The brain’s appetite-control centres are directly sensing the glucose and fats in a person’s bloodstream, and this project will map exactly how those signals go wrong in metabolic disease. This matters because current treatments for obesity and type 2 diabetes largely ignore the brain’s role in nutrient detection. While scientists know that certain brain regions respond to food-related molecules, the specific neurons, molecular pathways, and circuits involved remain unknown. The researcher has already developed new tools—including a non-invasive radio-genetic technique—to switch these neurons on and off in living animals, and will now use them to identify which cell populations sense which nutrients, how hormones like insulin and leptin modify that sensing, and how a high-fat or high-sugar diet disrupts the system. If successful, this fundamental science will reveal the neural wiring that normally keeps energy balance in check. That knowledge could eventually point toward new drug targets for metabolic disease—treatments that restore the brain’s ability to detect nutrients correctly, rather than simply managing blood sugar or suppressing appetite after the damage is done.
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Selective brain regions respond to changes in nutrients such as glucose and fatty acids to regulate energy and nutrient homeostasis. Dysregulation of CNS nutrient sensing is potentially critical to metabolic disease but the molecular components of the sensing pathways, role of responsive regions in specific homeostatic responses, interaction with hormonal signals, neuronal connections and dietary effects on nutrient sensing remain largely unknown. My work has identified individual nutrient-sensi ng populations (Stanley et al., PNAS,2010; Stanley et al., Cell Metabolism, in press) and developed novel non-invasive, radio-genetic tools to test their function in vivo (Stanley et al., Science, 2012). My aims are to investigate in detail how specific molecules, individual neurons and their circuits sense nutrients to regulate energy and nutrient homeostasis, establish how these are disrupted in metabolic disease and identify possibilities for therapeutic intervention. Specifically, I wil l: o Identify nutrient-sensing neural populations and their molecular pathways using transcriptional profiling with BAC-TRAP and phosphoTRAP. o Map circuits involving nutrient-sensing populations using selective monosynaptic and polysynaptic tracers. o Assess the physiological roles of subpopulations in energy and nutrient homeostasis by targeted, selective activation or silencing using novel radio-genetics and other tools. o Determine how hormonal signals such as insulin, leptin an d ghrelin modulate the function of these populations. o Examine the effects of altered nutrients and metabolic disease on the molecular profile and function of nutrient sensing populations. These studies will demonstrate the physiological roles of nutrient-sensing populations and may provide new therapeutic avenues for preventing and treating metabolic diseases.
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