Novel role for dual-specificity phosphatase 4 in adipocytes
- UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
- Wei Guo (Creator)
- Institution
- The University of North Carolina at Greensboro (UNCG )
- Web Site: http://library.uncg.edu/
- Advisor
- Ron F. Morrison
Abstract: The growing prevalence of obesity has resulted in a huge impact on global health. Obesity contributes to the development of cardiovascular diseases, insulin resistance (IR) and other comorbidities. Research over the past few decades has revealed important roles for adipose tissue (AT) in regulating whole-body metabolism under normal physiological and pathological states. It is well accepted that obesity-mediated chronic, low-grade inflammation contributes to the development of metabolic dysfunctions via the mitogen-activated protein kinase (MAPK) signaling pathways. While the upstream activation of MAPKs has been extensively investigated, how MAPK deactivation modulates cellular responses remains largely unsolved. In recent years, increasing attention has been given to the MAPK-specific, dual-specificity phosphatases (DUSPs) as key regulators that negatively control MAPK activity, potentially provide treatment against obesity-induced AT inflammation and IR. Early evidence has suggested a role for DUSP4 towards MAPKs signaling in other cell types. However, no study has addressed the role of DUSP4 in 3T3-L1 adipocytes under any condition. Data presented in this dissertation demonstrate that DUSP4 was induced via the MEK/ERK signaling pathway while JNK or p38 did not affect DUSP4 expression. Subsequently, we show that DUSP4 protein was also stabilized by ERK activation and proteasomal activity was partially involved in its protein degradation. Moreover, accumulation of DUSP4 correlated with the suppression of nuclear ERK signal and protein-protein interactions were observed between DUSP4 and ERK, suggesting a role for this phosphatase in spatiotemporal regulation of ERK activity in adipocytes. We further demonstrate that DUSP4 is suppressed in AT under conditions of genetic and diet-induced obesity that is associated with increased inflammation and IR. We report biphasic inductions of DUSP4 during adipocyte differentiation, with the early phase induction being ERK-dependent and the later phase induction being ERK-independent and differentiation-specific. Moreover, DUSP4 was suppressed in preadipocytes and adipocytes exposed to tumor necrosis factor-a. Additionally, DUSP4 knockdown did not inhibit adipocyte differentiation, suggesting a role for this phosphatase that is independent from adipogenesis. Collectively, data presented in this dissertation provide new insights into regulation and potential function of DUSP4 in adipocytes, highlighting new therapeutic targets for the treatment of obesity-mediated inflammation and metabolic disorders.
Novel role for dual-specificity phosphatase 4 in adipocytes
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Created on 12/1/2017
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Additional Information
- Publication
- Dissertation
- Language: English
- Date: 2017
- Keywords
- Adipocytes, DUSP4, Inflammation, MAPK, Singaling
- Subjects
- Dual specificity phosphatase 1
- Insulin resistance
- Fat cells
- Inflammation