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

Abstract

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 polymerase chain reaction 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, type 2 diabetes, 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 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.