Abstract 19088: The Plasminogen Receptor, Plg-RKT, Regulates Metabolic Homeostasis and Promotes Healthy Adipose Function
Introduction: Inhibition of the plasminogen activation system is linked to adipose fibrosis and insulin resistance in response to a high fat diet. However, the role of molecules that promote plasminogen activation has not been studied extensively. Plg-RKT is a novel transmembrane plasminogen receptor that promotes plasminogen activation and localizes plasmin activity on cell surfaces.
Hypothesis: Plg-RKT regulates systemic metabolic homeostasis and promotes healthy adipocyte function.
Methods: Plg-RKT null mice and wild-type littermates were fed a high fat (60%) diet (HFD) for 16 weeks.
Results: Plg-RKT-/- mice gained significantly more weight than Plg-RKT+/+ littermates over the course of the feeding regime (final wt., 54±0.9 g vs 39± 3.6 g, respectively, P<0.01 n=8). There were no differences in food intake by Plg-RKT-/- and Plg-RKT+/+ littermates. No genotype-dependent differences were observed when Plg-RKT-/- and Plg-RKT+/+ mice were fed a normal chow diet. Echo MRI measurements showed that total fat mass was significantly greater in HFD- Plg-RKT-/- mice compared with HFD- Plg-RKT+/+ littermates (20.8±0.7 g vs 14.7±2.7 g, respectively, P<0.05, n=8), epididymal adipose tissue weight was significantly less, while liver weights were significantly greater. Histological analysis showed dramatically greater levels of lipid accumulation in liver in HFD- Plg-RKT-/- mice, consistent with decreased ability of Plg-RKT-/- adipose tissue to store lipid, and enhanced ectopic fat accumulation, a hallmark of Type 2 Diabetes. Furthermore, greater fibrin and collagen deposition and greater accumulation of inflammatory cells was observed in adipose tissue of Plg-RKT-/- mice. Plg-RKT-/- mice exhibited more severe blunting of glucose tolerance and less efficient insulin-mediated suppression of plasma glucose compared to Plg-RKT+/+ littermates. In insulin signaling studies, Akt phosphorylation was 80% lower in adipose tissue of Plg-RKT-/- mice.
Conclusions: Plg-RKT coordinately regulates multiple aspects of adipose function and metabolic homeostais by maintaining an anti-fibrotic adipose environment, promoting insulin sensitivity and adipogenesis and maintaining an anti-inflammatory adipose environment.
Author Disclosures: L.A. Miles: Research Grant; Significant; National Institutes of Health, HL081046 and CA166473. N. Baik: None. H. Bai: None. J. Wang: None. F. Samad: Research Grant; Significant; National Institutes of Health HL104232. R.J. Parmer: Research Grant; Significant; U.S. Department of Veterans Affairs Merit Review Award #5I01BX002026.
- © 2016 by American Heart Association, Inc.