Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease
| dc.contributor.author | Fernando, Savanie | en |
| dc.contributor.author | Sellers, Jacob | en |
| dc.contributor.author | Smith, Shauri | en |
| dc.contributor.author | Bhogoju, Sarayu | en |
| dc.contributor.author | Junkins, Sadie | en |
| dc.contributor.author | Welch, Morgan | en |
| dc.contributor.author | Willoughby, Orion | en |
| dc.contributor.author | Ghimire, Nabin | en |
| dc.contributor.author | Secunda, Cassandra | en |
| dc.contributor.author | Barmanova, Marina | en |
| dc.contributor.author | Kumer, Sean C. | en |
| dc.contributor.author | Min, Kisuk | en |
| dc.contributor.author | Lawan, Ahmed | en |
| dc.date.accessioned | 2022-06-23T18:50:00Z | en |
| dc.date.available | 2022-06-23T18:50:00Z | en |
| dc.date.issued | 2022-06-15 | en |
| dc.date.updated | 2022-06-23T12:11:24Z | en |
| dc.description.abstract | The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, 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 mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. <i>Mkp-2</i><sup>−/−</sup> mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in <i>Mkp-2</i><sup>−/−</sup> mice. PTEN, a negative regulator of Akt, was downregulated in livers of <i>Mkp-2</i><sup>−/−</sup> mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease. | en |
| dc.description.version | Published version | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Fernando, S.; Sellers, J.; Smith, S.; Bhogoju, S.; Junkins, S.; Welch, M.; Willoughby, O.; Ghimire, N.; Secunda, C.; Barmanova, M.; Kumer, S.C.; Min, K.; Lawan, A. Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease. Nutrients 2022, 14, 2475. | en |
| dc.identifier.doi | https://doi.org/10.3390/nu14122475 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/110903 | en |
| dc.language.iso | en | en |
| dc.publisher | MDPI | en |
| dc.rights | Creative Commons Attribution 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
| dc.subject | obesity | en |
| dc.subject | mitogen-activated protein kinases | en |
| dc.subject | protein tyrosine phosphatase | en |
| dc.subject | lipid and glucose metabolism | en |
| dc.subject | insulin resistance | en |
| dc.subject | fatty liver disease | en |
| dc.title | Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease | en |
| dc.title.serial | Nutrients | en |
| dc.type | Article - Refereed | en |
| dc.type.dcmitype | Text | en |