The activation and recruitment of brown adipose tissue has become an exciting target in the fight against obesity and its related metabolic diseases. Brown adipose tissue differs from white adipose tissue in its critical ability to burn energy as heat through UCP-1 driven adaptive thermogenesis. Expression of mitochondrial UCP-1 uncouples oxidative phosphorylation, resulting in accelerated substrate oxidation but low ATP production. The resulting dissipation of energy is associated with plasma triglyceride clearance, a key factor in weight loss. The brown adipose depot has long been known to exist in rodents as well as in human infants. However, recent evidence has demonstrated the existence of active brown adipose tissue in human adults. These findings prompted a resurgence of research focusing on both the activation of brown adipose tissue and the browning of white adipose tissue, a phenomenon wherein UCP-1-mediated mitochondrial uncoupling is induced by stimuli. Studies using rodent models have demonstrated that brown fat activation or induction of browning can promote beneficial metabolic effects, and promising therapeutic targets have been identified. However, the therapeutic potential of these targets has not been confirmed due to the lack of a widely available human brown adipocyte model. Therefore, there is a pronounced need to validate existing therapeutic targets in the human system. ZenBio will address this need by providing both a primary and immortalized human brown adipocyte cell culture system to the research community and will utilize these tools to establish a screen to identify activators of human brown adipogenesis. The principal goal of this project is to generate and characterize a human adult brown adipocyte cell system. We will achieve this in a stepwise fashion, beginning with an initial feasibility study focused on human fetal brown adipocytes.
Aim I will use functional and genomic analyses to generate a widely available fetal brown adipocyte model which will be used as a tool to establish the adult cell system. The fetal model will be developed first due to the comparative ease of detecting fetal brown adipose tissue and its ready availability through existing procurement agencies.
The second aim i s to generate and characterize an immortalized fetal brown adipocyte system for high throughput/high content screening. These cells will circumvent the limited material and lifespan of primary cells and allow for the development of a high throughput screening platform to identify novel targets of brown adipocyte activation. Phase I will be expanded in Phase II with the goal of characterizing and commercializing the human adult brown adipocyte system from donors of differing BMI, age, gender and diabetic state. These studies will generate both primary and immortalized human adult adipocyte cells which will be used to identify novel targets of brown adipocyte energy expenditure for the treatment of obesity.
The worldwide prevalence of obesity and its related diseases is at epidemic proportions necessitating novel therapeutic approaches. The recent identification of human adult brown fat has led researchers to investigate new ways to increase this beneficial adipose tissue to deter obesity related diseases. We will generate human brown adipocyte systems that can be used to discover and validate novel therapeutic modalities.
