Mechanisms of fatty acid sensing and uptake by brown adipocytes

Obesity is currently a global pandemic, associated with high rates of metabolic co-morbidities such as type 2 diabetes mellitus and cardiovascular disease. Obesity results from an energy imbalance when energy intake exceeds energy expenditure and excess calories are stored in white adipose tissue. Given the relative lack of success with most obesity treatment options, there is a pressing need to better understand the physiological regulation of energy balance as well as the pathophysiology of obesity in order to identify new targets for the development of novel treatments. Brown adipose tissue (BAT), or the energy-expending thermogenic adipose tissue of the body, is a promising target in this respect. Increasing BAT mass or activity would likely combat obesity and reverse the development of co-morbidities. The development and functional properties of BAT are starting to be understood, but many questions remain unanswered. In order for BAT to undergo such high levels of energy expenditure, it requires a readily available fuel source, which includes fatty acids either stored in its multilocular lipid droplets taken up as fatty acids released from white adipose tissue lipolysis. It is currently unclear exactly how BAT regulates its fatty acid fuel supply, including the sensing, uptake and oxidation of these fats. Mouse models lacking the fatty acid transporters CD36 or FATP1 are unable to undergo theremogenesis and do not survive cold exposure, further underscoring the importance of fatty acids for BAT function. Our work has demonstrated that treatment with the bone morphogenetic protein 7 (BMP7) is able to increase fatty acid uptake and oxidation in brown adipocytes, resulting in greater rates of mitochondrial respiration. Furthermore, we have demonstrated that this situation of increased fatty acid uptake and utilization is also associated with an increase of the fatty acid sensor GPR120. Nothing is known about how fatty acid sensing, and specifically GPR120, affects BAT function. We seek to determine how GPR120, which has recently been associated with human obesity, affects fatty acid sensing and uptake by CD36 and FATP1 to affect mitochondrial activity and energy expenditure in brown adipocytes. A better understanding of the mechanisms underlying fuel utilization by BAT will provide novel opportunities for treating obesity.