Obesity has reached pandemic proportions contributing to the development of the metabolic syndrome, a group of disorders that include type 2-diabetes and cardiovascular disease. The obesity epidemic is increasing at an alarming rate and new therapies are needed. Lifestyle modifications alone, such as diet and exercise, are not sufficient to combat these diseases. Excess caloric intake causes the rapid expansion of adipocytes leading to lipotoxic side effects, including ectopic fat accumulation and insulin resistance. Obese white adipose tissue (WAT) undergoes substantial remodeling which includes infiltration of macrophages and fibrosis. Remodeling of WAT can also be beneficial and coincide with conditions that enhance insulin sensitivity and reduce inflammation. Exposure of mice to the cold or treating them with various pharmacological agents such as PPAR? agonists induce browning of WAT, which include recruitment of brown-like adipocytes referred to as beige and brite cells. Besides supplying the depot with thermogenic cells, browning has the potential to remodel obese WAT in ways associated with a lean phenotype including secretion of ?healthy? adipokines. It is our suggestion that identifying novel pathways and strategies to safely and specifically activate PPAR? is perhaps the most efficacious way to induce beige/brite adipocytes. Millions of individuals already take PPAR? ligands (Avandia and Actos) to treat their obesity-related insulin resistance. It is well accepted that the principal site of action of these TZDs is adipose tissue. Even though the TZDs are very effective and potent insulin sensitizers they are fraught with harmful side effects. Studies by others and us have shown that targeting specific posttranslational modifications of PPAR? is a means to circumvent the harmful effects of PPAR? agonists while retaining the insulin sensitizing activity. Our recent study on which this proposal is based demonstrated that roscovitine, a CDK inhibitor potently browned WAT and protected mice from diet-induced obesity (DIO) and insulin resistance. We hypothesize that roscovotine browns WAT through post-translational modifications of PPAR? and in doing so overcomes the harmful effects of obesity. We propose four aims to test this hypothesis: 1. Trace the origin of beige/brite adipocytes induced by treatment of mice with roscovitine. 2. Determine whether roscovitine prevents obesity-induced expansion and activation of myofibroblasts. 3. Identify and characterize the co-regulators (coactivators and corepressors) interacting with a phosphorylation (S112A/S273A) deficient form of PPAR? in adipocytes in mice. 4. Determine whether expression of the modified PPAR? in adipose depots induces browning of WAT and protects against diet- induced obesity and fibrosis. Successful completion of these aims will provide novel insights into pathways regulating beige/brite AT formation, thus advancing our understanding of how to therapeutically target adipose tissues for the treatment of human obesity.
The pandemic of obesity is a major cause of the increased incidence of type 2-diabetes and cardiovascular diseases, which is expected to double by 2030 resulting in associated healthcare expenditure exceeding $100 billion in the United States alone. Consumption of dietary fat in obese individuals leads to storage in white adipose tissue (WAT) as opposed to its metabolism in brown and beige adipose (BAT); consequently, enhancement of BAT mass has the potential to diminish WAT mass and reduce the incidence of type 2 diabetes and cardiovascular disease. The proposed studies are designed to identify the processes controlling the recruitment of brown-like (beige) adipocytes in WAT depots of obese individuals and the knowledge gained has the potential of leading to the development of anti-obesity therapeutics.
