Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. (360G-Wellcome-090662_Z_09_Z)

In infant humans and small mammals, brown adipose tissue (BAT) functions as a tissue for thermoregulation. This is achieved through its ability to uncouple oxidative metabolism from ATP synthesis; thus facilitating the conversion of caloric energy, especially fats, into heat. With the recent discovery that BAT is present in biologically relevant amounts in both lean and obese adults, the possibility of activating BAT as a means of increasing caloric loss in obese states are being investigated. When BAT is activated, there is a simultaneous increase in both fatty acid oxidation and synthesis. In addition, the synthesized fatty acids are extensively modified, including acyl-chain elongation and desaturation. We postulate that the ability of BAT to modify fatty acids is crucial to its function. Specifically, fatty acid chain length and saturation helps determine its intracellular fate; either towards oxidation, storage or other cellular compartments. The aim of this study is to investigate the role of fatty acid composition on BAT metabolism and asses the impact of this alteration on whole body energy balance and thermoregulation. Fatty acid elongation will be disrupted by altering the expression of Elovl6 (Elongase of very long chain fatty acid-6) in both in vitro and in vivo models. Supporting this, increasing amounts of published data supports the role of fatty acid chain length in obesity and insulin resistance. In addition, our preliminary data suggests that Elovl6 is highly expressed in BAT and its expression increases with BAT activation.