This study investigates the effects of butyric acid, a short-chain fatty acid, on insulin sensitivity and energy expenditure in mice fed a high-fat diet. The researchers administered sodium butyrate at 5% wt/wt in the high-fat diet to dietary-obese C57BL/6J mice. The results showed that butyrate supplementation prevented the development of insulin resistance and obesity, preserved fasting blood glucose and insulin levels, and maintained body fat content without reducing food intake. Butyrate also enhanced adaptive thermogenesis and fatty acid oxidation, increased mitochondrial function and biogenesis in skeletal muscle and brown fat, and enriched type I muscle fibers. Additionally, butyrate upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression at both mRNA and protein levels, elevated AMP kinase and p38 activities, and reduced histone deacetylase activity. In obese mice, butyrate supplementation improved insulin sensitivity and reduced adiposity. The study concludes that dietary supplementation with butyrate can prevent and treat diet-induced insulin resistance and obesity in mice, with mechanisms involving increased energy expenditure and mitochondrial function.This study investigates the effects of butyric acid, a short-chain fatty acid, on insulin sensitivity and energy expenditure in mice fed a high-fat diet. The researchers administered sodium butyrate at 5% wt/wt in the high-fat diet to dietary-obese C57BL/6J mice. The results showed that butyrate supplementation prevented the development of insulin resistance and obesity, preserved fasting blood glucose and insulin levels, and maintained body fat content without reducing food intake. Butyrate also enhanced adaptive thermogenesis and fatty acid oxidation, increased mitochondrial function and biogenesis in skeletal muscle and brown fat, and enriched type I muscle fibers. Additionally, butyrate upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression at both mRNA and protein levels, elevated AMP kinase and p38 activities, and reduced histone deacetylase activity. In obese mice, butyrate supplementation improved insulin sensitivity and reduced adiposity. The study concludes that dietary supplementation with butyrate can prevent and treat diet-induced insulin resistance and obesity in mice, with mechanisms involving increased energy expenditure and mitochondrial function.