Unraveling the homeostatic and hedonic circuits underlying feeding behavior and obesity

PROJECT SUMMARY
The striking prevalence of obesity and its associated personal and public health consequences highlights the
importance of understanding why individuals overeat and gain weight. It is widely recognized that overeating
results from a combination of homeostatic (i.e., nutrient need, hunger) and hedonic (i.e., pleasure, reward) drives.
While these homeostatic (e.g., hypothalamic) and hedonic [e.g., midbrain dopamine (DA)] systems have been
characterized as discrete drivers of food intake, there is considerable evidence that these systems overlap. For
example, DA signaling in response to food is potentiated by hunger, increasing the reward value of food during
times of homeostatic need. Our recent findings in rodent models revealed a neural correlate for the interaction
between homeostatic and hedonic systems. Activity in hunger-sensitive, hypothalamic agouti-related protein
(AgRP)-expressing neurons potentiates the DA response to food. Conversely, DA signaling enhances the
homeostatic AgRP neuron response to food. What are the circuits through which AgRP and DA neurons interact
in response to food? Do they help explain why some individuals are more likely to overeat and gain weight? This
proposal will test the overarching hypotheses that distinct AgRP and DA neuron subpopulations mediate the
interaction between homeostatic and reward signaling and that individual differences in AgRP and DA responses
to food predict future weight gain. Aim I experiments will determine the AgRP neuron projection subpopulations
that potentiate DA responses to food. We will leverage the anatomical organization of AgRP neurons, as well as
optogenetic and chemogenetic technologies, to individually test how each AgRP projection subpopulation
influences food-evoked DA signaling. Aim II experiments will determine sites of action for DA modulation of AgRP
neuron activity. We will use genetic and pharmacological approaches to examine how DA projections and
neurotransmitter signaling influence AgRP neuron activity. Aim III will determine how AgRP and DA activity
predicts future overeating and weight gain. Taking advantage of the variability in weight gain in response to a
high-fat, high-sugar diet, we will determine if individual differences in neural activity in lean mice predict future
overeating and the development of obesity. Overall, these experiments take a unique approach to understanding
weight gain by (1) determining the neural intersection of homeostatic and hedonic circuits that have classically
been considered discrete drivers of intake and (2) identifying neural activity biomarkers to predict overeating and
obesity predisposition. Ultimately, results from the proposed studies will reveal cellular and molecular targets
that can be leveraged to develop obesity prevention and more effective weight loss strategies.

Grant Number: 5R01DK131558-05
NIH Institute/Center: NIH
Principal Investigator: Amber Alhadeff