Arrdc4 Regulates Insulin‐Stimulated Glucose Metabolism

The molecular mechanisms that control glucose uptake into the cells are not yet completely defined. The Arrestin superfamily of proteins controls the inactivation, degradation and signaling of trans‐membrane receptors. Several members of the family, including Arrestin domain containing 3 and TXNIP, are now known to have important roles in metabolism. Arrestin domain containing protein 4 (ARRDC4) is a less‐investigated member of the ancient alpha‐arrestin family. Here, we show that ARRDC4 controls insulin‐stimulated glucose metabolism in vivo and in vitro . Both ARRDC4 and TXNIP suppressed insulin‐stimulated glucose uptake in differentiated adipocytes (Fig. ). In 8‐week old male C57Bl6 wildtype mice and mice with systemic deletion of the ARRDC4 gene (n=5–7/group) subjected to insulin tolerance tests (0.75U/kg), we found that mice with deletion of ARRDC4 were significantly more insulin sensitive compared to wildtype mice (Fig ). We also found that deletion of ARRDC4 in mice led to increased insulin‐stimulated Akt phosphorylation in adipose tissues (Fig ). Furthermore, in vitro and in mice, the expression of ARRDC4 is suppressed by insulin (Fig ). These data identify ARRDC4 as a regulator of mammalian insulin‐stimulated glucose metabolism. Support or Funding Information Supported by NIH/NIDDK to R.T.L 1R01DK107396 (A) Insulin‐stimulated H3 deoxy‐glucose uptake in differentiated 3T3‐L1 mature adipocytes that were transfected with either empty, ARRDC4 or TXNIP plasmid (n=6) (B) Insulin tolerance test (0.75U/kg) of 8‐week old ARRDC4 KO and WT mice (n=5–7) (C) Insulin‐stimulated Akt phosphorylation in adipose tissues of ARRDC4 KO and WT mice. ARRDC4 mRNA expression in the insulin‐stimulated HEPG2 cells (D) or livers of wildtype mice (E) (n=4) *p<0.05 **p<0.01. Figure 1