Editors' ChoiceInflammation

GPR120 Mediates the Benefits of Fish Oil

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Science Translational Medicine  29 Sep 2010:
Vol. 2, Issue 51, pp. 51ec150
DOI: 10.1126/scitranslmed.3001730

Fish oil has been prized for its many health benefits, including amelioration of inflammation and diabetes, ever since epidemiological studies from the middle of the 20th century showed that Eskimos have a low rate of heart disease, even though their fat consumption is very high. Most of the fat they ate was maritime in origin, however, containing high levels of ω-3 fatty acids such as docosahexanoic acid (DHA) and eicosapentanoic acid (EPA). In contrast to the traditional Eskimo diet, the high-fat diet that most of us consume is rich in saturated fatty acids and low in ω-3 fatty acids. Oh et al. have now elucidated a pathway through which ω-3 fatty acids signal and dissected its biological relevance.

They identified the orphan G protein–coupled receptor GPR120 as an ω-3 fatty acid sensor that is expressed in macrophages and fat cells. Both of these cell types play a critical role in linking inflammation and diabetes because they secrete cytokines and hormones that affect both systemic metabolism and the inflammatory state. Next, the authors demonstrated that activation of GPR120 by DHA antagonizes pro-inflammatory signaling by inhibiting nuclear factor κB (NFκB) and c-Jun N-terminal kinase (JNK) and the expression of cytokines. GPR120 also enhances glucose uptake, an insulin-like activity, although insulin’s own ability to stimulate glucose uptake after GPR120 activation does not seem to be enhanced in vitro. The authors go on to delineate which specific signaling pathways mediate the anti-inflammatory and the insulin-like actions.

GPR120 is known to signal through the Gq/11 family of G proteins. After DHA binds GPR120, Gq/11 is released, and G protein receptor kinases phosphorylate the receptor, thus recruiting β-arrestins that can cooperate with downstream signaling molecules. In a series of in vitro knockdown experiments, the investigators show that the anti-inflammatory actions of GPR120 depend on β-arrestin, but the insulin-like actions require Gq/11. They then show in vivo that supplementing a high-fat diet with ω-3 fatty acids reverses the insulin resistance in mice. Further, the knockdown of GPR120 in mice negates the beneficial effects of ω-3 fatty acids on both inflammation and glucose homeostasis. Thus, the identification of GPR120 as an ω-3 fatty acid sensor is a major step toward our understanding of the beneficial health effects of fish oil.

D. Y. Oh et al., GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010). [Abstract]

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