Stochastic neuropeptide signals compete to calibrate the rate of satiation

Stephen X Zhang; Angela Kim; Joseph C Madara; Paula K Zhu; Lauren F Christenson; Andrew Lutas; Peter N Kalugin; Praneel S Sunkavalli; Yihan Jin; Akash Pal; Lin Tian; Bradford B Lowell; Mark L Andermann

doi:10.1038/s41586-024-08164-8

Stochastic neuropeptide signals compete to calibrate the rate of satiation

Nature. 2024 Nov 6. doi: 10.1038/s41586-024-08164-8. Online ahead of print.

Authors

Stephen X Zhang^#¹, Angela Kim^#², Joseph C Madara², Paula K Zhu², Lauren F Christenson², Andrew Lutas^{2

3}, Peter N Kalugin², Praneel S Sunkavalli², Yihan Jin^{4

5

6}, Akash Pal^{4

6}, Lin Tian^{4

6}, Bradford B Lowell², Mark L Andermann^{7

8}

Affiliations

¹ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. x.stephen.zhang@gmail.com.
² Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
³ Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
⁴ Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA.
⁵ Neuroscience Graduate Group, Center for Neuroscience, University of California, Davis, Sacramento, CA, USA.
⁶ Max Planck Florida Institute for Neuroscience, One Max Planck Way, Jupiter, FL, USA.
⁷ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. manderma@bidmc.harvard.edu.
⁸ Department of Neurobiology, Harvard Medical School, Boston, MA, USA. manderma@bidmc.harvard.edu.

^# Contributed equally.

PMID: 39506113
DOI: 10.1038/s41586-024-08164-8

Abstract

Neuropeptides have important roles in neural plasticity, spiking and behaviour¹. Yet, many fundamental questions remain regarding their spatiotemporal transmission, integration and functions in the awake brain. Here we examined how MC4R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH^MC4R) integrate neuropeptide signals to modulate feeding-related fast synaptic transmission and titrate the transition to satiety^2-6. We show that hunger-promoting AgRP axons release the neuropeptide NPY to decrease the second messenger cAMP in PVH^MC4R neurons, while satiety-promoting POMC axons release the neuropeptide αMSH to increase cAMP. Each release event is all-or-none, stochastic and can impact multiple neurons within an approximately 100-µm-diameter region. After release, NPY and αMSH peptides compete to control cAMP-the amplitude and persistence of NPY signalling is blunted by high αMSH in the fed state, while αMSH signalling is blunted by high NPY in the fasted state. Feeding resolves this competition by simultaneously elevating αMSH release and suppressing NPY release^7,8, thereby sustaining elevated cAMP in PVH^MC4R neurons throughout a meal. In turn, elevated cAMP facilitates potentiation of feeding-related excitatory inputs with each bite to gradually promote satiation across many minutes. Our findings highlight biochemical modes of peptide signal integration and information accumulation to guide behavioural state transitions.