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Free fatty acid receptors as therapeutic targets for the treatment of diabetes.

ABSTRACT: Nutrition regulates energy balance; however, dysfunction of energy balance can cause metabolic disorders, such as obesity and diabetes. Fatty acids are an essential energy source and signaling molecules that regulate various cellular processes and physiological functions. Recently, several orphan G protein-coupled receptors were identified as free fatty acid receptors (FFARs). GPR40/FFAR1 and GPR120/FFAR4 are activated by medium- and/or long-chain fatty acids, whereas GPR41/FFAR3 and GPR43/FFAR2 are activated by short-chain fatty acids. FFARs are regarded as targets for novel drugs to treat metabolic disorders, such as obesity and type 2 diabetes, because recent studies have showed that these receptors are involved in the energy metabolism in various tissues, including adipose, intestinal, and immune tissue. In this review, we summarize physiological roles of the FFARs, provide a comprehensive overview of energy regulation by FFARs, and discuss new prospects for treatment of metabolic disorders.

SUBMITTER: Ichimura A

PROVIDER: S-EPMC4222138 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Free fatty acid receptors as therapeutic targets for the treatment of diabetes.

Ichimura Atsuhiko A Hasegawa Sae S Kasubuchi Mayu M Kimura Ikuo I

Frontiers in pharmacology 20141106

Nutrition regulates energy balance; however, dysfunction of energy balance can cause metabolic disorders, such as obesity and diabetes. Fatty acids are an essential energy source and signaling molecules that regulate various cellular processes and physiological functions. Recently, several orphan G protein-coupled receptors were identified as free fatty acid receptors (FFARs). GPR40/FFAR1 and GPR120/FFAR4 are activated by medium- and/or long-chain fatty acids, whereas GPR41/FFAR3 and GPR43/FFAR2 ...[more]

PMID: 25414667

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Project description:BackgroundThe free fatty acid receptors (FFAs), including FFA1 (orphan name: GPR40), FFA2 (GPR43) and FFA3 (GPR41) are G protein-coupled receptors (GPCRs) involved in energy and metabolic homeostasis. Understanding the structural basis of ligand binding at FFAs is an essential step toward designing potent and selective small molecule modulators.ResultsWe analyse earlier homology models of FFAs in light of the newly published FFA1 crystal structure co-crystallized with TAK-875, an ago-allosteric ligand, focusing on the architecture of the extracellular binding cavity and agonist-receptor interactions. The previous low-resolution homology models of FFAs were helpful in highlighting the location of the ligand binding site and the key residues for ligand anchoring. However, homology models were not accurate in establishing the nature of all ligand-receptor contacts and the precise ligand-binding mode. From analysis of structural models and mutagenesis, it appears that the position of helices 3, 4 and 5 is crucial in ligand docking. The FFA1-based homology models of FFA2 and FFA3 were constructed and used to compare the FFA subtypes. From docking studies we propose an alternative binding mode for orthosteric agonists at FFA1 and FFA2, involving the interhelical space between helices 4 and 5. This binding mode can explain mutagenesis results for residues at positions 4.56 and 5.42. The novel FFAs structural models highlight higher aromaticity of the FFA2 binding cavity and higher hydrophilicity of the FFA3 binding cavity. The role of the residues at the second extracellular loop used in mutagenesis is reanalysed. The third positively-charged residue in the binding cavity of FFAs, located in helix 2, is identified and predicted to coordinate allosteric modulators.ConclusionsThe novel structural models of FFAs provide information on specific modes of ligand binding at FFA subtypes and new suggestions for mutagenesis and ligand modification, guiding the development of novel orthosteric and allosteric chemical probes to validate the importance of FFAs in metabolic and inflammatory conditions. Using our FFA homology modelling experience, a strategy to model a GPCR, which is phylogenetically distant from GPCRs with the available crystal structures, is discussed.

Project description:Background:Obesity and its related metabolic syndrome continue to be major public health problems. Monosodium L-glutamate (MSG) may cause metabolic diseases such as obesity. Meanwhile, the Chinese population has undergone rapid transition to a high-fat diet. There is little information available on the effect of MSG and fat alone, or in combination, on free fatty acids (FFAs), lipid metabolism and FFA receptors. Objective:The aim of this study was to evaluate the effects of MSG and fat alone, or in combination, on intestinal luminal FFAs and expression of gastrointestinal FFA receptors. The aim was also to test whether dietary fat and/or MSG could affect expression of genes related to fatty acid metabolism. Design:A total of 32 growing pigs were used and fed with four iso-nitrogenous and iso-caloric diets. Pigs in the four treatments received diets with one of two fat concentrations levels (4.4 and 9.4%) and one of two MSG dose levels (0 and 3%), in which most of the fat were brought by soybean oil. The concentration of short chain fatty acids (SCFAs) in cecum and colon, long chain fatty acids (LCFAs) in ileum, cecum and colon, and FFAs receptors expression in hypothalamus and gastrointestinal tract were determined. Results:MSG and/or fat changed intestinal luminal SCFAs, levels of LCFAs, and showed an antagonistic effect on most of LCFAs. Simultaneously, MSG and/or fat decreased the expression of FFA receptors in hypothalamus and gastrointestinal tract. MSG and/or fat promoted fat deposition through different ways in back fat. Conclusion:Our results support that MSG and/or fat can alter intestinal luminal FFAs composition and concentration, especially LCFAs, in addition, the expression of FFA receptors in ileum and hypothalamus could be decreased. Moreover, MSG and/or fat can promote protein deposition in back fat, and affect the distribution and metabolism of fatty acids in the body tissues and the body's ability to perceive fatty acids; these results provide a reference for the occurrence of fat deposition and obesity caused by high-fat and monosodium glutamate diet.

Project description:Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids' synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.

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Free fatty acid receptors as therapeutic targets for the treatment of diabetes.

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Free fatty acid receptors as therapeutic targets for the treatment of diabetes.

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