MAP kinase phosphatase DUSP1 is overexpressed in obese humans and modulated by physical exercise

Abstract

Chronic low-grade inflammation and dysregulation of the stress defense system are cardinal features of obesity, a major risk factor for the development of insulin resistance and diabetes. Dual-specificity protein phosphatase 1 (DUSP1), known also as MAP kinase phosphatase 1 (MKP1), is implicated in metabolism and energy expenditure. Mice lacking DUSP1 are resistant to high-fat diet-induced obesity. However, the expression of DUSP1 has not been investigated in human obesity. In the current study, we compared the expression pattern of DUSP1 between lean and obese nondiabetic human subjects using subcutaneous adipose tissue (SAT) and peripheral blood mononuclear cells (PBMCs). The levels of DUSP1 mRNA and protein were significantly increased in obese subjects with concomitant decrease in the phosphorylation of p38 MAPK (p-p38 MAPK) and PGC-1α and an increase in the levels of phospho-JNK (p-JNK) and phospho-ERK (p-ERK). Moreover, obese subjects had higher levels of circulating DUSP1 protein that correlated positively with various obesity indicators, triglycerides, glucagon, insulin, leptin, and PAI-1 (P < 0.05) but negatively with V̇O(2max) and high-density lipoprotein (P < 0.05). The observation that DUSP1 was overexpressed in obese subjects prompted us to investigate whether physical exercise could reduce its expression. In this study, we report for the first time that physical exercise significantly attenuated the expression of DUSP1 in both the SAT and PBMCs, with a parallel increase in the expression of PGC-1α and a reduction in the levels of p-JNK and p-ERK along with attenuated inflammatory response. Collectively, our data suggest that DUSP1 upregulation is strongly linked to adiposity and that physical exercise modulates its expression. This gives further evidence that exercise might be useful as a strategy for managing obesity and preventing its associated complications.

Skeletal Muscle–Specific Deletion of MKP-1 Reveals a p38 MAPK/JNK/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance

“…Interestingly, p38 MAPK has also been reported to be downregulated in the livers of HFD-fed mice, which is in line with the observation that hepatic MKP-1 is upregulated (23,32). Additionally, in obese human subjects, MKP-1 has been shown to be overexpressed in adipose tissue and macrophages with concomitant downregulation of p38 MAPK and PGC-1a (33). It is well established that the expression levels of adiponectin are negatively correlated with obesity (34).…”

Mitogen-Dependent Regulation of DUSP1 Governs ERK and p38 Signaling During Early 3T3-L1 Adipocyte Differentiation

“…Interestingly, DUSP1 has recently been identified as being differentially expressed in visceral adipose tissue of severely obese men with versus without metabolic syndrome, while others have shown that single nucleotide polymorphisms (SNPs) in the DUSP1 gene of obese individuals were associated with modulation of plasma glucose and HDL-cholesterol levels (Bouchard et al, 2007;Guenard et al, 2013). More recent data demonstrated that increased adipose tissue and circulating DUSP1 in obese, nondiabetic, patients positively correlated to increased inflammatory markers IP-10 and RANTES (Khadir et al, 2015). Taken together, obesity-associated inflammation and not obesity per se, appear responsible for elevated DUSP1 gene expression in adipose tissue.…”

Acute exercise restores insulin clearance in diet-induced obese mice

“…This amelioration involves mechanisms such as reduction in the inflammatory state (Handschin & Spiegelman 2008), decreased phosphatase expression and activity (Khadir et al 2014, Souza Pauli et al 2014, and increased mitochondrial capacity (Joseph & Hood 2014). Endurance exercisemediated reduction in insulinemia is explained, at least in part, by a decrease in insulin secretion (Aarnio et al 2001).…”