This review finds that obesity is linked to reciprocal interactions between diet, the gut microbiome, microbial metabolites, and host metabolic pathways that influence appetite, insulin sensitivity, inflammation, and energy balance across the lifespan. It highlights diet as a particularly tractable way to influence this system, while emphasizing that microbiome changes associated with GLP-1 therapies remain difficult to separate from weight loss and that functional multi-omics approaches may help enable more personalized interventions.