Olfactory dysfunction in obesity and type 2 diabetes: mechanistic insights from preclinical models

Olfaction and its dysfunction have gained increasing interest across a broad spectrum of research areas including ageing and neurodegenerative and psychiatric disorders. In addition, olfactory dysfunction is increasingly recognised as a common feature of metabolic disorders, with mounting evidence linking an impaired sense of smell to obesity and type 2 diabetes. While the olfactory system was once considered negligible in humans, it has now emerged as a critical modulator of feeding-related behaviours, endocrine regulation, and energy and glucose homeostasis. Studies in both humans and animal models highlight the bidirectional interaction between olfactory processing and metabolic status, suggesting that olfactory changes are not merely consequences of obesity and type 2 diabetes, but may also contribute to their development and progression. This review summarises current findings on the mechanisms associated with olfactory dysfunction in obesity and type 2 diabetes in rodent models, from the initial detection of odorants in the nasal cavity to the downstream neural circuits and their physiological and behavioural outcomes. Particular emphasis is placed on the emerging concept of sensory regulation of metabolism, highlighting how food sensory cues, including food odours, influence whole-body metabolism and obesogenic responses. Finally, the therapeutic potential of targeting the olfactory system to improve olfactory performance and the olfactory regulation of whole-body metabolism is discussed. Olfactory-based therapeutics may offer novel and promising strategies for the prevention and treatment of metabolic diseases.