PPARγ acetylation in macrophages impairs adipose tissue function

PPARγ acetylation in macrophages impairs adipose tissue function

Role of macrophage PPARγ acetylation in determining adipose tissue remodeling. Credits: Nicole Aaron, Tarik Zahr, Ying He, Lexiang Yu, Brent Mayfield, Utpal B Pajvani, Li Qiang

As a chronic inflammatory disease, obesity is strongly associated with the development of various diseases such as type 2 diabetes, cardiovascular disease and cancer. Obesity is currently a major public health concern.

Macrophages have been known to play an important role in the development of obesity. Recent studies have shown that fat tissue residence macrophages responds to fat absorption and regulates fat storage in a parasecretory fashion. Macrophages are no longer just a “player” but a “culprit” of obesity development.

A growing body of evidence indicates that nuclear receptor peroxisome proliferation-activating receptor (PPARγ) plays a leading role in adipose tissue growth and remodeling. On the one hand, PPARγ is highly expressed in adipocytes and acts as a key regulator of adipocyte differentiation and function. On the other hand, PPARγ plays an anti-inflammatory role in macrophages, and knockdown of PPARγ in macrophages impairs lipid metabolism.

Although accumulating evidence suggests a strong correlation between PPARγ, macrophages, and lipid metabolism, how the post-translational modification of PPARγ in macrophages regulates adiposity remains unknown.

In a recent study by Metabolic lifegroup of Li Qiang at Columbia University revealed a novel role of PPARγ acetylation in macrophages in attenuating adipose tissue function.

They constructed a mouse line that expressed a constitutive, macrophage-specific acetylation mimetic form of PPARγ (K293Qfloating / floating:LysMcre, mK293Q) to systematically analyze the role of PPARγ acetylation in macrophages both in vitro and in vivo. Below high fat diet (HFD), mK293Q mice show a significant increase in M1-like macrophage infiltration in epithelial white adipose tissue (eWAT) and a significant decrease in M2 polarization of macrophages, partly through mediated by Mcp1. Metabolic and phenotypic analysis showed decreased acetylation of PPARγ by macrophages energy consumption and exacerbates weight and fat accumulation in HFD, reducing insulin sensitivity and glucose tolerance.

Further testing of plasma metabolic indices of mK293Q mice revealed decreased expression of Adiponectin and Adipsin, two key fat-secreting factors that regulate the system insulin sensitivity and glucose homeostasisand impaired expression of genes involved in adipocyte function in eWAT, as well as an overall decrease in Lipid metabolism. Notably, the adipose tissue of mK293Q mice exhibited severe fibrosis. Thus, acetylation of PPARγ in macrophages promotes macrophage infiltration, causes adipose fibrosis and dysfunction, and aggravates fatty liver with HFD feeding.

PPARγ synthesis activators thiazolidinediones (TZDs) are an important class of antidiabetic drugs that inhibit the inflammatory response of macrophages and reduce inflammation of adipose tissue in the body. In this study, the TZD drug Rosiglitazone (Rosi) was used to treat mK293Q mice after HFD feeding.

The results showed that, although Rosi could to some extent rescue insulin resistance and impaired glucose tolerance in mK293Q mice, the response of eWAT to TZD drugs was compromised. Macrophage infiltration, expression of pro-inflammatory and anti-inflammatory factors, and expression of adipocyte functional genes were not fully restored. In conclusion, deacetylation of PPARγ in macrophages is critical for remodeling and improved function of visceral fat in response to TZD.

Taken together, this study explores for the first time the role of macrophage PPARγ acetylation in determining adipose tissue remodeling, providing a novel mechanism of acetyl-mediated crosstalk. PPARγ metabolism between many cells in adipose tissue.

More information:
Nicole Aaron et al., Acetylation of PPARγ in macrophages promotes visceral fat degeneration in obese humans, Metabolic life (2022). DOI: 10.1093/lifemeta/loac032

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