Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Nariae Baik-Schneditz

Bernhard Schwaberger

Lukas Peter Mileder

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Oh, DY; Walenta, E; Akiyama, TE; Lagakos, WS; Lackey, D; Pessentheiner, AR; Sasik, R; Hah, N; Chi, TJ; Cox, JM; Powels, MA; Di Salvo, J; Sinz, C; Watkins, SM; Armando, AM; Chung, H; Evans, RM; Quehenberger, O; McNelis, J; Bogner-Strauss, JG; Olefsky, JM.
A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.
Nat Med. 2014; 20(8): 942-947. Doi: 10.1038/nm.3614 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Co-Autor*innen der Med Uni Graz: Pessentheiner Ariane Raphaela
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Abstract:: It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Arginase - biosynthesis; B-Lymphocytes, Regulatory - immunology; Base Sequence -; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Docosahexaenoic Acids - pharmacology; Fatty Acids, Omega-3 - metabolism; Fatty Liver - drug therapy; Hyperinsulinism - drug therapy; Inflammation -; Insulin Resistance - physiology; Macrophages - immunology; Male -; Mice -; Mice, Inbred C57BL -; Mice, Knockout -; Mice, Obese -; Molecular Sequence Data -; Nitric Oxide Synthase Type II - biosynthesis; Obesity - genetics; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; T-Lymphocytes, Regulatory - immunology