MKP‐2 Deficiency Improves Insulin Sensitivity and Protects Against Fatty Liver Disease

Abstract

The function of MAPK phosphatase‐2 (MKP‐2), a type 1 dual‐specific phosphatase (DUSP) in metabolic regulation is largely unknown. Here we demonstrate that MKP‐2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease, and in insulin‐responsive tissues in mice with obesity. MKP‐2 deficient mice have enhanced p38 MAPK, JNK and ERK activities in insulin‐responsive tissues compared with wild type mice. MKP‐2 deficiency in mouse protects against diet‐induced obesity and hepatic steatosis and was accompanied with improved glucose homeostasis and insulin sensitivity. This was associated with enhanced circulating insulin‐like growth factor‐1 (IGF‐1) and stromal cell‐derived factor 1 (SDF‐1) levels in Mkp‐2‐/‐ mice. PTEN, a negative regulator of Akt, was upregulated in livers of Mkp‐2‐/‐ mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. Pancreatic islet analysis demonstrated that MKP‐2 deficiency altered islet composition and this has the potential to regulate in b‐cell physiology. These studies demonstrate for the first time that MKP‐2 is essential in the regulation of metabolic homeostasis and pathophysiology of obesity‐induced insulin resistance and fatty liver disease.