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

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.

Interleukin-6: An Under-Appreciated Inducer of Thermogenic Adipocyte Differentiation

“…Key genes necessary for mitochondrial biogenesis—i.e., the expansion of the mitochondrial network, allowing increased β-oxidation and mitochondrial thermogenesis—as well as genes of thermogenic adipocyte development and mitochondrial uncoupling form a gene network associated with IL-6 signaling ( Figure 3 a). Coherently, several genes of mitochondrial biogenesis and uncoupling have binding sites for STAT3 in their promoter regions ( Figure 3 b), suggesting that IL-6 may control the expression of these genes [ 90 ]. Indeed, IL-6 produced within the adipose tissue appears to stimulate thermogenic fat differentiation by autocrine and paracrine mechanisms [ 21 , 31 , 50 ] ( Figure 2 c,d).…”