This is renewal of my past Faculty-Initiated Project.
Obesity and Type 2 diabetes (T2D) are serious health issues across the world, as they are directly related to increased morbidity and mortality rate. Despite years of extensive research efforts, we do not have efficient therapeutic strategy to fight with these two global epidemics.
Two types of fat tissues- white and brown adipose - play pivotal roles in the control of whole body metabolism and energy homeostasis. Thus, dysregulation of adipose development and function is central to the pathogenesis of obesity and T2D. While white fat cells store extra energy, brown adipocytes dissipate energy through a process called adaptive thermogenesis. This process occurs at the mitochondrial inner membrane using Uncoupling Protein-1 (UCP1) that uncouples the respiratory chain from ATP synthesis. In addition to classical brown fat that is constitutively active, beige fat (inducible form of brown fat) can develop within white adipose depots in response to various stimuli including cold challenge. This process is referred to as ‘browning’.With recent findings of active brown fat in adult humans. and an inverse correlation between high brown fat activity and obesity, targeting brown fat holds great promise for an anti-obesity therapy.
Epigenetics is defined as gene function and activity that does not involve direct changes in DNA sequences. DNA methylation is a major epigenetic change and is mediated by DNA methyltransferases and DNA demethylases in response to various environmental signals. We recently have found that the expression of DNA demethylases is highly modulated during browning. Our preliminary studies have shown that DNA demethylases have direct role in the gene regulation of UCP1 in brown adipocytes.
We are currently performing in vitro and in vivo loss-of function study of Tet proteins that exert DNA demethyase activity in the regulation of brown adipose development and metabolism using brown adipose-specific knock-out animals. Students under Faculty-Initiated SPUR project get to participate in various metabolic studies using this mutant mouse model.
Technical support to do mouse tissue dissection and gene expression analysis
High level of motivation and responsibility