| Metabolic syndrome is increasing in prevalence in the western world at an alarming rate and is defined by multiple sequelae including obesity, insulin resistance, hepatic steatosis, cardiovascular disease, and hyperlipidemia. The molecular mechanisms controlling the development of metabolic syndrome remain unclear. Though it is generally accepted that Mitogen Activated Protein Kinases (MAPK)s play important roles in metabolic processes, little is known about the function of the inactivators of MAPKs, the MAP Kinase Phosphatases (MKP)s, in metabolism.;MKP-1 is ubiquitously expressed, localized to the nucleus and induced by multiple stimuli. MKP-1 dephosphorylates all three MAPKs with a specificity of p38MAPK ≥ JNK > Erk. Though the role of MKP-1 in a cellular context has been thoroughly investigated, the role of MKP-1 in vivo has yet to be fully defined. Here, we report that MKP-1 plays a non-redundant role in regulation of MAPK activity in several different tissues in vivo. Mice lacking MKP-1 expression are resistant to diet-induced obesity and have enhanced energy expenditure.;Though resistant to weight gain, mkp-1-/- mice still succumb to glucose intolerance upon high fat feeding, an observation that challenges the idea that insulin sensitivity inversely correlates with weight. These data may be explained by the fact that MKP-1 inhibits nuclear MAPK activity, which modulates metabolic gene expression, whereas MAPK signaling in the cytosol regulates insulin signaling events.;In order to gain mechanistic insight into why mkp-1 -/- mice are resistant to obesity, we investigated the role of MKP-1 in skeletal muscle and found that its expression increases upon high fat feeding, which is commensurate with a decrease in skeletal muscle oxidative capacity. Notably, HFD-fed mkp-1-/- mice are resistant to these changes. This may be explained at the molecular level as MKP-1 negatively regulates the stability of PGC-1alpha, a transcriptional coactivator and master regulator of metabolism. We further investigated the role of MKP-1 as a regulator of hepatic lipid metabolism, and found that MKP-1 expression is involved in the development of hepatic steatosis.;Taken together, this dissertation provides evidence that MKP-1 regulates metabolism in multiple tissues and gives insight to the mechanisms by which MKP-1 may regulate these processes. |
