Rapid communication between the gut and the brain is critical for maintaining homeostasis, and is thought to be disrupted in disease states including obesity. However, the molecular mechanisms and in vivo neuronal dynamics underlying these processes and how they go awry remain poorly understood. Among the cell types involved in this communication is a population of critical, hunger-activated neurons located in the arcuate nucleus of the hypothalamus called AgRP neurons. Recording from these neurons using calcium imaging techniques such as fiber photometry has revealed they are regulated by multiple nutritionally relevant signals including striking inhibition within minutes in response to nutrient delivery to the gastrointestinal (GI) tract. We have previously shown that nutrient infusion into the stomach inhibits AgRP neurons regardless of macronutrient composition, but the specific molecular mechanisms involved appear to be dependent on macronutrient identity. The goal of this project is to unravel the mechanisms of glucose-induced AgRP neuron inhibition and to determine how this is altered in obesity induced by diets of varying macronutrient composition. This will be accomplished across three aims using fiber photometry recordings in conjunction with gastric nutrient infusion and pharmacologic manipulations. First, I will determine whether glucose metabolism is required to induce AgRP neuron inhibition. Second, I will determine whether glucose induced hormone release can drive this inhibition. Third, I will examine how these dynamics are altered in animals overfed with diets high in fat versus carbohydrates. The data generated here will offer novel insights into carbohydrate-induced satiation and how over-nutrition with carbohydrates leads to obesity. Additionally, these data will enable me to obtain additional funding to propel my recently established laboratory in new directions allowing molecular and circuit based dissection of the mechanisms driving nutrient-mediated gut-brain communication in health and disease.
|Effective start/end date||4/1/20 → 3/31/21|
- University of Chicago (AWD035726-03-PR (SUB00000302)//3P30DK020595-43S1)
- National Institute of Diabetes and Digestive and Kidney Diseases (AWD035726-03-PR (SUB00000302)//3P30DK020595-43S1)