Dissecting the mechanisms of metaboregulatory thermogenesis (360G-Wellcome-096825_Z_11_A)

The recent discovery of brown adipose tissue (BAT) in adult humans makes possible a new therapeutic approach to treat obesity, by activating endogenous BAT or making white adipose tissue more like BAT. To understand how to achieve these aims, physiological activation of BAT must be understood. Whiles much is known about thermoregulatory thermogenesis, the neuronal networks regulating metabregulatory thermogenesis (thermogenesis to counteract increased calorie intake) are not well understood. The central and peripheral mechanisms of metaboregulatory thermogenesis will be examined unsing three approaches in mice. Firstly, to determine whether the neuronal pathways regulating thermoregulatory and metaboregulatory thermogenesis are distinct, candidate hypothalamic nuclei that respond to a HFD will be identified by measuring c-Fos activation. Secondly, control of sympathetic tone to BAT by orexin neurons will be evaluated by ablating orexin neurons in adult mice and determining the effect on thermoregulatory and metaboregulatory thermogenesis. Finally, the molecular mechanisms by which Bmp8b increases sensitivity to adrenergic stimulation and thermogenesis in BAT will be investigated. Candidates signalling pathways and molecules will be identified by transcriptomic and proteomic approaches, and characterised in vitro. These experiments will help to eradicate the mechanisms of metaboregulatory thermogenesis, from central to peripheral regulation.