Investigating the role of DUSP22 in metabolic disease

Project: Experimental Development/Translation Research

Project Details

Abstract

Obesity, the accumulation of excess adipose/fat tissue, is a major health challenge across the globe. Obesity is a major risk factor for cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), type 2 diabetes and several cancers. CVD is the leading cause of death from non-communicable diseases in Qatar and the incidence of heart attacks among young Qataris is one of the highest in the world. According to the Qatar Biobank (QBB), the prevalence of obesity and T2D in Qatar is very high. Thus, Qatar is facing a cardiometabolic health crisis driven by an obesity epidemic, something that will have wide-ranging health, social and economic consequences. Adipocyte differentiation has been studied extensively in vitro and in vivo, including in animal models of obesity. We recently used a different approach to study adipocyte biology, focusing on changes in DNA methylation in patients suffering from a rare form of lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy type 2 (CGL2). These patients have loss-of-function mutations in BSCL2, the gene encoding the Seipin protein. Seipin plays a critical role during adipogenesis by controlling the formation and maintenance of lipid droplets. Thus, CGL2 patients lack adipose tissue and instead accumulate lipids in other tissues, resulting in the development of cardiometabolic complications at an early age. In our original study, we found that the promoter of the gene encoding dual-specificity phosphatase 22 (Dusp22) was hypomethylated in CGL2 patients. We also found that the expression of DUSP22 was regulated during adipocyte differentiation and that inactivation of BSCL2 had a negative impact on the expression of DUSP22. In follow-up studies, we have found that inactivation of DUSP22 blocks adipocyte differentiation in vitro, suggesting that DUSP22 is an important regulator of adipogenesis. In addition, we have also found that DUSP22 deficient preadipocytes display reduced sensitivity to insulin, an important regulator of adipogenesis in vivo. The current proposal is aimed at identifying the molecular role(s) of DUSP22 in adipocyte differentiation and function, with a special focus on its role in the insulin-dependent regulation of these processes. The proposal also aims to explore if DUSP22 plays a role in other insulin-sensitive cells, including liver cells. In this work, we will combine genetic gain- and loss-of-function approaches with functional analyses. We will also take advantage of stem cell-derived physiologically relevant cell models developed as part of an ongoing QNRF-supported award (NPRP13S-0127-200178).

Submitting Institute Name

Hamad Bin Khalifa University (HBKU)
Sponsor's Award NumberARG01-0517-230199
Proposal IDEX-QNRF-ARG-84
StatusActive
Effective start/end date1/02/241/02/27

Primary Theme

  • None

Primary Subtheme

  • None

Secondary Theme

  • None

Secondary Subtheme

  • None

Keywords

  • Adipose tissue
  • Obesity
  • Insulin signaling

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