| RRC ID |
88554
|
| 著者 |
Heyward FD, Liu N, Jacobs C, Machado NLS, Ivison R, Uner A, Srinivasan H, Patel SJ, Gulko A, Sermersheim T, Tsai L, Rosen ED.
|
| タイトル |
AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin's acute effects.
|
| ジャーナル |
Nat Commun
|
| Abstract |
AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.
|
| 巻・号 |
15(1)
|
| ページ |
4646
|
| 公開日 |
2024-5-31
|
| DOI |
10.1038/s41467-024-48885-y
|
| PII |
10.1038/s41467-024-48885-y
|
| PMID |
38821928
|
| PMC |
PMC11143326
|
| MeSH |
Agouti-Related Protein / genetics
Agouti-Related Protein / metabolism
Animals
Arcuate Nucleus of Hypothalamus / metabolism
Chromatin
Epigenesis, Genetic
Fasting
Gene Expression Regulation
Hunger* / physiology
Interferon Regulatory Factor-3* / genetics
Interferon Regulatory Factor-3* / metabolism
Leptin* / metabolism
Male
Mice
Mice, Inbred C57BL
Neurons* / metabolism
Signal Transduction
Transcriptome
|
| リソース情報 |
| 実験動物マウス |
RBRC00858 |
