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. The central molecular clock aligns feeding with the sleep/wake state. Cedernaes et al. employ RNA sequencing in AgRP neurons across different nutrient states, revealing time-of-day-dependent enrichment of circadian and bioenergetic gene networks. They discover that the behavioral and transcriptional response to leptin varies from morning to evening, as the AgRP clock coordinates the leptin response and glucose metabolism with arousal.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1078-1091.e5 |
| Journal | Cell Metabolism |
| Volume | 29 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 7 2019 |
Funding
We thank Grant Barish and members of the Bass laboratory for helpful discussions and Mia Andreoli, Varun Mehta, Celestine He, Paul Brandfonbrener, and Weimin Song for technical assistance. This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK090625, R01DK113011, R01DK100814, and P01DK049210; the National Institute on Aging grant P01AG011412; the National Institute of Mental Health grant R01MH110556; the Chicago Biomedical Consortium S-007; the University of Chicago Diabetes Research and Training Center grant P60DK020595 (J.B.); the NIDDK award K01DK105137-02 (C.B.P.); the Swedish Research Council grant 2014-6888 (J.C.); and the Swedish Society for Medical Research (J.C.). Research by J.C. is also supported by the Swedish Brain Foundation. This research was also supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553). Conceptualization, J.C. W.H. K.M.R. and J.B.; Formal Analysis, J.C. W.H. and N.W.; Investigation, J.C. W.H. N.W. D.C.L. C.B.P. C.O. L.C. Y.K. R.D. and M.M.; Resources, C.A.B, X.A.W. and J.S.T.; Writing, J.C. W.H. K.M.R. and J.B.; Visualization, B.M.; Supervision, J.C. W.H. R.A. and J.B.; Funding Acquisition, J.C. C.B.P. and J.B. The authors declare no competing interests. We thank Grant Barish and members of the Bass laboratory for helpful discussions and Mia Andreoli, Varun Mehta, Celestine He, Paul Brandfonbrener, and Weimin Song for technical assistance. This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK090625 , R01DK113011 , R01DK100814 , and P01DK049210 ; the National Institute on Aging grant P01AG011412 ; the National Institute of Mental Health grant R01MH110556 ; the Chicago Biomedical Consortium S-007; the University of Chicago Diabetes Research and Training Center grant P60DK020595 (J.B.); the NIDDK award K01DK105137-02 (C.B.P.); the Swedish Research Council grant 2014-6888 (J.C.); and the Swedish Society for Medical Research (J.C.). Research by J.C. is also supported by the Swedish Brain Foundation . This research was also supported by the Northwestern University RHLCCC Flow Cytometry Facility and a Cancer Center Support Grant ( NCI CA060553 ).
Keywords
- AgRP
- Agouti-related protein
- RNA sequencing
- RNA-seq
- RiboTag
- SCN
- circadian
- metabolism
- suprachiasmatic nucleus
- time-restricted feeding
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology