Lipid sensing GPCRs as therapeutic targets G protein coupled

Lipid-sensing GPCRs as therapeutic targets G-protein-coupled receptors (GPCRs) comprise a family of cell-surface receptors that respond to various extracellular stimuli such as light, odorants, neurotransmitters and hormones, and trigger a cascade of intracellular signaling. There are approximately 850 predicted human GPCRs [1] that have specific cell type or tissue-specific CD 3254 and are involved in various physiological and clinical processes [2]. The importance of identification and characterization of GPCRs is underscored by the fact that ∼30% of all prescription drugs target GPCRs [3]. Because these drugs modulate approximately half of the well-characterized GPCRs, it is probable that many more GPCRs remain to be explored as potential drug targets. GPCRs in humans and mice show striking orthology, and the fact that highly related receptors are evolutionarily conserved suggests that these receptors are not functionally redundant [2]. Because human diseases involving GPCR mutations are extremely rare, occurring in less than 1 per 1000 people, they also provide a stable therapeutic target [4]. Free fatty acids (FFAs) can act as ligands of several GPCRs, including GPR119, GPR84, GPR120, GPR40 (FFAR1), GPR43 (FFAR2) and GPR41 (FFAR3) (Table 1). Fatty acids are categorized by the length of their aliphatic tails; short-chain fatty acids have less than 6 carbons, medium-chain fatty acids have 6–12 carbons and long-chain fatty acids have 12 or more carbons. Fatty acids can act as signaling molecules that modulate receptor signaling and gene expression [5]. GPR120 and GPR40 are activated by medium- and long-chain FFAs, and GPR119 is activated by long-chain fatty acids. GPR84 is activated by medium-chain fatty acids, whereas GPR43 and GPR41 are activated by short-chain FFAs [6]. In obesity and type 2 diabetes, elevated levels of plasma FFAs are observed, resulting in lipid accumulation and insulin resistance in target tissues [7]. FFAs exert divergent effects on insulin secretion from β cells. Acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs insulin secretion [7]. The dual and opposing effects of FFAs on insulin secretion raise the possibility that FFAs contribute to both hyperinsulinemia and hypoinsulinemia during the development of type 2 diabetes. Thus, GPCRs that recognize fatty acids are of particular interest in the treatment of type 2 diabetes [8]. Chronic low-grade metabolic inflammation, referred to as ‘metaflammation’ [9], has been established in the pathogenesis for obesity, insulin resistance and type 2 diabetes. The contribution of inflammation to insulin resistance has been extensively studied, and immunological changes occurring in adipose tissue, liver, brain, islets, the vasculature and circulating leukocytes, with concomitant changes in cytokines and chemokines, are important components of the etiology of insulin resistance and type 2 diabetes 9, 10. Although recent studies have identified the presence of different cells of the adaptive immune system, such as T cells and mast cells in adipose tissue, macrophages are the most abundant leukocyte population and are generally considered as the effector cell contributing to inflammation-mediated insulin resistance [10]. In addition, macrophage-mediated inflammation has been associated with many other diseases such as rheumatoid arthritis, cancer, inflammatory bowel disease, cardiovascular disease 11, 12, psoriasis [13], multiple sclerosis [14] and periodontitis [15]. A very interesting recent study showed that macrophages might mediate metastasis in breast cancer [16]. Macrophages can express a wide variety of GPCRs that modulate physiological processes such as inflammation and immunity. Furthermore, the expression of GPCRs differ in proinflammatory and anti-inflammatory macrophages [17]. The identification of endogenous and synthetic ligands to target inflammatory disease is therefore of great importance, and FFA-sensing GPCRs expressed in macrophages and insulin target tissues have emerged as therapeutic targets.