Understanding the biophysical basis of energy storage in adipocyte lipid droplets and the metabolic consequences of the failure of this process. (360G-Wellcome-107064_Z_15_Z)

My proposal hinges on the hypothesis that having evolved in a nutritionally challenging environment, humans are particularly well adapted to ensuring sufficient energy intake, but considerably less well adapted to coping with sustained access to energy dense foodstuffs. And that failure to optimally store surplus energy as neutral lipid within cytosolic lipid droplets (CLDs) in adipocytes, results in lipid accumulation in other tissues such as the liver where it plays a seminal role in causing i nsulin resistance, type 2 diabetes, fatty liver, dyslipidaemia and ultimately cardiovascular disease. The aim is therefore to deepen and broaden understanding of the molecular basis of lipid storage within CLDs as well as the physiological consequences of overload/failure of this process. The approach we have adopted is distinguished by being primarily based on studies involving patients with a rare disease characterised by a lack of body fat i.e. lipodystrophy. Paradoxically, lipodystrophy leads to severe manifestations of the same metabolic diseases typically associated with obesity. In both cases, we hypothesise that metabolic disease arises as a result of a mismatch between the need and capacity to store surplus energy in adipocytes. This mismatch is particularly extreme in lipodystrophy, providing a more tractable model in which to study the pathophysiology of this problem. Having made some important genetic discoveries recently, we are now seeking to address fundamental biol ogical questions which have emerged from our primary genetic discoveries, whilst also seeking to broaden our knowledge of the genetic basis of other rare adipose tissue diseases.