Abstract
Pathogenic factors driving obesity to type 2 diabetes (T2D) are not fully understood. Group 1 innate lymphoid cells (ILC1s) are effectors of innate immunity and enriched in inflamed tissues. Here we show that the number of adipose ILC1s increases in obese T2D patients and correlates with glycemic parameters and with the number of ILC1s in the blood; circulating ILC1 numbers decrease as a result of metabolic improvements after bariatric surgery. In vitro co-culture experiments show that human adipose ILC1s promote adipose fibrogenesis and CD11c+ macrophage activation. Reconstruction of the adipose ILC1 population in Prkdc−/−IL2rg−/− mice by adoptive transfer drives adipose fibrogenesis through activation of TGFβ1 signaling; however, transfer of Ifng−/− ILC1s has no effect on adipose fibrogenesis. Furthermore, inhibiting adipose accumulation of ILC1s using IL-12 neutralizing antibodies attenuates adipose tissue fibrosis and improves glycemic tolerance. Our data present insights into the mechanisms of local immune disturbances in obesity-related T2D.
Highlights
Pathogenic factors driving obesity to type 2 diabetes (T2D) are not fully understood
Higher numbers of ILC1s resident in the omental adipose tissue were detected in the obese group compared with the control group (15 ± 3 vs. 5 ± 3, P < 0.001, two-way ANOVA tests followed by Bonferroni post hoc test, Fig. 1c), which was even higher in obese T2D patients
Through a comprehensive set of experiments in humans and mice, we demonstrated that adipose ILC1s promote adipose tissue fibrogenesis via increasing CD11c+ macrophages and activating the transforming growth factor β-1 (TGF-β1)/Smad[3] signaling pathway
Summary
Pathogenic factors driving obesity to type 2 diabetes (T2D) are not fully understood. Emerging findings indicate that innate and adaptive immune responses in adipose tissue have critical functions in the regulation of metabolic homeostasis, while in obesity, type 1 inflammation-associated immune cells are predominant in adipose tissue and exert metabolically deleterious impacts[5]. A study has shown that accumulation of adipose ILC1s directly induces local inflammation and systemic insulin resistance in high-fat-diet (HFD)-fed mice[11]. Adipose tissue macrophages (ATMs) are reported to have an important function in regulating adipose tissue fibrosis: macrophage-secreted factors are shown to promote a profibrotic phenotype in preadipocytes;[16] in addition, proinflammatory CD11c+ macrophages drive adipose tissue fibrogenesis by regulating distinct cell types[17,18]. Induced mice[11], but whether adipose ILC1s regulate adipose tissue fibrogenesis and the underlying mechanisms are unclear
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