The motivation to eat depends on the relative balance of activity between orexigenic (appetite inducing) and anorexigenic (appetite suppressing) populations of neurons in the brain. An abnormal balance of activity in these systems can lead to substantial health problems with high associated economic costs. In the United States, over half the population is considered overweight, and the aggregate economic cost is estimated in excess of $60 billion per year. Undernourishment is also a substantial problem: abnormal appetite suppression, as can occur during infection, old age, or cancer, can lead to severely low body weight and malnutrition. However, despite obvious importance, the neural basis of hunger and appetite suppression continues to be poorly understood at a neuronal level. In recent years, two populations of neurons have emerged as key regulators of appetite and body weight. A group of neurons in the hypothalamus called AgRP neurons sense homeostatic signals from the body and increase appetite. When stimulated, AgRP neurons cause a robust increase in food intake. In contrast, a group of neurons in the parabrachial nucleus (PBN) called PBel CGRP neurons sense signals from the stomach and viscera and decrease appetite. When stimulated, PBel CGRP neurons cause a substantial decrease in food intake. The opposing roles of orexigenic AgRP neurons and anorexigenic PBel CGRP neurons raise important questions about how they interact. AgRP neurons release the inhibitory neurotransmitter GABA and project to the region where PBel CGRP neurons are located. However, it is unknown whether AgRP neurons directly inhibit PBel CGRP neurons, nor is it known whether this inhibition could overcome PBel CGRP neuron-mediated suppression of appetite. The purpose of this proposal is to determine how orexigenic AgRP neurons anatomically and functionally interact with anorexigenic PBel CGRP neurons to regulate food intake behavior.
In Aim 1, we will test the hypothesis that AgRP neurons send direct, monosynaptic projections to PBel CGRP neurons.
In Aim 2, we will test the hypothesis that inhibition of AgRP neurons or AgRP-to-PBN projections decreases food intake and increases activity in PBel CGRP neurons.
In Aim 3, we will test the hypothesis that stimulation of AgRP neurons or AgRP-to-PBN projections inhibits PBel CGRP neurons and increases food intake during conditions when appetite is normally suppressed, such as during visceral malaise, illness, or satiety. To pursue these aims, we will use cutting edge viral gene delivery tools and genetically encoded tracers and neuromodulators in mice to provide new insights into how the brain balances orexigenic and anorexigenic information.

Public Health Relevance

The motivation to eat depends on the relative balance of activity in distinct brain regions that individually induce or suppress appetite. An abnormal amount of activity in appetite suppression neurons, as can occur during infection, inflammation, and illnesses such as cancer, can cause malnutrition and a severe reduction in body weight. The purpose of this proposal is to determine whether a population of neurons known to induce appetite ('AgRP neurons') directly inhibits a population of neurons known to suppress appetite ('PBel CGRP neurons'), providing new insights into how the brain regulates food intake and potentially yielding novel therapeutic targets for the re-establishment of appetite in conditions o extreme loss of appetite.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-MDCN-R (86))
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Stoeckel, Luke
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Williams College
Schools of Arts and Sciences
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Goldstein, Nitsan; Levine, Brian J; Loy, Kelsey A et al. (2018) Hypothalamic Neurons that Regulate Feeding Can Influence Sleep/Wake States Based on Homeostatic Need. Curr Biol 28:3736-3747.e3
Iyer, Manasi; Essner, Rachel A; Klingenberg, Bernhard et al. (2018) Identification of discrete, intermingled hypocretin neuronal populations. J Comp Neurol 526:2937-2954
Essner, Rachel A; Smith, Alison G; Jamnik, Adam A et al. (2017) AgRP Neurons Can Increase Food Intake during Conditions of Appetite Suppression and Inhibit Anorexigenic Parabrachial Neurons. J Neurosci 37:8678-8687