The role of macrophage PPARγ acetylation in determining adipose tissue remodeling was discovered for the first time

As a chronic pro-inflammatory disease, obesity is closely related
to the occurrence of type 2 diabetes, cardiovascular disease, cancer and other diseases.
Obesity is now a major public health problem
.

Macrophages play an important role
in the development of obesity.
Recent studies have shown that adipose tissue macrophages respond to fat intake and regulate fat storage
in a paracrine manner.
Macrophages are no longer just a "player", but the "culprits"
of the development of obesity.

There is growing evidence that nuclear receptor peroxisome proliferation activates receptor γ (PPARγ) in the development and remodeling of adipose tissue
.
On the one hand, PPARγ is highly expressed in adipocytes and is the main regulator of adipocyte differentiation and function
.
On the other hand, PPARγ has anti-inflammatory effects in macrophages, where loss of PPARγ impairs lipid metabolism
.
Although there is growing evidence that PPARγ is closely related to macrophage and lipid metabolism, how post-translational modifications of PPARγ in macrophages regulate fat metabolism remains unknown
.

In a recent study, Li Qiang's group at Columbia University revealed a novel role
in macrophage PPARγ acetylation in impairing adipose tissue function.

They constructed a mouse line expressing a constitutive mimetic form of macrophage-specific PPARγ (K293Q liquid oxygen^{/liquid oxygen}: LysMcre, mK293Q) to systematically analyze the role of PPARγ acetylation in macrophages in vitro as well as in living organisms.
Under high-fat diet (HFD) conditions, m1-like macrophage infiltration and significantly decreased macrophage M2 polarization in mK293Q mouse epididymal white adipose tissue (eWAT) were significantly increased, and macrophage M2 polarization was significantly reduced, partly through mcp1-mediated mechanisms
.
Metabolic and phenotypic analysis showed that macrophage PPARgamma acetylation reduced energy expenditure, exacerbated body weight and fat accumulation during HFD, and impaired insulin sensitivity and glucose tolerance
.
Further investigation of metabolic indexes in plasma of mK293Q mice showed that the expression of adiponectin and lipoprotein, two key adipocytic secretion factors that regulate systemic insulin sensitivity and glucose homeostasis, decreased expression, impaired expression of genes related to adipocyte function in eWAT, and overall impaired
lipid metabolism.
Notably, adipose tissue from mK293Q mice exhibited severe fibrosis
.
Thus, PPARγacetylation in macrophages promotes macrophage infiltration, leading to fatty fibrosis and dysfunction, and aggravating hepatic steteaosis
.

PPARγ synthesis activators thiazolidinediones (TZDs) are an important class of anti-diabetic drugs that inhibit the inflammatory response of macrophages and relieve adipose tissue inflammation in living organisms.
In this study, the TZD drug rosiglitazone (Rosi) was used to treat
mK293Q mice after HFD feeding.
The results showed that although Rosi was able to save mK293Q mice from impaired insulin resistance and glucose tolerance to some extent, the response of eWAT to TZD drugs was affected
.
Macrophage infiltration, expression of inflammatory and anti-inflammatory factors, and expression of functional genes in fat cells were not completely restored
.
In summary, PPARγ deacetylation in macrophages is essential
for visceral fat remodeling and functional improvement.

In conclusion, this study explores for the first time the role of macrophage PPARγacetylation in determining adipose tissue remodeling, and provides a new mechanism
for PPARγacetylation-mediated multicellular crosstalk in adipose tissue.