A deeper understanding of the biologic origins of obesity will require mapping the neural networks that control feeding. Two key neural populations that control feeding are AgRP and POMC neurons in the hypothalamus. Despite extensive study of these cells over the past 20 years little is known about their natural dynamics in vivo. We have used fiber photometry to record the natural activity of AgRP and POMC neurons in awake behaving mice. Using this approach we have discovered that AgRP and POMC neurons are rapidly (seconds) and dramatically modulated by sensory cues associated with food. This regulation is cell-type-specific, is sensitive to food palatability and nutritional state, and occurs before any food is consumed. These data indicate the existence of an unanticipated neural pathway by which sensory detection of food generates rapid anticipatory changes in the activity of AgRP and POMC neurons. Importantly, this rapid regulation provides a mechanism for AgRP and POMC neurons to integrate sensory and hedonic cues with homeostatic information about nutritional state, suggesting a more complex role for these first order neurons than is currently appreciated. We propose here to delineate the neural mechanisms underlying the remarkable rapid regulation of these cells by food detection. We propose further to explore the downstream pathways to which these sensory cues are communicated in order to understand their role within a distributed feeding network.

Public Health Relevance

Food intake is controlled by neural circuits in the brain that remain poorly understood. A better understanding of the dynamics of these circuits would greatly advance our ability to develop anti-obesity therapies. This proposal utilizes state-of-the-art approaches in neuroscience to record for the first time the activity of key neurons that contro feeding and are dysregulated in obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Beutler, Lisa R; Knight, Zachary A (2018) A Spotlight on Appetite. Neuron 97:739-741
Tan, Chan Lek; Knight, Zachary A (2018) Regulation of Body Temperature by the Nervous System. Neuron 98:31-48
Leib, David E; Zimmerman, Christopher A; Poormoghaddam, Ailar et al. (2017) The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement. Neuron 96:1272-1281.e4
Garrison, Jennifer L; Knight, Zachary A (2017) Linking smell to metabolism and aging. Science 358:718-719
Chung, Shinjae; Weber, Franz; Zhong, Peng et al. (2017) Identification of preoptic sleep neurons using retrograde labelling and gene profiling. Nature 545:477-481
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Beutler, Lisa R; Chen, Yiming; Ahn, Jamie S et al. (2017) Dynamics of Gut-Brain Communication Underlying Hunger. Neuron 96:461-475.e5
Tan, Chan Lek; Cooke, Elizabeth K; Leib, David E et al. (2016) Warm-Sensitive Neurons that Control Body Temperature. Cell 167:47-59.e15
Chen, Yiming; Knight, Zachary A (2016) Making sense of the sensory regulation of hunger neurons. Bioessays 38:316-24
Leib, David E; Zimmerman, Christopher A; Knight, Zachary A (2016) Thirst. Curr Biol 26:R1260-R1265

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