Acetylation of PPARγ in macrophages promotes visceral fat degeneration in obesity

Abstract

Obesity is characterized by chronic, low-grade inflammation, which is driven by macrophage infiltration of adipose tissue. PPARγ is well established to have an anti-inflammatory function in macrophages, but the mechanism that regulates its function in these cells remains to be fully elucidated. PPARγ undergoes post-translational modifications (PTMs), including acetylation, to mediate ligand responses, including on metabolic functions. Here, we report that PPARγ acetylation in macrophages promotes their infiltration into adipose tissue, exacerbating metabolic dysregulation. We generated a mouse line that expresses a macrophage-specific, constitutive acetylation-mimetic form of PPARγ (K293Qflox/flox:LysM-cre, mK293Q) to dissect the role of PPARγ acetylation in macrophages. Upon high-fat diet feeding to stimulate macrophage infiltration into adipose tissue, we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice, including responses to the PPARγ agonist Rosiglitazone. Macrophage-specific PPARγ K293Q expression promotes pro-inflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue, but not in subcutaneous or brown adipose tissue, leading to decreased energy expenditure, insulin sensitivity, glucose tolerance and adipose tissue function. Furthermore, mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling. Our study reveals that acetylation is a new layer of PPARγ regulation in macrophage activation, and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.

Metformin increases the expression of proinflammatory cytokines and inhibits supraspinatus fatty infiltration

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Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice

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“…PPARγ plays an important role in regulation of cell metabolism and function. Constitutive acetylation of PPARγ in macrophages impedes their ability to skew toward anti-inflammatory state, and mice with constitutive acetylation-mimetic form of PPARγ in macrophages shows heightened macrophage infiltration to adipose tissue and activation toward pro-inflammatory state ( 146 ). In atherosclerosis, multiple macrophage populations detected in the plaque and vessel wall have at least some characteristics of MMe and can be accounted also as inflammatory macrophages.…”