Polymorphic Variation in FFA Receptors: Functions and Consequences.

Overfeeding of fat can cause various metabolic disorders including obesity and type 2 diabetes (T2D). Diet provided free fatty acids (FFAs) are not only essential nutrients, but they are also recognized as signaling molecules, which stimulate various important biological functions. Recently, several G protein-coupled receptors (GPCRs), including FFA1-4, have been identified as receptors of FFAs by various physiological and pharmacological studies. FFAs exert physiological functions through these FFA receptors (FFARs) depending on carbon chain length and degree of unsaturation. Functional analyses have revealed that several important metabolic processes, such as peptide hormone secretion, cell maturation and nerve activities, are regulated by FFARs and thereby FFARs contribute to the energy homeostasis through these physiological functions. Hence, FFARs are expected to be promising pharmacological targets for metabolic disorders since imbalances in energy homeostasis lead to metabolic disorders. In human, it is established that different responses of individuals to endogenous ligands and chemical drugs may be due to differences in the ability of such ligands to activate nucleotide polymorphic variants of receptors. However, the clear links between genetic variations that are involved in metabolic disorders and polymorphisms receptors have been relatively difficult to assess. In this review, I summarize current literature describing physiological functions of FFARs and genetic variations of those receptors to discuss the potential of FFARs as drug targets for metabolic disorders.