Novel insight into the req uirement of adipose iNKT cells in the actions of GLP-1 analog therapy

My reason for choosing science as a career was to make a difference to human health. The major focus of my research is to understand the interface of the immune system and metabolism, especially in the setting of inflammation, and this has opened many new pathways for exploration in obesity, insulin resistance, type 2 diabetes. My specific long-term objectives are 1) to understand the effects of obesity on the immune system which leads to poorer immune surveillance and increased risk of cancers and infections in certain obese individuals, and 2) to investigate the effects of the local adipose immune system on metabolic and weight control, 3) Develop therapeutic strategies to safely manipulate the immune system in obesity, type 2 diabetes and obesity-induced inflammatory disease. These goals are very timely as obesity and metabolic disorders continue to be a major human health burden which threatens to shorten human lifespan by 5-20 years.

Research design and methods: I have >8 years experience in studying the dysregulation of the immune system in obesity and inflammatory diseases in humans and mice, and in the effects of weight loss through diet intervention or bariatric surgery on the immune system (Lynch et al, Obesity, 2008, Eur. J. Immunology, 2009, Immunity, 2012, Nature Immunology, 2014). To achieve my research goals, I have begun to develop state-of-the-art immunometabolic facility in Harvard Medical School to specifically study immune and metabolic systems in vivo in obesity and insulin resistance models. These include Complete Lab Animal Monitoring System (CLAMS), MRI and calorimetry for animal studies which allows us to measure the effects of manipulating the immune system and inflammation in the adipose tissue and other organs, and on whole body metabolism. I have also developed novel ways to study leukocyte traffic in adipose tissue including parabiosis and 2-photon intravital microscopy in live adipose tissue, which allows us to visualize immune and adipocyte interactions in real time in vivo. I have established excellent collaborative relationships with clinicians and surgeons in Brigham and Women’s Hospital including bariatric surgeon Dr. Ali Tavakkoli and vascular surgeon Dr. Keith Ozaki, as well with my mentor Prof. Michael Brenner, a leader in the field of iNKT cells, and Prof. Ulrich von Andrian, a world leader in leukocyte trafficking and intravital microscopy. Important for this application, I have established a collaboration with Prof. Daniel Drucker at University of Toronto, who is a leading expert in GLP-1 research. My next goal is to obtaining further funding from NIH, as well as the ADA and private organizations to lead and develop a research group in cutting edge science in immunometabolism. Relevance to public health: Over 1.4 billion adults and 40 million children under age 5 are overweight or obese worldwide, and obesity is a major risk factor for many serious diseases such as cardiovascular disease, diabetes, and cancer. Inflammation is an underlying cause or contributor to many of these diseases, and thus, preventing obesity-induced inflammation should be a key priority in tacking the obesity burden. This project will try to determine what starts this inflammation and if it can be lessened or prevented, by using or manipulating the bodies own immune system.