Neuroanatomical and functional characterization of hindbrain leucine-sensing circuits implicated in the regulation of feeding behaviour

After food ingestion, the brain receives information about the nutrient content of the meal and uses this information to regulate appetite and energy storage. We have identified specialized areas in the brain that can detect the amino acid L-leucine, a signal of protein intake, and suppress appetite in response to this signal. Our aim is to understand how the brain processes this signal and characterize the brain electrical connections that are turned on or off to regulate feeding. This research will increase our understanding of how the brain contributes to the regulation of appetite and body weight and could help develop new drugs for the prevention or treatment of obesity.

The brain, through the function of specialized cell populations, receives and integrates convergent neuronal, hormonal and nutritional signals of energy availability, and orchestrates the behavioural, endocrine and metabolic feedback control necessary for the maintenance of energy homeostasis. The hypothalamus is established as one of the major brain regions containing these metabolic sensing cell populations, but there is expanding body of knowledge highlighting the role of extra-hypothalamic centres in the co-ordination of energy balance. These include the nucleus of the solitary tract in the caudo-medial brainstem, which combines nutrient and hormonal sensing properties with a unique neuro-anatomical connection to both gustatory and visceral nutrient sensors, and forebrain homeostatic and hedonic circuits. Our previous research supports the idea that circulating L-leucine concentrations represent a signal of energy availability, detected by hindbrain nutrient-sensing cells to modulate central feeding-regulatory circuits. The aim of the proposed research is to use a combination of state-of -the-art neurosurgical, histological, imaging, viral tract-tracing and molecular genetic tools to characterize the neurocircuits engaged downstream from hindbrain L-leucine sensing to regulate food intake. Results from this research will increase our understanding of the connectomics of the central regulation of energy balance, may challenge the hypothalamic-centric view of central metabolic sensing that is currently predominant in the field, and promote the idea that the brainstem is a major center of metabolic integration and effector coordination in the control of energy homeostasis.

Scientific, technical and conceptual advances made through the proposed research will be of benefit to academic scientists working in the field of the central regulation of energy balance, scientist working in adjacent fields, and institutions associated with the work.
The proposed research will be of benefit to the general population through potential long term developments of therapies to prevent or treat metabolic disorders, increasing health and well being. Public diffusion of the results obtained from these studies will increase public awareness of how different components of our diet signal via unique pathways to induce satiety, and may lead to the development of new dietary advice and public health policies. Diffusion of our findings will also benefit to the general public by increasing their understanding of science.

Potential economical impact include the reduction of health care costs, and the development of pharmaceutical drugs in the prevention or treatment of obesity by bringing novel insights into the mechanisms underlying appetite control and potentially identifying novel therapeutic targets.