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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / genetics
  • Agouti-Related Protein / metabolism*
  • Animals
  • Circadian Clocks / genetics*
  • Circadian Rhythm / genetics*
  • Eating / physiology
  • Fasting / physiology
  • Gene Regulatory Networks
  • Glucose / metabolism
  • Hunger / physiology*
  • Hypothalamus / metabolism
  • Leptin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / metabolism*
  • Signal Transduction / genetics
  • Sleep / physiology
  • Transcription, Genetic / genetics*
  • Transcriptome
  • Wakefulness / physiology


  • Agouti-Related Protein
  • Agrp protein, mouse
  • Leptin
  • Glucose