The nose knows: Olfaction as a metabolic gatekeeper in health and disease

Long regarded as an accessory sense, olfaction is now emerging as a metabolic architect—an active agent in energy homeostasis, appetite regulation, and systemic physiology. This review explores the converging lines of evidence positioning the olfactory system not as a passive enhancer of flavor but as a dynamic mediator between environment, behavior, and internal metabolic state. Food odors engage specific olfactory receptors (OR s ), which are embedded in neural circuits that project to hypothalamic, limbic, and reward regions. These circuits modulate insulin release, lipid metabolism, thermogenesis, and feeding behavior—often before a single bite is taken. This sensory-metabolic dialogue is continuously tuned by hormonal signals (e.g., leptin, ghrelin, insulin) and deeply shaped by genetic variation across the ~400 human OR genes, where individual differences in perception carry metabolic consequences. Yet this ancient sensory system now operates in a radically altered chemical landscape. Synthetic volatiles, industrial food aromas, and urban pollutants desensitize olfactory pathways, potentially contributing to overeating and metabolic disease. In parallel, a new therapeutic frontier is emerging: targeted modulation of olfactory pathways—via intranasal hormones, neuromodulation, sensory retraining, and personalized interventions informed by OR genotypes—offers a compelling strategy for precision metabolic care. Revisiting Sydney Whiting's 1853 satire, in which “Smell” was cast as a meddling underling at the digestive gates, we now find this once-overlooked sentinel wielding remarkable authority. The nose, it turns out, knows—and may yet hold the key to rebalancing metabolism in a world that smells very different from the one we evolved to navigate.