Abstract
Free fatty acids (FFAs)2 take part in many physiological processes in different tissues such as skeletal muscle, liver, heart, and pancreas by providing an oxidative energy source. In addition, FFAs are potent signaling molecules (1). Dysregulation of FFA metabolism is responsible for insulin resistance and type 2 diabetes mellitus (2). The presence of some FFAs is essential for glucose-stimulated insulin secretion from pancreatic β-cells. However, if FFAs are chronically in excess, they can reduce insulin biosynthesis and secretion and induce β-cell apoptosis (2). The regulatory effect of FFAs occurs in part by their involvement as substrates in intracellular lipid signaling pathways; however, FFAs also signal directly via seven transmembrane-spanning receptors (7TMRs; G protein-coupled receptors). Here, we consider 7TMRs that are activated by FFAs and FFA amides. Furthermore, we describe the identification and characterization of small molecule ligands for these FFA receptors (FFARs) that may be useful for treating patients with diabetes mellitus.
Highlights
Free fatty acids (FFAs)2 take part in many physiological processes in different tissues such as skeletal muscle, liver, heart, and pancreas by providing an oxidative energy source
FFAR1 and GPR120 are activated by medium- to longchain fatty acids, whereas FFAR2 and FFAR3 are activated by short-chain fatty acids
FFAR2 and FFAR3 have different tissue distributions and more broad expression profiles; FFAR2 is abundant in leukocytes and adipose tissue [6], whereas FFAR3 is highly expressed in brain, lung, and adipose tissue
Summary
All members of a previously characterized cluster of orphan 7TMRs comprising FFAR1 (previously known as GPR40), FFAR2 (previously known as GPR43), and FFAR3 (previously known as GPR41) are activated by FFAs within physiological concentration ranges [3]. The FFAR1 cluster is tandemly located on chromosome 19q13.1. These receptors share a relatively high sequence similarity but have diverse tissue distribution. The ability of FFAs to elevate Ca2ϩ in mouse intestinal endocrine STC-1 cells via GPR120 indicates interaction with members of the Gq family [11]. GPR120 is abundantly expressed in the intestine but is not expressed in the pancreas or clonal -cells [5]. FFAR2 and FFAR3 have different tissue distributions and more broad expression profiles; FFAR2 is abundant in leukocytes and adipose tissue [6], whereas FFAR3 is highly expressed in brain, lung, and adipose tissue
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