Fishing for Drugs That Mitigate Metabolic Syndrome

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Science Translational Medicine  16 Jul 2014:
Vol. 6, Issue 245, pp. 245ec121
DOI: 10.1126/scitranslmed.3009806

The fish oil frenzy in health food stores stems from the oil’s premier ingredient—omega-3 fatty acids. These agents have anti-inflammatory properties and enhance insulin sensitivity at least in part by functioning as a ligand for Gpr120, a G protein–coupled receptor that is highly expressed in macrophages and adipose tissue. A major hurdle to translating these discoveries is the clinically impractical amounts of fish oils required to sustain chronic agonism of Gpr120. But small-molecule drugs with potent and specific Gpr120 agonist activity may effectively activate this signaling pathway and serve as potential therapeutics for patients with metabolic syndrome. Now, Oh et al. report the generation of such an agonist, which they named compound A.

Highly potent, specific, and orally bioavailable, compound A activated human Gpr120 in vitro with a median effective concentration in the nanomolar range but did not activate the closely related lipid-sensing receptor Gpr40. Functional in vitro assays demonstrated that compound A exerted robust anti-inflammatory effects in macrophages that were largely dependent on Gpr120. After 5 weeks of compound A administration (30 mg/kg/day orally), adult mice with preestablished metabolic syndrome (15 weeks on a high-fat diet) showed improved glucose tolerance, increased insulin sensitivity, and decreased hepatic steatosis (fatty liver). Gpr120-null mice did not show these anti-inflammatory and salutary metabolic effects when treated with compound A, corroborating the agonist’s target specificity. Although it is likely that compound A exerts direct effects on macrophages in mice, further studies with conditional deletion of Grp120 in myeloid, adipose, and other types of cells will help to decipher the tissue-specific effects of compound A in the setting of obesity and metabolic syndrome.

This study demonstrates the successful creation of a highly potent and specific small-molecule Gpr120 agonist with druglike properties that has efficacy in an experimental model of metabolic syndrome. Further exploration of the pharmacology, biology, and toxicology of compound A and other potential Gpr120 modulators might lead to early-phase clinical trials and spearhead a new class of drugs to combat the current metabolic disease epidemic.

D. Y. Oh et al., A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat. Med. 10.1038/nm.3614 (2014). [Full Text]

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