Microbiota-derived metabolites as nutritional signals in insulin resistance and obesity

Obesity and insulin resistance represent major global health challenges driven by complex interactions between diet, host metabolism, and environmental factors. Beyond traditional calorie- and macronutrient-centered models, growing evidence highlights the gut microbiota as a critical metabolic interface linking dietary substrates to host metabolic regulation. In particular, metabolites produced by gut microorganisms including short-chain fatty acids, secondary bile acids, indole derivatives, branched-chain amino acid related metabolites, and trimethylamine N-oxide function as active nutritional signals that influence glucose homeostasis, energy balance, inflammation, and insulin sensitivity through defined receptor-mediated and intracellular signaling pathways. Dietary composition strongly determines microbial metabolite production by shaping substrate availability and fermentation flux, thereby modulating host metabolic responses. This review summarizes the evidence across mechanistic, translational, and human dietary intervention studies to outline how microbial metabolites mediate the effects of dietary fibers, fat quality, protein sources, and bioactive food components on obesity and insulin resistance. Key signaling pathways, including SCFA-GPCR signaling, bile acid-FXR/TGR5 signaling, and indole-aryl hydrocarbon receptor interactions, are discussed in relation to metabolic tissues such as the gut, liver, adipose tissue, and skeletal muscle. The review further highlights inter-individual variability in metabolite responses, emerging metabolite signatures associated with insulin resistance, and the therapeutic potential of nutrition-based strategies that target microbial metabolic outputs rather than microbial composition alone. Collectively, focusing on microbiota-derived metabolites enables a direct understanding of how diet influences host metabolic pathways, supporting the development of targeted nutrition-based strategies for insulin resistance and obesity.