Sustained NPY signaling enables AgRP neurons to drive feeding

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Abstract

Artificial stimulation of Agouti-Related Peptide (AgRP) neurons promotes intense food consumption, yet paradoxically during natural behavior these cells are inhibited before feeding begins. Previously, to reconcile these observations, we showed that brief stimulation of AgRP neurons can generate hunger that persists for tens of minutes, but the mechanisms underlying this sustained hunger drive remain unknown (Chen et al., 2016). Here we show that Neuropeptide Y (NPY) is uniquely required for the long-lasting effects of AgRP neurons on feeding behavior. We blocked the ability of AgRP neurons to signal through AgRP, NPY, or GABA, and then stimulated these cells using a paradigm that mimics their natural regulation. Deletion of NPY, but not AgRP or GABA, abolished optically-stimulated feeding, and this was rescued by NPY re-expression selectively in AgRP neurons. These findings reveal a unique role for NPY in sustaining hunger in the interval between food discovery and consumption.

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Most cited references 26

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Sensory detection of food rapidly modulates arcuate feeding circuits.

Yiming Chen, Yen-Chu Lin, Tzu-Wei Kuo … (2015)

Hunger is controlled by specialized neural circuits that translate homeostatic needs into motivated behaviors. These circuits are under chronic control by circulating signals of nutritional state, but their rapid dynamics on the timescale of behavior remain unknown. Here, we report optical recording of the natural activity of two key cell types that control food intake, AgRP and POMC neurons, in awake behaving mice. We find unexpectedly that the sensory detection of food is sufficient to rapidly reverse the activation state of these neurons induced by energy deficit. This rapid regulation is cell-type specific, modulated by food palatability and nutritional state, and occurs before any food is consumed. These data reveal that AgRP and POMC neurons receive real-time information about the availability of food in the external world, suggesting a primary role for these neurons in controlling appetitive behaviors such as foraging that promote the discovery of food.

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Rapid rewiring of arcuate nucleus feeding circuits by leptin.

Shirly Pinto, Aaron Roseberry, Hongyan Liu … (2004)

The fat-derived hormone leptin regulates energy balance in part by modulating the activity of neuropeptide Y and proopiomelanocortin neurons in the hypothalamic arcuate nucleus. To study the intrinsic activity of these neurons and their responses to leptin, we generated mice that express distinct green fluorescent proteins in these two neuronal types. Leptin-deficient (ob/ob) mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto neuropeptide Y and proopiomelanocortin neurons. When leptin was delivered systemically to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects.

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Agouti-related peptide-expressing neurons are mandatory for feeding.

Eva Gropp, Marya Shanabrough, Erzsebet Borok … (2005)

Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.

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Author and article information

Contributors

Zachary A Knight:

ORCID: http://orcid.org/0000-0001-7621-1478

Richard D Palmiter: Role: Reviewing Editor

Catherine Dulac: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 29 April 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: e46348

Affiliations

[1 ]deptKavli Institute for Fundamental Neuroscience University of California, San Francisco San FranciscoUnited States

[2 ]deptNeuroscience Graduate Program University of California, San Francisco San FranciscoUnited States

[3 ]deptDepartment of Physiology University of California, San Francisco San FranciscoUnited States

[4 ]deptHoward Hughes Medical Institute University of California, San Francisco San FranciscoUnited States

Howard Hughes Medical Institute, University of Washington United States

Harvard University United States

Howard Hughes Medical Institute, University of Washington United States

NIH/NIDDK United States

Author notes

[†]

These authors contributed equally to this work.

Author information

Yiming Chen https://orcid.org/0000-0002-9569-1929

Rachel A Essner https://orcid.org/0000-0003-2240-3911

Zachary A Knight http://orcid.org/0000-0001-7621-1478

Article

Publisher ID: 46348

DOI: 10.7554/eLife.46348

PMC ID: 6513552

PubMed ID: 31033437

SO-VID: 4eb2b8df-a0b9-4e40-a56f-54e0fb5a6a1c

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 26 February 2019

Date accepted : 26 April 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;

Award ID: International Student Fellowship

Award Recipient : Yiming Chen

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes & Digestive & Kidney Diseases;

Award ID: 1F32DK118843

Award Recipient : Oliver H Miller

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01DK106399