Obesity has reached pandemic proportions contributing to the dramatic increases in the incidence of type 2- diabetes and cardiovascular disease. The expansion of adipose tissue in obese individuals is a direct cause of these diseases due to an excessive accumulation of triglycerides (TGs) within white adipose (WAT) adipocytes. There are two major types of adipose, white that stores TGs and brown (BAT) that oxidizes them to produce heat. Until recently, it was thought that BAT only existed within the interscapular regions of newborns, but several recent investigations have identified BAT depots in the cervical, supraclavicular, axillary and paravertebral regions of adult humans. The contribution of BAT to resting metabolic rate and healthy body weight homeostasis in animals is now well established. In obese individuals, long-term weight loss can only be maintained if the adipostat is readjusted to a lower level. The mechanisms participating in this adipostat are not known in detail, but BAT appears to play an important role. BAT is a flexible tissue that can be recruited by various stimuli including cold exposure in rodents and humans. In fact, many earlier studies implicated the recruitment of brown adipocytes to WAT to explain changes in energy balance in response to different effectors. We have recently shown that the synthetic PPAR? ligand class of insulin sensitizers induces BAT functions in white adipocytes in mice and in culture. Establishment of this brite/beige phenotype by PPAR? involves a selective expression of BAT and hypoxia-responsive genes as well as repression of genes associated with insulin resistance. We have also discovered that this unique browning activity is regulated by a dephosphorylation of S273 as well as deacetylation of K268/K293 within the ligand-binding region of PPAR?. Based on these data, we hypothesize that the browning of WAT is regulated by post-translational modifications of PPAR? in response to changes in nutrient/metabolic status of the individual. We propose three aims to test this hypothesis.
In Aim 1, we will define the phenotypes of the brown-like adipocytes recruited to WAT in response to posttranslational modification of PPAR?.
In Aim 2, we will determine whether specific post-translationally modified PPAR? molecules bind to select regulatory elements in promoters/enhancers of target genes.
In Aim 3, we will determine the effect of dephosphorylation on S273 or deacetylation of K268 and K293 of PPAR? on browning of white adipose tissue and energy expenditure in mice. Identifying the molecular mechanisms by which physiological effectors regulate the browning activity of PPAR? will significantly contribute to the development of therapeutics for obesity and it associated disorders.
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 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 adipocytes in WAT depots and the knowledge gained has the potential of leading to the development of anti-obesity therapeutics.
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