Overexpression of Plg-R_KT protects against adipose dysfunction and dysregulation of glucose homeostasis in diet-induced obese mice

ABSTRACT

The plasminogen receptor, Plg-R_KT, is a unique cell surface receptor that is broadly expressed in cells and tissues throughout the body. Plg-R_KT localizes plasminogen on cell surfaces and promotes its activation to the broad-spectrum serine protease, plasmin. In this study, we show that overexpression of Plg-R_KT protects mice from high fat diet (HFD)-induced adipose and metabolic dysfunction. During the first 10 weeks on the HFD, the body weights of mice that overexpressed Plg-R_KT (Plg-R_KT-OEX) were lower than those of control mice (CagRosaPlgRKT). After 10 weeks on the HFD, CagRosaPlgRKT and Plg-R_KT-OEX mice had similar body weights. However, Plg-R_KT-OEX mice showed a more metabolically favourable body composition phenotype. Plg-R_KT-OEX mice also showed improved glucose tolerance and increased insulin sensitivity. We found that the improved metabolic functions of Plg-R_KT-OEX mice were mechanistically associated with increased energy expenditure and activity, decreased proinflammatory adipose macrophages and decreased inflammation, elevated brown fat thermogenesis, and higher expression of adipose PPARγ and adiponectin. These findings suggest that Plg-R_KT signalling promotes healthy adipose function via multiple mechanisms to defend against obesity-associated adverse metabolic phenotypes.

KEYWORDS:

• Plg-R_KT
• adipose tissue
• adipose inflammation
• insulin resistance
• brown fat thermogenesis

Acknowledgments

Study was funded by NIH Grants HL149511 (to F.S., R.J.P. and L.A.M.), HL-104232 (to F.S.), HL-081046 (to L.A.M.) and Merit Review Award I01BX003933 from the U.S. Department of Veterans Affairs (to R.J.P.). We thank Amanda J. Roberts and the Scripps Research Animal Core Facility for the metabolic and EchoMRI services.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

H.B., S.C., N.B. and Y.Z. performed experiments and analysed data. L.A.M., R.J.P. and F.S. conceived and designed experiments, analysed data and wrote the manuscript.

Data availability statement

The data that support the findings of this study are available from the corresponding authors [L.A.M., R.J.P. and F.S], upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21623945.2023.2252729

Additional information

Funding

This work was supported by the National Institutes of Health 520 [HL149511, HL081046, HL104232]; Department of Veterans Affairs [Merit Review Award Q2 I01BX003933].