Acute and circadian feedforward regulation of agouti-related peptide hunger neurons

Amelia M Douglass; Hakan Kucukdereli; Joseph C Madara; Daqing Wang; Chen Wu; Elijah D Lowenstein; Jenkang Tao; Bradford B Lowell

doi:10.1016/j.cmet.2024.11.009

Acute and circadian feedforward regulation of agouti-related peptide hunger neurons

Cell Metab. 2024 Dec 17:S1550-4131(24)00455-8. doi: 10.1016/j.cmet.2024.11.009. Online ahead of print.

Authors

Amelia M Douglass¹, Hakan Kucukdereli², Joseph C Madara², Daqing Wang², Chen Wu², Elijah D Lowenstein², Jenkang Tao², Bradford B Lowell³

Affiliations

¹ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: adougla3@bidmc.harvard.edu.
² Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
³ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Program in Neuroscience, Harvard Medical School, Boston, MA, USA. Electronic address: blowell@bidmc.harvard.edu.

PMID: 39719709
DOI: 10.1016/j.cmet.2024.11.009

Abstract

When food is freely available, eating occurs without energy deficit. While agouti-related peptide (AgRP) neurons are likely involved, their activation is thought to require negative energy balance. To investigate this, we implemented long-term, continuous in vivo fiber-photometry recordings in mice. We discovered new forms of AgRP neuron regulation, including fast pre-ingestive decreases in activity and unexpectedly rapid activation by fasting. Furthermore, AgRP neuron activity has a circadian rhythm that peaks concurrent with the daily feeding onset. Importantly, this rhythm persists when nutrition is provided via constant-rate gastric infusions. Hence, it is not secondary to a circadian feeding rhythm. The AgRP neuron rhythm is driven by the circadian clock, the suprachiasmatic nucleus (SCN), as SCN ablation abolishes the circadian rhythm in AgRP neuron activity and feeding. The SCN activates AgRP neurons via excitatory afferents from thyrotrophin-releasing hormone-expressing neurons in the dorsomedial hypothalamus (DMH^Trh neurons) to drive daily feeding rhythms.

Keywords: AgRP neurons; circadian; dorsomedial hypothalamus; feeding; gastric infusion; homeostasis; in vivo fiber photometry; suprachiasmatic nucleus.