oa Differential regulation of brown adipose tissue physiology by orexin A and orexin B

Abstract: Prevalence of obesity and co-morbidities is increasing alarmingly in recent years with over 1 billion adults globally being classified as overweight. Importantly, this also applies to the population in Qatar where about 70% of the total population are expected to be overweight and nearly 20% diabetic by 2015. The profound increase in obesity has a severe socio-economic burden for public health systems worldwide. Brown adipose tissue (BAT) has high metabolic activity. Increasing BAT mass in itself as well as through trans-differentiation of white adipose tissue (WAT) to BAT can combat obesity, reverse insulin resistance and diabetes. Orexin A (ORA) and orexin B (ORB) neuropeptides mediate multiple physiological functions including sleep and wakefulness, appetite, metabolism, analgesia, stress response and thermogenesis. Orexins mediate physiological responses via activating two GPCRs OXR1 and OXR2. In the current study we demonstrate for the first time the expression of OXR1 and OXR2 in human BAT, and compare the effects of ORA and ORB on BAT functions i.e. thermogenesis, BAT angiogenesis and trans-differentiation of WAT to BAT using cellular and mouse models. Peripheral administration of ORA and ORB in mice resulted in a significant differential up-regulation of thermogenic (UCP1, PPARγ, PGC1α, BMP7, PRDM16 and BMP8b) genes, proteins, increase in BAT angiogenesis and up-regulating pro-angiogenic (VEGF, CD31, NGF2, FOXC2, HIF-1α, eNOS and MMPs) molecules in BAT. We also observed induction of BAT like phenotype in classical WAT, specifically, in inguinal and subcutaneous WAT following orexin treatment. In particular, our findings demonstrate that ORB has more potent effects on BAT function compared to ORA. Thermogenesis mediated by ORB predominantly involves activation of OXR2. In addition, we found that ORA mediated UCP1 (a key protein in thermogenesis) activation in thermogenesis involved p38 and ERK1/2 dependent pathways, whereas ORB induced UCP1 activation, was mainly through the p38 but not ERK1/2 pathway. Therefore, induction of brown phenotype in WAT by orexins could serve as a promising target to combat obesity and insulin resistance. We would like to highlight our data that ORB appears to have a more potent effect on trans-differentiation of WAT to 'brown-like' phenotype compared to ORA. In summary, our findings highlight the importance of orexins, in particular, ORB in the regulation of BAT physiology. Given that ORB is a potent inducer of BAT thermogenesis, angiogenesis and regulates trans-differentiation of WAT to BAT like phenotype, we propose that ORB has therapeutic potential for the treatment of obesity.