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

Area of Science:

• Endocrinology
• Immunology
• Metabolic Research

Background:

• Glucocorticoids (GCs) are potent drugs with significant metabolic side effects, including obesity.
• Macrophages play a crucial role in adipose tissue homeostasis and are key targets of GC action.
• The precise mechanisms by which GCs induce obesity remain incompletely understood.

Purpose of the Study:

• To elucidate the role of macrophages in glucocorticoid-induced obesity.
• To investigate the function of Krüppel-like factor 9 (Klf9) in macrophages during GC treatment.
• To identify potential therapeutic targets for mitigating GC-induced metabolic dysfunction.

Main Methods:

• Treatment of mice with dexamethasone (Dex) and genetic manipulation of Klf9 expression in myeloid cells.
• Assessment of macrophage polarization markers (M1, M2a) and activity.
• Analysis of gene expression, thermogenesis, lipid accumulation, and STAT3 signaling in adipocytes.

Main Results:

• Dexamethasone (Dex) significantly upregulated Krüppel-like factor 9 (Klf9) in macrophages, leading to macrophage deactivation.
• Myeloid-specific Klf9 overexpression promoted obesity, while myeloid Klf9 knockout (mKlf9KO) mice were lean.
• mKlf9KO largely prevented obesity induced by chronic GC treatment.
• GC-inducible KLF9 recruits the SIN3A/HDAC complex to inhibit key inflammatory and metabolic genes, reducing thermogenesis and increasing lipid accumulation via STAT3 inhibition in adipocytes.

Conclusions:

• Macrophages are essential mediators of glucocorticoid-induced obesity.
• Krüppel-like factor 9 (Klf9) in macrophages is a critical molecular link between GCs and metabolic dysregulation.
• KLF9 in macrophages integrates both anti-inflammatory and adverse metabolic effects of GCs, presenting a potential therapeutic target.