Intestinal microbiota play an important role in determining susceptibility to obesity. Their ability to ferment non-digestible carbohydrates, to produce short-chain fatty acids (SCFAs), is thought to be important in influencing host metabolism. However, the underlying mechanisms are poorly understood. Using mice that lack the short-chain fatty acid receptor; free fatty acid receptor 2 (FFAR2), it was found that this receptor is essential for transducing the effects of fermentable carbohydrate to reduce food intake and prevent body weight gain. These beneficial metabolic effects were associated with an increase in the anorectic gut hormone peptide YY (PYY) due to an FFAR2-dependent increase in the density of PYY-expressing cells within the proximal colon. Inulin supplementation also increased GLP-1 cell density in the proximal colon, resulting in increased circulating GLP-1 concentrations. However, this was not dependent on expression of FFAR2. Further investigation revealed that the increase in PYY cell density was associated with increased expression of the paired-box transcription factor Pax4 known to function in terminal differentiation of PYY cells. It is, therefore, apparent that SCFAs, produced by microbial fermentation of inulin, act via FFAR2 to increase Pax4 expression and thereby enhance PYY cell proliferation. The ability of SCFAs to influence enteroendocrine cell fate and potentiate anorectic gut-brain signalling represents a paradigm shift in the understanding of nutrient sensing and highlights the potential for cellular engineering approaches for the treatment obesity.