Molecular Determinants of Human Brown Fat Lineage Specification and Reprogramming
Brown fat, once thought to be present in humans only during the neonatal period, has now definitively been shown to be present throughout human life. As opposed to white fat (that stores energy), brown fat burns energy and increasing the levels of brown fat has the potential to dramatically improve energy metabolism in humans. The proposed research focuses on: 1) revealing the molecular mechanism of a new factor we identified that determines if a cell will become a brown fat cell (identity) and 2) if stem cell biology can be used to generate patient specific brown fat as a therapeutic strategy for people with metabolic diseases such as obesity and diabetes. In particular, we will test if the brown fat that we can generate from patients' skin cells using stem cell biology, is competent to improve metabolism in an animal. We will also compare engineered brown fat to endogenously formed human fat at molecular and functional levels to test how faithful our system is to bona fide brown fat. Finally, we will elucidate the molecular mechanism by which our factor directs brown fat identity. Our vision is that these initial basic stem cell biology studies will make it possible to overcome the current hurdle to develop potent and effective therapies for patients with life-threatening complications from metabolic diseases.
According to the Center for Disease Control, over 24% of Californians (greater than 9 million people in this state alone) are obese and this rate continues to rise every year. The reason for the dramatic increase over the past decades is not fully understood but seems to be multifactorial including changes in: lifestyle, environment and epigenetics. As obesity is directly linked to a number of diseases such as diabetes, dyslipidemia and hypertension, the impact of this problem in terms of morbidity and mortality for Californians has been devastating. In spite of an enormous effort from a number of approaches, ranging from changes in public policy to medical interventions, the incidence of obesity and the associated diseases continues to escalate. This dismal success rate underscores the urgent need for new ideas and approaches to address this major public health problem. The proposed study seeks to capitalize on the potential of stem cell biology to offer new alternative therapies for these devastating diseases. If successful, our studies will lay the foundation for a new paradigm opening up the possibility to regenerate a healthy energy balance in patients suffering from the consequences metabolic diseases. In addition to the health benefits for citizens, developing this new technology and potential therapy in California could contribute to the state's important biotechnology industry.