Study of hypothalamic amino acid sensing pathways implicated in the regulation of energy balance

Obesity and its associated conditions, such as type 2 diabetes and cardiovascular disease, are major health threats worldwide. The brain plays a huge role in the regulation of energy balance. Specialized brain cells process information about ingested food and fat stores and directly regulate food intake, energy expenditure or storage. Among other signals of energy availability, the brain monitors circulating levels of nutrients such as glucose and amino acids. In this project we want to characterize the mechanisms implicated in brain amino acid detection in the regulation of energy balance. This research will improve our understanding of the pathways implicated in the regulation of body weight and potentially identify novel therapeutic targets for the treatment of obesity.

Central detection of the nutrient L-leucine, alone and through synergistic interactions with other signals of energy availability such as CCK or leptin, suppresses acute and long-term feeding, leading to a reduction in body weight. We have shown that activation of the mTORC1 and Erk1/2 signalling pathways contribute to this sensing, but the mechanisms linking amino acid detection to neuronal electrical and synaptic activity remain unknown, and the specific molecular specificity of L-leucine sensing cells remains to be established. In this project, we will characterize the neurophysiological and neurochemical responses to changes in L-leucine concentrations in adult hypothalamic primary culture using calcium imaging. We will use pharmacological and molecular genetic tools to characterize the mechanisms through which L-leucine alters neuronal electrical activity and interacts with other signals of energy availability. We will test the functional relevance of these mechanisms in vivo, and we will identify molecular markers specific for L-leucine sensing cells that will allow us to specifically target these cells with transgenic approaches in vivo.