Brain derived neurotrophic factor BDNF is the most

Brain-derived neurotrophic factor (BDNF) is the most abundant growth factor in the brain and is critical for neuronal development and synaptic plasticity (Bekinschtein et al., 2008; Lu et al., 2014). Besides playing an important role in mood and cognition, BDNF is also involved in the regulation of energy homeostasis (Passaro et al., 2014; Schwartz and Mobbs, 2012; Xiang et al., 2015). Recent evidence suggests that decreased hypothalamic BDNF signaling elicits hyperphagia and obesity in mice, suggesting that BDNF also acts as an anorexigenic signaling molecule (Fox et al., 2013). However, the relationship between GPR40 and BDNF in complex schemes of energy homeostasis in diabesity, a condition of obesity and type-II diabetes together, is not yet understood. In this study, we for the first time show that decreased expression of GPR40 correlates with reduced expression of BDNF in a mouse model of diabesity. We demonstrate that chronic treatment of db/db mice and high-fat diet (HFD) -induced obese mice with DHA or GW9508 significantly normalizes BDNF expression in the brain and improves cognitive behavior. Using primary cortical neurons, we further showed that DHA specifically activates GPR40, not GPR120 (Free fatty TG003 receptor 4), and modulates BDNF expression via the extracellular receptor kinase (ERK) and the P38-mitogen-activated protein kinase (MAPK) pathways. Moreover, intracerebroventricular (i.c.v.) administration of the GPR40 antagonist, GW1100, attenuated the beneficial effects of DHA on cognition and BDNF expression in the hippocampus of mice models of diabesity. These results reveal an underlying molecular mechanism of DHA-mediated beneficial effects in central nervous system (CNS) -related co-morbidities associated with diabesity.
Materials and methods
Results
Discussion Previously, it was believed that diabesity primarily affects cardiovascular and metabolic functions, thereby neglecting the detrimental effects on brain tissue. Emerging evidence during the last decade has established that a bidirectional causal relationship exists between diabesity and comorbid psychiatric conditions, such as cognitive impairments (Biessels and Reagan, 2015; Tu et al., 2017). However, mechanisms elucidating the precise nature of this relationship are still lacking. Furthermore, chronic hyperglycemia and dyslipidemia adversely affect, not only tissues directly involved in metabolic regulation, but also various neurotransmitter systems mediating mood and cognitive processes (Biessels et al., 2006b). Although the essential role of GPR40 in glucose homeostasis in the periphery is well-established (Burant, 2013), very little is known about the precise functions of this receptor in the brain. The abundant expression of GPR40 in the brain, and the widely known and appreciated beneficial effects of DHA, an agonist of GPR40 in several CNS conditions, indicates a role of GPR40 signaling well beyond glucose homeostasis. Moreover, a large body of recent literature suggests that BDNF is central to energy homeostasis (Marosi and Mattson, 2014). However, the mechanistic relationship between BDNF and GPR40 has not been elucidated yet. Based on the observations made in this study, we propose that GPR40 activation by DHA increases BDNF expression, which in turn regulates energy homeostasis as well as a comorbid cognitive decline in diabesity. Consistent with previous reports (Khan and He, 2015; Ma et al., 2007; Nakamoto et al., 2012; Nakamoto et al., 2013), we have found abundant expression of GPR40 in cortex and hippocampus of normal C57BL/6 J mice. In this study, we, for the first time, provide evidence for the decreased expression of GPR40 in the hippocampus (key brain region involved in cognition) of HFD and db/db mice, and demonstrate that chronic activation of this receptor by DHA or by the GPR40 selective agonist GW9508 (pEC50 at GPR40 = 7.32 ± 0.03 v/s GPR120 = 5.46 ± 0.09; (Briscoe et al., 2006)), alleviates cognitive deficits by increasing BDNF expression. Since it has been shown that transcription factor Pax6 is essential for GPR40 expression (Gosmain et al., 2012) and this factor is reduced in β-cells of diabetic mice (Swisa et al., 2017), it is likely that a similar mechanism is apparent for the expression of GPR40 in neurons. Further, Pax6 expression in the brain has been found to be essential for neurodevelopment as well as for adult neurogenesis (Lledo et al., 2006), indicating that GPR40 expression is directly linked to normal brain functioning, besides its role in energy homeostasis. Although involvement of endothelial GPR40 in trans-arachidonic acid mediated hypoxic-ischemic induced cerebral micro-vascular degeneration has been shown (Honore et al., 2013), no adverse effect of DHA or GPR40 activation on neurons and cognition has been reported. It is possible that activation of GPR40 in endothelial cell lead to completely different pathway than in neurons, a widely reported phenomenon for several GPCR ligands called as “functional selectivity or biased agonism” (Dogra and Yadav, 2015).