In agreement with previous studies, we found that Vsig4−/− obese mice exhibit exacerbated insulin resistance along with diminished p-IRS-1 and p-Aktser473 in the WAT and the liver tissues (Fig. 1h), indicating that Vsig4 deficiency eliminates the negative control signals, thus allowing ATMs to produce proinflammatory cytokines and switching on HFD-associated insulin tolerance in vivo. Here, IRS1 is linked to Insulin resistance.