The Beneficial Effects of n-3 Polyunsaturated Fatty Acids on Diet Induced Obesity and Impaired Glucose Control Do Not Require Gpr120

Abstract

GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.

Long chain polyunsaturated fatty acids (LCPUFAs) and nordihydroguaiaretic acid (NDGA) modulate metabolic and inflammatory markers in a spontaneous type 2 diabetes mellitus model (Stillman Salgado rats)

“…GPR120 has also been shown to mediate the anti-inflammatory and insulin-sensitizing effects of ω-3 LCPUFAs and its lack or defincency is responsible for reduced fat metabolism, thereby leading to obesity and DM [37]. It may also be noted here that ω-3 LCPUFAs may bring about their beneficial actions independent of GPR120 [38]. …”

“…It is generally believed that under normal physiological conditions a balance is maintained between pro- and anti-inflammatory products formed to maintain normal homeostasis and suppress the initiation of low-grade systemic chronic inflammation in DM [5, 43]. In this context, it is noteworthy that ω-3 LCPUFAs induce their anti-inflammatory effects by acting on the GPR120 and Toll-like receptors (TLRs) [5, 28, 29, 36–38, 42, 43] that results in the suppression of formation of TNF-α and other pro-inflammatory cytokines especially in macrophages, adipocytes and hepatocytes [5, 28, 29, 43]. As a result, pro-inflammatory events are switched off or suppressed.…”

In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

“…These data suggest that dietary n-3 and n-6 PUFAs, though atheroprotective in LDLrKO mice relative to PO, have GRP120-independent (i.e., attenuation of hypercholesterolemia, hepatosteatosis, and aortic atherosclerosis) and GRP120-dependent (i.e., attenuation of and smooth muscle cells) that express GPR120/FFAR4 may play important atheroprotective roles in the context of dietary PUFA feeding and the expression of GPR120/ FFAR4 in these cells would not have been affected in our study. Finally, the intake of dietary PUFAs may not have been sufficient to activate GPR120/FFAR4 in vivo, as our study used much lower n-3 PUFA-enriched diets compared with previous studies (7,46).…”

“…Oh et al (7) have shown that activation of GPR120/FFAR4 results in a  arrestin 2-mediated internalization of GPR120/FFAR4 and binding to TAB1, preventing its activation of TAK1 and blunting a common node of inflammatory signaling for Tolllike receptors, TNF receptor, and inflammasome activation. However, another study using a different GPR120/FFAR4 gene targeting construct showed that reversal of insulin resistance by feeding a high n-3 PUFA-containing diet was independent of GPR120/FFAR4 expression, suggesting the in vivo metabolic impact of GPR120/FFAR4 expression is not fully elucidated (46).…”

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

“…Contradicting the majority of existing literature [17, 21, 22], recent evidence suggests that FFAR4 is dispensable for the beneficial effects of ω 3-PUFAs on HFD-induced obesity [23], whereas the anti-inflammatory nature of FFAR4 remains largely unchallenged. Here we show that feeding mice a high dose of ω 3-PUFAs protects against HFD-induced obesity, steatosis, insulin resistance, and visceral adipose tissue inflammation independent of FFAR4 status.…”