FFAR4 (GPR120) Signaling Is Not Required for Anti-Inflammatory and Insulin-Sensitizing Effects of Omega-3 Fatty Acids

Abstract

Free fatty acid receptor-4 (FFAR4), also known as GPR120, has been reported to mediate the beneficial effects of omega-3 polyunsaturated fatty acids (ω3-PUFAs) by inducing an anti-inflammatory immune response. Thus, activation of FFAR4 has been reported to ameliorate chronic low-grade inflammation and insulin resistance accompanying obesity. However, conflicting reports on the role of FFAR4 in mediating the effects of ω3-PUFAs are emerging, suggesting that FFAR4 may not be the sole effector. Hence analyses of the importance of this receptor in relation to other signaling pathways and prominent effects of ω3-PUFAs remain to be elucidated. In the present study, we used Ffar4 knockouts (KO) and heterozygous (HET) mice fed either low fat, low sucrose reference diet; high fat, high sucrose ω3-PUFA; or high fat, high sucrose ω6-PUFA diet for 36 weeks. We demonstrate that both KO and HET mice fed ω3-PUFAs were protected against obesity, hepatic triacylglycerol accumulation, and whole-body insulin resistance. Moreover, ω3-PUFA fed mice had increased circulating protein levels of the anti-inflammatory adipokine, adiponectin, decreased fasting insulin levels, and decreased mRNA expression of several proinflammatory molecules within visceral adipose tissue. In conclusion, we find that FFAR4 signaling is not required for the reported anti-inflammatory and insulin-sensitizing effects mediated by ω3-PUFAs.

Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases

“…Notably, the in vivo significance of GPR120/FFA4 to suppress chronic low‐grade inflammation also has lately been contended. While GPR120/FFA4 activation by ω3‐PUFAs was initially reported to be critical to reduce high‐fat diet‐induced adipose tissue inflammation, more recent studies found GPR120/FFA4 to be dispensable for the therapeutic effects of ω3‐PUFAs in mouse models of both high‐fat diet‐induced adipose tissue inflammation, and of atherosclerosis . The reason for these discrepant findings is unknown and numerous explanations are conceivable.…”

“…While GPR120/FFA4 activation by ω3-PUFAs was initially reported to be critical to reduce high-fat diet-induced adipose tissue inflammation, 14 more recent studies found GPR120/FFA4 to be dispensable for the therapeutic effects of ω3-PUFAs in mouse models of both high-fat diet-induced adipose tissue inflammation, and of atherosclerosis. 35,36 The reason for these discrepant findings is unknown and numerous explanations are conceivable. Inflammation is a most complex process and ω3-PUFAs can exert diverse pharmacological actions independent of GPR120/FFA4.…”

The Role of Metabolite-Sensing G Protein-Coupled Receptors in Inflammation and Metabolic Disease

“…FFAs by inducing an anti-inflammatory response and regulating insulin metabolism is discussed by Paerregaard et al (124). In their latest study, and contradicting most existing literature, they proposed that GPR120 is dispensable for the beneficial effects that ω-3 FFAs display in obese mice.…”

Immuno‐Resolving Ability of Resolvins, Protectins, and Maresins Derived from Omega‐3 Fatty Acids in Metabolic Syndrome

“…Dietary omega‐3 fatty acids have been demonstrated to reduce the inflammation derived from adipose tissues as summarized in Table . In the adipose tissue, omega‐3 fatty acids reduce the mRNA levels of pro‐inflammatory adipokines such as MCP‐1 , IL‐6 , and TNF‐α in high‐fat‐induced obese mice and MCP‐1 in obese humans . In addition, supplementation of omega‐3 fatty acids reduces systemic inflammation, resulting in a decrease in plasma MCP‐1 levels in insulin‐resistant obese individuals and plasma CRP levels in obese pregnant women …”

“…GPR120 was suggested to mediate the anti‐inflammatory effects (i.e., suppression of macrophage pro‐inflammatory cytokine secretion) of omega‐3 fatty acids . However, this was contradicted by the results of other studies and the receptors that bind omega‐3 fatty acids remain unclear.…”