The plasminogen receptor Plg‐RKT regulates adipose function and metabolic homeostasis

Background

Plg-RKT, a unique transmembrane plasminogen receptor, enhances the activation of plasminogen to plasmin, and localizes the proteolytic activity of plasmin on the cell surface.

Objectives

We investigated the role of Plg-RKT in adipose function, metabolic homeostasis and obesity.

Methods

We used adipose tissue (AT) sections from bariatric surgery patients and from high fat diet (HFD)-induced obese mice together with immunofluorescence and real-time PCR to study adipose expression of Plg-RKT. Mice genetically deficient in Plg-RKT and littermate controls fed a HFD or control low fat diet (LFD) were used to determine the role of Plg-RKT in insulin resistance, glucose tolerance, T2D, and associated mechanisms including adipose inflammation, fibrosis, and ectopic lipid storage. The role of Plg-RKT in adipogenesis was determined using 3T3-L1 preadipocytes and primary cultures established from Plg-RKT deficient and littermate control mice.

Results

Plg-RKT was highly expressed in both human and mouse adipose tissue AT, and its levels dramatically increased during adipogenesis. Plg-RKT deficient mice, when fed a HFD, gained more weight, developed more hepatic steatosis and were more insulin resistant/glucose intolerant than HFD-fed wild type littermates. Mechanistically, these metabolic defects were linked with increased AT inflammation, AT macrophage and T cell accumulation, adipose and hepatic fibrosis, and decreased insulin signaling in the AT and liver. Moreover, Plg-RKT regulated the expression of PPARγ and other adipogenic molecules, suggesting a novel role for Plg-RKT in the adipogenic program.

Conclusions

Plg-RKT coordinately regulates multiple aspects of adipose function that are important to maintain efficient metabolic homeostasis.

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