Presenting Author University of Alabama in Huntsville
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.
