The obesity epidemic is accelerating at an alarming rate and contributes to the increased incidence of type 2 diabetes. Lifestyle modifications, like diet and exercise, have not proven effective as methods to attenuate metabolic dysfunction; thus, new therapeutics are needed to treat obesity related disorders. It is believed that the `spillover' of lipids from adipose tissue into the liver and muscle is the primary etiology of insulin resistance in obesity. Numerous studies have shown obese human subjects exhibit fibrosis, decreased vascularization, inflammation, and hypertrophy of adipocytes, suggesting that the extracellular matrix (ECM) plays an important role in the pathology of obesity. The ECM functions to provide mechanical support, however ECM accumulates in the fibrotic interstitial space during obesity, limiting the expansion of adipocytes and inhibiting angiogenesis and adipogenesis. Understanding the mechanics and kinetics of adipose tissue remodeling in order to modulate lipid storage is an intriguing therapeutic strategy. Additionally, identifying myofibroblast progenitor cells in order to attenuate their accumulation during obesity-induced fibrosis may have therapeutic potential. It is well appreciated that myocardin-related transcription factor A (MRTFA) regulates myofibroblast activation and tissue remodeling; however, its role in adipose tissue fibrosis is not clear. Our data show that MRTFA null mice are protected from diet-induced insulin resistance and have decreased expression of collagen genes in adipose tissue. We hypothesize that MRTFA mediates adipose tissue remodeling and fibrosis and hence, inhibition of MRTFA may be a potential therapeutic target to facilitate lipid storage and the healthy expansion of adipose tissue. We propose the following three aims to test our hypothesis that adverse adipose tissue remodeling causes metabolic dysfunction.
In Aim 1, we will determine whether SMA+ myofibroblasts contribute to the collagen-rich ECM in adipose tissue fibrosis.
In Aim 2, we will determine the role of MRTFA in myofibroblast activation in adipose-derived mesenchymal stem cells and adipose tissue remodeling and fibrosis associated with obesity.
In Aim 3, we will determine whether myofibroblasts originate from vascular smooth muscle-like cells using inducible lineage tracing technology to fate-map progenitors to interstitial fibrotic areas. A comprehensive study of adipose tissue remodeling in an obese mouse model will provide new insights into the progression of obesity and fibrosis.
The prevalence of obesity is the primary cause of the increased incidence of type 2 diabetes mellitus, dyslipidemia and cardiovascular disease. The intake of excess calories initially causes a rapid expansion of adipocytes and fat storage in adipose tissue; however, persistent caloric excess causes ectopic fat accumulation and results in metabolic disorders, such as insulin resistance and liver dysfunction. The proposed studies are designed to identify the processes controlling remodeling of adipose tissue and the knowledge gained has the potential of leading to new therapeutic targets for anti-diabetic intervention.
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