Figure 7.

Ube4A maintains metabolic homeostasis by mediating insulin signaling.

A. Whole-body Ube4A deletion causes mild hyperinsulinemia and moderate impairment in glucose uptake in young, chow-fed mice. Moreover, HFD feeding develops severe insulin resistance in the knockouts. HFD-fed UKO mice also exhibit increased obesity, adipocyte dysfunction, hepatic steatosis, and liver injury.

B. In WT conditions, Ube4A mediates K63-Ub of Akt and APPL1, leading to Akt activation and insulin-induced metabolic effects. In UKO mice, K63-Ub of these proteins is disrupted, affecting insulin signaling and metabolism. Solid and open arrows indicate fully and partially active processes, respectively.