Abstract
Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.
Highlights
Insulin resistance is a characteristic defect in the majority of patients with type 2 diabetes mellitus (T2DM)[1]
PU.[1] is expressed in the liver but expression levels are unchanged after high fat diet (HFD) feeding in both hepatocytes and non-parenchymal cells (NPCs) (Fig. 1A)
PU.[1] is a potent re-programming factor which can confer macrophage-like phenotypic features and functions on other differentiated cell types through reprogramming and trans-differentiation[8,9,10,11]
Summary
Adipocyte PU.[1] expression in obesity could promote the proinflammatory, insulin resistant state. The role of PU.[1] in adipocytes is poorly defined in vivo in the context of obesity. We generated adipocyte-specific PU.[1] knockout (PU.[1] AKO) mice to assess its role in adipogenesis, adipose tissue inflammation, and insulin resistance in the obese state. We show that PU.[1] AKO mice fed high fat diet (HFD) have improved glucose tolerance and insulin sensitivity, with decreased adipose tissue inflammation, increased PPARg-target gene expression and decreased hepatic steatosis
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