Abstract
Obesity is strongly associated with metabolic syndrome, a combination of risk factors that predispose to the development of the cardiometabolic diseases: atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Prevention of metabolic syndrome requires novel interventions to address this health challenge. The objective of this study was the identification of candidate molecules for the prevention and treatment of insulin resistance and atherosclerosis, conditions that underlie type 2 diabetes mellitus and cardiovascular disease, respectively. We used an unbiased bioinformatics approach to identify molecules that are upregulated in both conditions by combining murine and human data from a microarray experiment and meta-analyses. We obtained a pool of eight genes that were upregulated in all the databases analysed. This included well known and novel molecules involved in the pathophysiology of type 2 diabetes mellitus and cardiovascular disease. Notably, matrix metalloproteinase 12 (MMP12) was highly ranked in all analyses and was therefore chosen for further investigation. Analyses of visceral and subcutaneous white adipose tissue from obese compared to lean mice and humans convincingly confirmed the up-regulation of MMP12 in obesity at mRNA, protein and activity levels. In conclusion, using this unbiased approach an interesting pool of candidate molecules was identified, all of which have potential as targets in the treatment and prevention of cardiometabolic diseases.
Highlights
Metabolic syndrome is a multifactorial condition, which includes insulin resistance, visceral obesity, hypertension and atherogenic dyslipidemia, conferring a markedly elevated risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease, collectively called cardiometabolic diseases. [1,2] According to data from the World Health Organization, cardiovascular diseases are the leading cause of death globally
The microarrays were performed with aortae and Gonadal white adipose tissue (GWAT) of mouse models of atherosclerosis and obesity
Microarrays were evaluated for upregulation of gene expression caused by high-fat diet (HFD) and HFSC as compared with control diet (CD) in GWAT from wild type (WT) mice and aortae from Ldlr-/- mice, respectively
Summary
Metabolic syndrome is a multifactorial condition, which includes insulin resistance, visceral obesity, hypertension and atherogenic dyslipidemia, conferring a markedly elevated risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease, collectively called cardiometabolic diseases. [1,2] According to data from the World Health Organization, cardiovascular diseases are the leading cause of death globally. [1,2] According to data from the World Health Organization, cardiovascular diseases are the leading cause of death globally. Research has identified chronic lowgrade inflammation induced by obesity as a common mechanism that is causally involved in obesity-related insulin resistance and atherosclerosis, precursors for type 2 diabetes and cardiovascular disease, respectively. The aim of this study was to identify candidate molecules that could be targeted for the prevention and treatment of cardiometabolic disease. An unbiased bioinformatics approach was used to identify genes from different published databases related to cardiometabolic disease and mouse models, thereby analyzing the main tissues involved in the development of type 2 diabetes and cardiovascular disease by microarrays, combining published [14] as well as newly obtained original data. The differentially expressed and upregulated genes present in all these studies were selected, resulting in a list of genes that included known as well as novel candidate molecules for the treatment of cardiometabolic disease
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