Asprosin is one of the very few orexigenic hormones known to facilitate food intake. Asprosin-deficient (Fbn1+/-) mice with knockout of single-allele of the fibrillin gene are resistant to weight gain even on a high-fat diet (HFD). As gut biota changes are linked with weight gain and obesity, we studied the microbiome of the heterozygote mice (Fbn1+/-) maintained on a standard Chow or HFD. Interestingly, we observed that Asprosin-deficient mice do not demonstrate gut dysbiosis on HFD. A higher abundance of butyrate-producing bacteria, faecal butyric acid (15-20µM/g faeces), and expression of the incretin hormone glucagon-like peptide 1 (Glp1) were observed. On the other hand, wild type animals on HFD had lower faecal butyrate concentrations and demonstrated significant gut dysbiosis. We hypothesised that butyrate plays a central role in obesity via regulation of incretin hormones and the microbiome. To establish causality, we infused butyric acid (0.11µL/min) in a wildtype (C57BL/6J) high-fat diet mouse model. We observed that butyrate infusion to the proximal colon reversed gut dysbiosis in just four days of infusion. To further study underlying mechanistic role of butyric acid, and assess implications for human insulin sensitivity, we exposed human (primary colonic) gut cells as well as human gut cell lines (T84, HT29) to high (10mM) concentration of butyric acid for four days. This resulted in increased expression of GLP1 (GCG), and cholecystokinin (CCK) by ~10-fold (n>40 biological replicates for cell lines and n=10 human primary colonic tissues, p<0.0001), with simultaneous downregulation of several HDAC regulators (HDAC1, HDAC6, HDAC7, etc.). Chromatin immunoprecipitation identified H3K4 activation at proglucagon region, confirming the epigenetic regulation of GLP1 production by butyric acid. Taken together, high concentrations of gut butyric acid may aid in the regulation of obesity by preventing microbial dysregulation and through epigenetic regulation of incretin (GLP1) expression.