Research Interests:
Human obesity is a disease of brain pathways controlling appetite. Our aim is to help characterize these pathways to eventually develop safe and efficient weight-loss therapies. We employ a multi-disciplinary approach to define how nutritional signals are detected by the brain to maintain energy and glucose homeostasis in health and disease.
Brain protein sensing
A major focus of our research programme is to define the role of the brain in amino acid homeostasis. Half of the amino acids, building blocks for proteins, cannot be synthesised by mammalian cells and must be obtained through the diet; shortage in these essential amino acids rapidly drives protein hunger. Conversely, high circulating levels of amino acids can promote metabolic and neurological diseases; mammals have evolved strategies to putatively avoid chronic amino acid excess, including the robust satiety response to high-protein diets.
We work on the hypothesis that homeostatic mechanisms regulate peripheral amino acid availability to maintain nutritional homeostasis and survival. Our goal is to understand how the mammalian brain senses peripheral amino acid availability and produces behaviour and metabolic responses allowing the maintenance of amino acid homeostasis. Our prediction is that under conditions of dietary protein excess or shortage, brain protein sensing pathways are prioritised to achieve amino acid homeostasis at the expense of energy homeostasis. By extension, we predict that brain protein sensing pathways might represent effective weight-loss targets.
Median eminence oligodendrocyte plasticity
A second research focus is to identify the role of median eminence oligodendrocytes in energy and glucose homeostasis. We know that energy and glucose homeostasis rely on the ability of specialised hypothalamic circuits to respond to changes in peripheral levels of nutritional and metabolic signals, but how neurons accurately monitor peripheral concentrations of these signals is unclear.
Oligodendrocytes are myelin forming cells that ensheathe axons to allow rapid saltatory conduction of action potentials. Oligodendrocytes are normally long-lived in the healthy brain, but rapidly turnover in the median eminence, the brain region through which hypothalamic neurons access blood signals, leading to rapid myelin renewal. We work on the hypothesis that nutrient sensing by median eminence oligodendrocytes promotes structural remodelling in neuroendocrine circuits, tuning their activity and sensitivity to metabolic signals. In addition, we propose that hypothalamic myelin represents peripheral energy availability and regulates neuroendocrine functions to promote energy homeostasis.
Group Members:
Dr Sophie Buller, Research Associate - sab236 at medschl.cam.ac.uk
Dr Thomas Brown, Research Associate - tb807 at medschl.cam.ac.uk
Dr Anthony Tsang, Research Associate - at783 at medschl.cam.ac.uk
