Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages
Yinliang Zhang,
Chunyuan Du,
Wei Wang,
Wei Qiao,
Yuhui Li,
Yujie Zhang,
Sufang Sheng,
Xuenan Zhou,
Lei Zhang,
Heng Fan,
Ying Yu,
Yong Chen,
Yunfei Liao (),
Shihong Chen () and
Yongsheng Chang ()
Additional contact information
Yinliang Zhang: Tianjin Medical University
Chunyuan Du: Tianjin Medical University
Wei Wang: Hubei University
Wei Qiao: Tianjin Medical University
Yuhui Li: Tianjin Medical University
Yujie Zhang: Tianjin Medical University
Sufang Sheng: Tianjin Medical University
Xuenan Zhou: Tianjin Medical University
Lei Zhang: Tianjin Medical University
Heng Fan: General Hospital of Ningxia Medical University
Ying Yu: Tianjin Medical University
Yong Chen: Hubei University
Yunfei Liao: Huazhong University of Science and Technology
Shihong Chen: The Second Hospital of Shandong University
Yongsheng Chang: Tianjin Medical University
Nature Communications, 2024, vol. 15, issue 1, 1-20
Abstract:
Abstract The mechanisms underlying glucocorticoid (GC)-induced obesity are poorly understood. Macrophages are the primary targets by which GCs exert pharmacological effects and perform critical functions in adipose tissue homeostasis. Here, we show that macrophages are essential for GC-induced obesity. Dexamethasone (Dex) strongly induced Krüppel-like factor 9 (Klf9) expression in macrophages. Similar to Dex, lentivirus-mediated Klf9 overexpression inhibits M1 and M2a markers expression, causing macrophage deactivation. Furthermore, the myeloid-specific Klf9 transgene promotes obesity. Conversely, myeloid-specific Klf9-knockout (mKlf9KO) mice are lean. Moreover, myeloid Klf9 knockout largely blocks obesity induced by chronic GC treatment. Mechanistically, GC-inducible KLF9 recruits the SIN3A/HDAC complex to the promoter regions of Il6, Ptgs2, Il10, Arg1, and Chil3 to inhibit their expression, subsequently reducing thermogenesis and increasing lipid accumulation by inhibiting STAT3 signaling in adipocytes. Thus, KLF9 in macrophages integrates the beneficial anti-inflammatory and adverse metabolic effects of GCs and represents a potential target for therapeutic interventions.
Date: 2024
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DOI: 10.1038/s41467-024-45477-8
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