Role of inflammation in adipose tissue ECM remodeling and its potential link to insulin resistance and type 2 diabetes
Abstract
The central idea of this thesis is that obesity causes metabolic dysregulation in adipose tissue that is marked by adipose tissue extracellular matrix (ECM) remodeling and chronic inflammation. A connection between the ECM and inflammation in adipose tissue may associate ECM proteins with obesity-linked metabolic disorders. However, details of the changes in ECM with adiposity and its association with inflammation are poorly understood. The effect of acute and chronic inflammation in a model of diet induced obesity was examined on ECM remodeling in different adipose depots. Additionally, the role of Toll like receptor 4 (TLR4) on the expression of ECM genes was investigated. The possibility of modulating ECM remodeling using anti-inflammatory treatment with sodium salicylate was also investigated. To determine if acute inflammation plays a role in ECM remodeling, we conducted our first study in a mouse model of diet-induced obesity with and without lipopolysaccharide (LPS) administration. Most of the effects of high fat diet on ECM gene expression were observed in the epididymal adipose depot but not in the subcutaneous adipose depot. Acute inflammation had a limited effect on the ECM gene expression and was mostly restricted to epididymal adipose depot. Protein levels of type 1 collagen alpha 1 subunit (COL1A1) relative to β actin levels were reduced in epididymal adipose tissue. We also examined subcutaneous adipose tissues (SCAT) from lean and obese human subjects and found reduced COL1A1 protein levels in obese subjects. In addition to ECM genes, we determined the expression of matrix metalloproteases (MMPs) which are matrix remodeling enzymes. High fat diet and to some extent endotoxin challenge, induced the expression of matrix metalloproteases (MMPs). Therefore, although obesity and HFD led to depot specific increases in ECM genes, the induction of MMPs may cause reduced ECM protein abundance in obesity and contribute to the discordance between mRNA and protein expression of matrix genes in adipose tissue. The role of Toll like receptor 4 (TLR4) and chronic inflammation induced by diet on ECM gene expression was studied in a TLR4 KO mouse model. Toll like receptor 4 may regulate the basal expression of ECM genes in the epididymal adipose tissue. The impact of TLR4 on the MMPs was very prominent in the epididymal adipose tissue implicating its role in the basal expression of the MMPs. Although high fat diet and obesity lead to induction of transcripts of ECM and MMP genes, TLR4 may contribute to the basal expression of ECM and MMP genes in the epididymal adipose tissue. Suppression of inflammation using sodium salicylate in high fat diet fed mice downregulated the expression of ECM genes in the subcutaneous adipose tissue. Surprisingly, salicylate treatment had limited effect on the ECM gene expression in the epididymal adipose depot. This finding implicates inflammation as a major driving force for adipose tissue ECM remodeling in the subcutaneous depot and further reinforces that potential differences exist in ECM gene regulation between the adipose depots. Data from experiments described in this thesis indicate that inflammation can induce the expression of ECM genes. Targeting inflammatory pathways may ameliorate excessive deposition of ECM proteins and adipose tissue dysfunction. Furthermore, it shows the importance of depot specific regulation of ECM gene expression. A better understanding of the molecular mechanisms connecting inflammation and ECM remodeling will aid in elucidating the regulatory mechanisms that can be therapeutically targeted for the prevention of adipose tissue dysfunction.
Degree
M.S.
Advisors
Ajuwon, Purdue University.
Subject Area
Molecular biology|Animal sciences|Nutrition
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