Communication between the gut and the brain is essential for energy homeostasis, but how this communication is represented in the dynamics of hypothalamic feeding circuitry is unknown. Early studies of the gut-brain axis relied upon indirect measurements of the effects of nutritionally regulated peripheral signals on feeding circuitry. These studies led to a model in which the activity of key hypothalamic hunger neurons – AgRP neurons – fluctuates gradually as the animal’s nutritional state changes. With the development of techniques to record the activity of genetically-defined neuronal populations in awake animals, the dynamics of AgRP neurons were recently observed in vivo for the first time. These studies revealed, contrary to the prevailing model, that AgRP neurons are inhibited rapidly when an animal sees or smells food, before it takes a single bite; however, food ingestion is required for maintenance of this inhibition. We have developed a tool combining in vivo monitoring of AgRP neuron dynamics with intragastric nutrient infusion to show for the first time that nutrient delivery to the gut, in the absence of the sensory stimuli normally associated with eating, is sufficient to inhibit AgRP neurons over a time-scale of minutes. This inhibition is independent of the macronutrient composition of the food but depends upon the number of calories ingested. The goal of this proposal is to determine the molecular and circuit-based mechanisms by which each macronutrient inhibits AgRP neurons. This will be accomplished across three aims: to identify the hormonal mediators responsible, to identify the nutrient sensors involved, and to dissect the pathway by which these signals reach AgRP neurons.
|Effective start/end date||8/1/19 → 4/30/23|
- National Institute of Diabetes and Digestive and Kidney Diseases (5K08DK118188-05)
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