Role for dual-specificity phosphatases on mitogen-activated protein kinase signaling in adipocytes

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Bradley S. Ferguson (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Ron F. Morrison

Abstract: Obesity and diabetes are major public health concerns that contribute to cardiovascular disease, hypertension, and stroke. It is now widely accepted that chronic inflammation is an important element of pathogenic mechanisms linking obesity to diabetes. Moreover, clinical and experimental evidence has established the mitogen-activated protein kinase (MAPK) signaling pathway as a pivotal mediator during inflammatory stress in coupling obesity to insulin resistance (IR). While numerous studies have examined the upstream kinase activation of MAPKs, few have examined mechanisms that dephosphorylate, and thus, deactivate these pathways, potentially affording protection against adipose tissue (AT) inflammation and obesity-induced IR. Data presented in this dissertation demonstrate that several MAPK-specific dual-specificity phosphatases (DUSPs) are induced in AT under conditions of genetic and diet-induced obesity that is associated with increased inflammation and IR. While AT is composed of multiple cell types, evidence suggests an essential role for preadipocytes (PAs) and adipocytes (ADs) in the development of AT inflammation and IR. Therefore, we further report phenotypic differences in DUSP expression where four of the ten MAPK-specific DUSPs are more abundant in PAs compared to ADs while two of the ten DUSPs are more abundant in ADs compared to PAs, suggesting a regulatory role for these phosphatases that is cell type specific. Moreover, phenotypic differences were observed regarding MAPK signaling and DUSP expression in PAs and ADs exposed to TNFalpha-mediated inflammatory stress, where ERK, JNK, and p38 phosphorylation was markedly elevated and transient in PAs while ERK and JNK phosphorylation was prolonged in ADs concomitant with the phenotypic differences in inducible DUSPs. As induction of DUSPs in PAs kinetically mirrored MAPK dephosphorylation, we further show that de novo mRNA synthesis was essential for MAPK dephosphorylation, suggesting a role for inducible DUSPs in the modulation of MAPK signaling. Based on these data, we present empirical evidence that DUSP knockdown markedly increased the magnitude and duration of ERK, JNK, and p38 phosphorylation in response to inflammatory stress, subsequently elevating MAPK-dependent pro-inflammatory cytokine and chemokine gene expression. Collectively, these findings demonstrate an essential role for DUSPs in the timely modulation of MAPK signaling, highlighting prospective therapeutic targets linking obesity with metabolic inflammatory diseases.

Additional Information

Language: English
Date: 2011
Adipocytes, DUSP, Inflammation, MAPK, Obesity
Dual specificity phosphatase 1 $x Research
Mitogen-activated protein kinases $x Research
Fat cells $x Research

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