Background
Metabolic syndrome is a major public health issue, increasing the risk of type 2 diabetes and cardiovascular disease. While traditional dietary strategies focus on macronutrients and bioactive compounds, recent studies have focused on the role of ectopic olfactory receptors (ORs), expressed in non-nasal tissues, as novel metabolic sensors responsive to food-derived odorants. OR-odorant interactions are emerging as a novel mechanism contributing to the amelioration of metabolic syndrome.

Scope and approach
This review provides a comprehensive overview of research investigating ORs as potential therapeutic targets for metabolic syndrome. It covers tissue-specific expression of ectopic ORs, their signaling mechanisms, and metabolic responsiveness in metabolically relevant tissues, including adipose tissue, liver, pancreas, skeletal muscle, gut, and kidney.

Key findings and conclusions
Ectopic ORs exhibit tissue-specific expression and activate distinct signaling pathways in each tissue, reflecting their specialized roles in metabolic regulation. In adipose tissue and liver, OR activation regulates lipid metabolism, thermogenesis, and gluconeogenesis through distinct cAMP-PKA-based signaling pathways. In the pancreas, ORs in α- and β-cells modulate glucagon and insulin secretion via Ca2+-dependent or Gi-cAMP pathways, affecting glucose homeostasis. ORs in skeletal muscle, gut, and kidney regulate processes such as glucose uptake, mitochondrial biogenesis, intestinal hormone release, and renal glucose reabsorption, underscoring their broad impact on systemic energy homeostasis. These findings suggest that ORs act as functional mediators linking dietary odorants to systemic metabolic regulation; however, further research is needed to clarify the roles of uncharacterized ORs and evaluate their potential as therapeutic targets.