Free fatty acid receptors: emerging targets for treatment of diabetes and its complications - PubMed (original) (raw)

Free fatty acid receptors: emerging targets for treatment of diabetes and its complications

Venkat Vangaveti et al. Ther Adv Endocrinol Metab. 2010 Aug.

Abstract

Fatty acids (FAs) are important as metabolic substrates and as structural components of biological membranes. However, they also function as signalling molecules. Recently, a series of G protein-coupled receptors (GPRs) for FAs has been described and characterized. These receptors have differing specificities for FAs of differing chain length and degree of saturation, for FA derivatives such as oleoylethanolamide, and for oxidized FAs. They are a critical component of the body's nutrient sensing apparatus, and small molecule agonists and antagonists of these receptors show considerable promise in the management of diabetes and its complications. Agonists of the long-chain free fatty acid receptors FFAR1 and GPR119 act as insulin secretagogues, both directly and by increasing incretins. Although, drugs acting at short-chain FFA receptors (FFAR2 and FFAR3) have not yet been developed, they are attractive targets as they regulate nutrient balance through effects in the intestine and adipose tissue. These include regulation of the secretion of cholecystokinin, peptide YY and leptin. Finally, GPR132 is a receptor for oxidized FAs, which may be a sensor of lipid overload and oxidative stress, and which is involved in atherosclerosis. Regulation of its signalling pathways with drugs may decrease the macrovascular risk experienced by diabetic patients. In summary, FA receptors are emerging drug targets that are involved in the regulation of nutrient status and carbohydrate tolerance, and modulators of these receptors may well figure prominently in the next generation of antidiabetic drugs.

Keywords: G protein-coupled receptor; atherosclerosis; diabetes; drug therapies; free fatty acid.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Figure 1.

Figure 1.

Oleoylethanolamide.

Figure 2.

Figure 2.

Effects mediated through free fatty acid receptors. CCK, cholecystokinin; FFAR1, free fatty acid receptor-1; FFAR2, free fatty acid receptor-2; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; PMNCs, peripheral blood mononuclear cells.

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References

    1. Batterham R.L., Cohen M.A., Ellis S.M., Le Roux C.W., Withers D.J., Frost G.S., et al. (2003) Inhibition of food intake in obese subjects by peptide YY3–36. N Engl J Med 349: 941–948 - PubMed
    1. Bergman R.N., Ader M. (2000) Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol Metab 11: 351–356 - PubMed
    1. Bharate S.B., Nemmani K.V., Vishwakarma R.A. (2009) Progress in the discovery and development of small-molecule modulators of G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1): An emerging target for type 2 diabetes. Expert Opin Ther Pat 19: 237–264 - PubMed
    1. Bharate S.B., Rodge A., Joshi R.K., Kaur J., Srinivasan S., Kumar S.S., et al. (2008) Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists. Bioorg Med Chem Lett 18: 6357–6361 - PubMed
    1. Bolick D.T., Skaflen M.D., Johnson L.E., Kwon S.C., Howatt D., Daugherty A., et al. (2009) G2 A deficiency in mice promotes macrophage activation and atherosclerosis. Circ Res 104: 318–327 - PMC - PubMed

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