br Introduction GPR also known as

Introduction GPR40 (also known as free fatty eicosapentaenoic acid receptor 1), a member of the G-protein coupled receptor (GPCR) family, is expressed in pancreatic beta cells, intestine and the central nervous system (Bekinschtein et al., 2008; Itoh et al., 2003). It is activated by medium- and long-chain saturated and unsaturated fatty acids, including docosahexaenoic acid (DHA) (Briscoe et al., 2006). Several preclinical and clinical studies have established GPR40 as a potential target for the treatment of type 2 diabetes (Briscoe et al., 2006; Kebede et al., 2008). Similar to GPR40, another closely related receptor, GPR120 (also known as free fatty acid receptor 4), has also been shown to bind medium- and long-chain fatty acids (e.g. DHA and eicosapentaenoic acid) and produce beneficial effects in diabetes and obesity (Derkach et al., 2007; Ichimura et al., 2012). However, the recent termination of phase III clinical trials with GPR40 agonist Fasiglifam due to liver toxicity in diabetic patients indicates an incomplete understanding of this receptor's role in physiological functions other than glucose homeostasis (Kaku et al., 2016). Despite the trial termination, few pharmaceutical companies are still pursuing this target and consider the structure and off-target activity of Fasiglifam rather than those of GPR40 to be a target for diabetes (Hamdouchi et al., 2016; Li et al., 2015; Li et al., 2016). Moreover, GPR40 signaling in the brain remains controversial. Trans-arachidonic acid, a GPR40 and GPR120 agonist was shown to induce neuromicrovascular degeneration in mice model of hypoxic-ischemic in GPR40-dependent manner (Honore et al., 2013). Further, GPR40 knock-out mice exhibited a decreased propensity to fatty liver but increased brain inflammation and insulin resistance due to conjugated linoleic acid, another known GPR40 agonist (Sartorius et al., 2015; Schmidt et al., 2011). Recent emerging evidence also suggests that GPR40 signaling plays an essential role in the regulation of the endogenous pain control system, which comprises dopaminergic, serotonergic and noradrenergic neurons (Karki et al., 2015; Khan and He, 2015; Nakamoto et al., 2015). These studies suggest that omega-3 fatty acids (e.g, DHA and EPA) produce beneficial effects, while omega-6 fatty acids (e.g. trans arachidonic acid and conjugated linoleic acid) that bind GPR40 induce the detrimental effects (Honore et al., 2013). However, it is unclear how GPR40 signaling in various organ/tissue systems is responsible for disparate physiological and pathological effects. Although basal/endogenous GPR40 signaling (in the absence of any drug treatment) has been shown to be necessary for pain modulation (Nakamoto et al., 2015), and affect (Aizawa et al., 2016), it is not known if basal/endogenous GPR40 signaling is essential for cognition as well as other DHA-associated beneficial effects. Importantly, deficiencies of n-3 polyunsaturated fatty acids (PUFA) have been associated with psychiatric conditions (Beilharz et al., 2015; Calon et al., 2005; Sharma et al., 2012) as they have been shown to modulate several physiological functions in the brain, including cell membrane fluidity, neurotransmission and endocannabinoid-dependent synaptic plasticity (Liperoti et al., 2009). Several studies have demonstrated the importance of DHA in brain development (Nguyen et al., 2014). Dietary supplementation of DHA has also been shown to have beneficial effects on mood and cognition (Bondi et al., 2014; Calon et al., 2004). Furthermore, high consumption of western diets, known for their low levels of n-3 PUFAs, is widely considered as a reason for metabolic syndromes and associated cognitive deficits (Whitmer et al., 2008). Given that GPR40 is abundantly expressed in brain (Ma et al., 2007) and are involved in DHA induced neurogenesis (Boneva and Yamashima, 2012; Nascimento et al., 2016), it is quite likely that GPR40 might be involved in cognition. A recent study has shown that GPR40 agonist GW9508 alleviates cognitive deficits in a rodent model of Alzheimer's (Khan et al., 2017), but beneficial effect was shown at doses equivalent to 60 micromolar in the brain, which is too high a concentration for any receptor specificity. Although several studies mentioned above have significantly advanced the understanding of the underlying pleiotropic effects of DHA in the brain, a precise mechanism of the relationship between GPR40 signaling and comorbid psychiatric conditions (cognitive impairment) associated with metabolic syndrome is still lacking.