Liver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis

Masanori Fujimoto, Masataka Yokoyama, Masahiro Kiuchi, Hiroyuki Hosokawa, Akitoshi Nakayama, Naoko Hashimoto, Ikki Sakuma, Hidekazu Nagano, Kazuyuki Yamagata, Fujimi Kudo, Ichiro Manabe, Eunyoung Lee, Ryo Hatano, Atsushi Onodera, Kiyoshi Hirahara, Koutaro Yokote, Takashi Miki, Toshinori Nakayama and Tomoaki Tanaka ()
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Masanori Fujimoto: Chiba University
Masataka Yokoyama: Chiba University
Masahiro Kiuchi: Chiba University
Hiroyuki Hosokawa: Tokai University School of Medicine
Akitoshi Nakayama: Chiba University
Naoko Hashimoto: Chiba University
Ikki Sakuma: Chiba University
Hidekazu Nagano: Chiba University
Kazuyuki Yamagata: Chiba University
Fujimi Kudo: Chiba University
Ichiro Manabe: Chiba University
Eunyoung Lee: Chiba University, Graduate School of Medicine
Ryo Hatano: Chiba University, Graduate School of Medicine
Atsushi Onodera: Chiba University
Kiyoshi Hirahara: Chiba University
Koutaro Yokote: Chiba University
Takashi Miki: Chiba University, Graduate School of Medicine
Toshinori Nakayama: Chiba University
Tomoaki Tanaka: Chiba University

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract The liver stores glycogen and releases glucose into the blood upon increased energy demand. Group 2 innate lymphoid cells (ILC2) in adipose and pancreatic tissues are known for their involvement in glucose homeostasis, but the metabolic contribution of liver ILC2s has not been studied in detail. Here we show that liver ILC2s are directly involved in the regulation of blood glucose levels. Mechanistically, interleukin (IL)-33 treatment induces IL-13 production in liver ILC2s, while directly suppressing gluconeogenesis in a specific Hnf4a/G6pc-high primary hepatocyte cluster via Stat3. These hepatocytes significantly interact with liver ILC2s via IL-13/IL-13 receptor signaling. The results of transcriptional complex analysis and GATA3-ChIP-seq, ATAC-seq, and scRNA-seq trajectory analyses establish a positive regulatory role for the transcription factor GATA3 in IL-13 production by liver ILC2s, while AP-1 family members are shown to suppress IL-13 release. Thus, we identify a regulatory role and molecular mechanism by which liver ILC2s contribute to glucose homeostasis.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33171-6

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DOI: 10.1038/s41467-022-33171-6

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