Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages.

Nat Commun

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Tianjin Medical University, Tianjin, China.

Published: February 2024

AI Article Synopsis

  • Glucocorticoids (GCs) like dexamethasone are linked to obesity, but the exact mechanisms are unclear, and macrophages play a central role in this process.
  • The study reveals that the expression of Krüppel-like factor 9 (Klf9) in macrophages is significantly increased by GCs, leading to their deactivation and promoting obesity.
  • Knocking out Klf9 in macrophages prevents obesity from chronic GC treatment by blocking inflammatory and metabolic pathways, suggesting that targeting Klf9 could be a potential therapeutic strategy for managing GC-induced obesity.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10853261PMC
http://dx.doi.org/10.1038/s41467-024-45477-8DOI Listing

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