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Cell Metab. 2019 May 7;29(5):1078-1091.e5. doi: 10.1016/j.cmet.2019.01.023. Epub 2019 Feb 28.

Transcriptional Basis for Rhythmic Control of Hunger and Metabolism within the AgRP Neuron.

Author information

1
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Medical Sciences, Uppsala University, Uppsala SE-75124, Sweden.
2
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
3
Weinberg College of Arts and Sciences, Northwestern University, Evanston, IL 60208, USA.
4
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Neurology and Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
6
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53706, USA.
7
Department of Molecular Sciences, Weinberg College of Arts and Sciences, Northwestern University, Evanston, IL 60208, USA.
8
Department of Neuroscience and Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
9
Division of Gastroenterology and Hepatology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA 52242, USA.
10
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: j-bass@northwestern.edu.

Abstract

The alignment of fasting and feeding with the sleep/wake cycle is coordinated by hypothalamic neurons, though the underlying molecular programs remain incompletely understood. Here, we demonstrate that the clock transcription pathway maximizes eating during wakefulness and glucose production during sleep through autonomous circadian regulation of NPY/AgRP neurons. Tandem profiling of whole-cell and ribosome-bound mRNAs in morning and evening under dynamic fasting and fed conditions identified temporal control of activity-dependent gene repertoires in AgRP neurons central to synaptogenesis, bioenergetics, and neurotransmitter and peptidergic signaling. Synaptic and circadian pathways were specific to whole-cell RNA analyses, while bioenergetic pathways were selectively enriched in the ribosome-bound transcriptome. Finally, we demonstrate that the AgRP clock mediates the transcriptional response to leptin. Our results reveal that time-of-day restriction in transcriptional control of energy-sensing neurons underlies the alignment of hunger and food acquisition with the sleep/wake state.

KEYWORDS:

AgRP; Agouti-related protein; RNA sequencing; RNA-seq; RiboTag; SCN; circadian; metabolism; suprachiasmatic nucleus; time-restricted feeding

Comment in

PMID:
30827863
PMCID:
PMC6506361
[Available on 2020-05-07]
DOI:
10.1016/j.cmet.2019.01.023

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