Myeloid-CITED2 Deficiency Exacerbates Diet-Induced Obesity and Pro-Inflammatory Macrophage Response

Zafar, Atif and Ng, Hang Pong and Chan, E. Ricky and Dunwoodie, Sally L. and Mahabeleshwar, Ganapati H. (2023) Myeloid-CITED2 Deficiency Exacerbates Diet-Induced Obesity and Pro-Inflammatory Macrophage Response. Cells, 12 (17). p. 2136. ISSN 2073-4409

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Macrophages are the principal component of the innate immune system that are found in all tissues and play an essential role in development, homeostasis, tissue repair, and immunity. Clinical and experimental studies have shown that transcriptionally dynamic pro-inflammatory macrophages are involved in the pathogenesis of diet-induced obesity and insulin resistance. However, cell-intrinsic mechanisms must exist that bridle uncontrolled pro-inflammatory macrophage activation in metabolic organs and disease pathogenesis. In this study, we show that CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) is an essential negative regulator of pro-inflammatory macrophage activation and inflammatory disease pathogenesis. Our in vivo studies show that myeloid-CITED2 deficiency significantly elevates high-fat diet (HFD)-induced expansion of adipose tissue volume, obesity, glucose intolerance, and insulin resistance. Moreover, myeloid-CITED2 deficiency also substantially augments HFD-induced adipose tissue inflammation and adverse remodeling of adipocytes. Our integrated transcriptomics and gene set enrichment analyses show that CITED2 deficiency curtails BCL6 signaling and broadly elevates BCL6-repressive gene target expression in macrophages. Using complementary gain- and loss-of-function studies, we found that CITED2 deficiency attenuates, and CITED2 overexpression elevates, inducible BCL6 expression in macrophages. At the molecular level, our analyses show that CITED2 promotes BCL6 expression by restraining STAT5 activation in macrophages. Interestingly, siRNA-mediated knockdown of STAT5 fully reversed elevated pro-inflammatory gene target expression in CITED2-deficient macrophages. Overall, our findings highlight that CITED2 restrains inflammation by promoting BCL6 expression in macrophages, and limits diet-induced obesity and insulin resistance.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 01 May 2024 05:07
Last Modified: 01 May 2024 05:07

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