigates the role of acetate in the gut microbiota-brain-β cell axis and its impact on metabolic syndrome. The authors found that increased production of acetate by an altered gut microbiota leads to activation of the parasympathetic nervous system, which in turn promotes increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia, and obesity. The gut microbiota is identified as the primary source of increased acetate production, and the study demonstrates that this acetate drives GSIS through parasympathetic activation. Chronic increases in acetate turnover lead to obesity, hyperphagia, and metabolic syndrome, which can be mitigated by vagotomy. The gut microbiota's role in generating acetate and its subsequent effects on GSIS and metabolic health suggest potential therapeutic targets for obesity and related conditions.