Overall this study provides compelling evidence that overexp

Overall, this study provides compelling evidence that overexpression of catalase coupled with an enriched diet of OM3 fatty acids are metabolically beneficial. This combination was shown to increase adipose tissue expression of the GPR120/FFAR4, which by interacting with the Nrf2 pathway, resulted in decreased body weight and fat mass, enhanced or maintained circadian rhythm, anti-inflammation and insulin sensitivity, and regulation of key adipokines compared to HFD fed mice (Graphical abstract). In fact, to our knowledge, this is the first study to provide evidence that GPR120 expression may be modulated by redox status in addition to providing the evidence of the GPR120-Nrf2 cross-talk mechanism. With the beneficial outcomes seen within the ‘stress-less’ Bob-Cat mice model provided an OM3 diet, we believe that this model is an excellent tool to further study adipose tissue function, crosstalk with other metabolic tissues, and metabolic signaling pathways involving glucagon receptor antagonist homeostasis in both male and female mice. Also, in addition to obesity, inflammation in adipose tissue has been linked to a number of types of carcinogenesis [137] and cardiovascular events. [[138], [139], [140]]. Thus, using the ‘stress-less’ mice as a novel model, future studies may be conducted to look at the combination of antioxidant overexpression and other therapies for diseases of metabolic syndrome as well as lowering the risk and progression of the metabolic syndrome-associated cancers and CVD. The following are the supplementary data related to this article.
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Acknowledgements The authors acknowledge Dr. Jung Han Kim for her assistance with ECHO-MRI and CLAMS studies as well as Logan Efaw, Melissa Massie, Aaron Roberts, Jonique George and Sarah Marshall for their assistance with the feeding studies, quantitative PCR and Western Blotting. This study was partially supported by NIH Grant 5R01HL-074239 (NS), 5P20RR016477 (NS), 1R15AG051062-01 (NS), and WV-NASA Grant Consortium (DA).
Receptors for Long-Chain Fatty Acids In recent years, it has become clear that many components of foodstuffs, or metabolites derived thereof, act as homeostatic monitors of nutrient availability [1]. In many cases, such metabolites do so by binding to, and activating, members of the rhodopsin-like or ‘class A’ family of GPCRs [1]. Among such metabolites is the group of long-chain, nonesterified or ‘free’ fatty acids. A broad range of long-chain fatty acids of varying chain length and position and extent of unsaturation (Box 1) are able to activate a pair of these GPCRs 2, 3. Initially designated GPR40 [4] and GPR120 [5], upon acceptance that long-chain FFAs are indeed the key endogenous activators of these receptors, they were systematically renamed FFA1 (GPR40) [6] and FFA4 (GPR120) [7], although the initial, colloquial terminologies remain in widespread use. FFA1 has been validated clinically as a therapeutic target able to control blood glucose levels. Although the potential for FFA4 to also be a therapeutic target for regulating blood glucose levels and improving tissue insulin sensitivity appears clear from rodent model studies, this remains to be addressed in a clinical setting. However, recent studies exploring further roles of FFA4 in lung function and in the development of resistance to platinum-containing chemotherapeutics suggest that interest in FFA4 should be expanded beyond metabolic diseases and should also consider potential therapeutic applications of FFA4 antagonists as well as agonists.
FFA1 FFA1 is highly expressed by pancreatic β cells and, because fatty acids are known, at least in acute settings, to promote insulin release from pancreatic islets, synthetic small-molecule activators of FFA1 were initially assessed for their ability to mimic this effect. Rapid translation to show that such ligands were also efficacious in various glucose tolerance tests, resulted in the optimisation of potentially drug-like FFA1 agonist ligands and the introduction into first-in-human clinical trials of fasiglifam TAK-875, 2-[(3S)-6-( 3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid 8, 9, 10 as a potential antidiabetic medication. Although substantial efficacy was noted in both Phase II and initial Phase III studies, development of fasiglifam was discontinued in late 2013 based on concerns of potential liver toxicity [11]. Subsequent reports have indicated that these adverse effects are likely related to the build-up of high concentrations of fasiglifam and an acyl glucuronide derivative of the ligand in the bile, reflecting blockage of various bile acid transporters including, but not limited to, the bile salt export pump (BSEP) 12, 13. Given the clinical validation of targeting FFA1, there remains significant interest in the potential of novel ligands at this receptor for the treatment of T2DM 14, 15, 16. Recent publications from various pharmaceutical companies several, of what appear, at least in animal models, to be highly effective and potent FFA1 ligands 17, 18, 19, support this. Clearly, issues akin to those that resulted in the removal of fasiglifam from clinical development, including inhibition of BSEP, would need to be addressed directly before further clinical studies commence.