A comparison of adiponectin-deficient mice reveals the fundamental role of intracellular adiponectin

Adiponectin is an important adipokine with insulin-sensitizing, anti-inflammatory, and anti-fibrotic properties. The physiological roles of adiponectin have been studied using global adiponectin knockout (KO) mice. However, the reported phenotypes of adiponectin KO mice vary based on the mouse lines generated by different strategies and investigators. We performed a head-to-head comparison of the adiponectin KO mice that were generated in Dallas, Houston and Osaka. RNAseq revealed that the expression of the bioactive domain of adiponectin - the globular domain - was preserved in the Houston and Osaka KO mice. A complete adiponectin KO model, such as the Dallas KO mouse, exhibits a lower body weight, the highest adipocyte mitochondrial function and displays a susceptibility to DNA damage-mediated lung fibrosis. The reconstitution of globular adiponectin into the Dallas KO mice prompted an increase in body weight and a partial recapitulation of the Osaka KO model transcriptome signature. The intracellular globular adiponectin form is important, as we found that globular adiponectin enhances PPARγ activity by modulating the coregulators interacting with PPARγ. Overall, the residual expression of globular adiponectin regulates adipose tissue metabolism by altering PPARγ activity, highlighting an important novel role of intracellular adiponectin.