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. 2022 Sep 15;13:5408. doi: 10.1038/s41467-022-33171-6

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — a Blood glucose levels in wild-type (wt) mice treated with phosphate-buffered saline (PBS) or IL-13 as measured by the pyruvate tolerance test (PTT) (n = 8 per group). b, c Il13 expression levels in liver tissue (normalized to L32) (b) and serum IL-13 concentrations (c) in wt, nude, and NOD/Scid/Il2Rγ^null (NSG) mice intraperitoneally (i.p.). injected with PBS or recombinant IL-33 (rIL-33) for 5 consecutive days (wt rIL-33[-]: n = 8, wt rIL-33[+]: n = 9, nude rIL33[-]: n = 9, nude rIL33[+]: n = 10, NSG rIL-33[-] n = 6, and NSG rIL-33[+]: n = 6 in b; wt rIL-33[-]: n = 4, wt rIL-33[+]: n = 4, nude rIL33[-]: n = 4, nude rIL33[+]: n = 4, NSG rIL-33[-] n = 6, and NSG rIL-33[+]: n = 5 in c). d, e Fasting blood glucose (d) and blood glucose levels as measured by PTT (e) in Il13^+/-, Il13^+/- and Il13^-/- mice after 5 days of rIL-33 injection (Il13^+/+rIL-33[-]: n = 5, Il13^+/+rIL-33[+]: n = 5, Il13^+/-rIL-33[-]: n = 7, Il13^+/-rIL-33[+]: n = 4, Il13^-/- rIL-33[-]: n = 9 and Il13^-/- rIL-33[+]: n = 7 in (d), Il13^+/+rIL-33[-]: n = 7, Il13^+/+rIL-33[+]: n = 5, Il13^+/-: n = 4, Il13^+/-rIL-33: n = 7 and Il13^+/-rIL-33: n = 6 in e). f Schema of the experiment. PBS, liver ILC2s from Il13^+/- mice or liver ILC2s from Il13^-/- mice were injected intravenously into NSG mice. rIL-33 was i.p. injected for 5 consecutive days, and fasting blood glucose levels were measured after 3 and 5 days. g Fasting blood glucose levels in NSG mice without ILC2 transfer and with Il-13^+/-, Il-13^+/- or Il-13^-/- liver ILC2 transfer at days 3 and 5 (n = 3). h Experimental schema for coculture and subsequent real-time quantitative PCR (RT–qPCR) and metabolome analysis. After 6 h of coculture with ILC2s, the hepatocytes were used for RT–qPCR and metabolomic analysis. i RT–qPCR analysis of gluconeogenesis-related genes in primary hepatocytes cocultured with ILC2s (Ct: control hepatocytes, +ILC2: hepatocytes cocultured with ILC2s, + ILC2 + anti-IL13 Ab: hepatocytes cocultured with ILC2s in the presence of an anti-IL-13 antibody; n = 3 per group). j, k, l Metabolomic analysis of primary hepatocytes after coculture with ILC2s (Ct: control hepatocytes, +ILC2s: hepatocytes cocultured with ILC2s; n = 6 per group). j Amino acid metabolites categorized into the pyruvic acid pathway, acetoacetate pathway, 2-oxoglutaric acid pathway and others. k Metabolites in the gluconeogenesis-related pathway. (G6P; glucose 6-phosphate, F6P; fructose 6-phosphate, F1,6P; fructose 1,6-diphosphate, G3P; glyceraldehyde 3-phosphate, 3-PG; 3-phosphoglyceric acid, PEP; phosphoenolpyruvic acid, OAA; oxaloacetate, Pklr; pyruvate Kinase L/R, Pcx; pyruvate carboxylase). l Metabolites in the tricarboxylic acid (TCA) cycle. Unpaired one-sided Student’s t-test. ^*P < 0.05; ^**P < 0.01; ^***P < 0.001. Each bar and its error bars represent the mean ± SD.