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Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance
and Fatty Liver Disease.
Authors Fernando S, Sellers J, Smith S, Bhogoju S, Junkins S, Welch M, Willoughby O,
Ghimire N, Secunda C, Barmanova M, Kumer SC, Min K, Lawan A
Submitted By Submitted Externally on 10/5/2022
Status Published
Journal Nutrients
Year 2022
Date Published 6/1/2022
Volume : Pages 14 : Not Specified
PubMed Reference 35745205
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. Mkp-2-/-
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 Mkp-2-/- mice. PTEN, a negative regulator of Akt, was
downregulated in livers of Mkp-2-/- 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.


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