Chronic activation of inflammatory pathways mediates the pathogenesis of insulin resistance, and the macrophage/adipocyte nexus provides a key mechanism underlying decreased insulin sensitivity. Free fatty acids are important in the pathogenesis of insulin resistance, although their precise mechanisms of action have yet to be fully elucidated. Recently, a family of G-protein-coupled receptors has been identified that exhibits high affinity for fatty acids. This review summarizes recent findings on six of these receptors, their ligands, and their potential physiological functions in vivo.
Upon activation, the free fatty acid receptors affect inflammation, glucose metabolism, and insulin sensitivity. Genetic deletion of GPR40 and GPR41, receptors for long-chain and short-chain fatty acids, respectively, results in resistance to diet-induced obesity. Deletion of GPR43 and GPR84 exacerbates inflammation, and deletion of the long-chain fatty acid receptors GPR119 and GPR120 reduces or is predicted to reduce glucose tolerance.
These studies provide a new understanding of the general biology of gastric motility and also shed valuable insight into some potentially beneficial therapeutic targets. Furthermore, highly selective agonists or antagonists for the free fatty acid receptors have been developed and look promising for treating various metabolic diseases.
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA
*Da Young Oh and William S. Lagakos contributed equally to the writing of this article.
Correspondence to William S. Lagakos, PhD, Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA Tel: +1 856 904 8026; fax: +1 858 534 6653; e-mail: email@example.com