Obesity and type 2 diabetes (T2D) in children and adolescents are serious health problems. Prevalence estimates a 31% increase in T2D among people aged 10-19 years in US. A body of evidence suggests that immune cells play an important role in obesity and T2D, and this has led to the new but fast growing field of ?immunometabolism?. Studies in humans have suggested that B cells promote inflammation in obesity and T2D. B cells were also found in human subcutaneous adipose tissue and the function of B cells has been shown to be impaired in obese subjects. One of the major functions of B cells is to secrete antibodies. However, not much is known about the role of antibodies in obesity and T2D. In determining the causality and mechanism, we will take advantage of activation-induced cytidine deaminase deficient (AID-/-) mice. In these mice, we are able to specifically investigate the role of IgM in immune-metabolism and IgM-associated gut bacteria in obesity, while not affecting other functions of B cells, as the B cell compartment will be intact. Moreover, we are able to determine the early-life effects of IgG on later development of obesity. Our preliminary data suggest that IgM accelerates obesity in mice. Transferring fecal gut microbiota, we are able to transfer the metabolic abnormalities in AID-/- mice to wild type germ free (GF) mice in less than 2 weeks. We have also discovered that obese adolescent subjects with T2D have increased IgM-bound gut , which promote body weight gain and impaired glucose tolerance in GF mice. Our central hypothesis of this project is that IgM and IgM-bound gut microbiota induce imbalance of immune-metabolism and promote obesity and T2D. We will test the central hypothesis in mouse (Specific Aim 1) and man (Specific Aim 2), in vitro and in vivo. We also hypothesize that the immune-pathogenic role of IgM and dysbiosis of gut microbiota synergistically contribute to obesity, metabolic inflammation and dysregulation. We will test this hypothesis in Specific Aim 3 using bone marrow chimeric mice and germ-free mice. Once we establish causality and the mechanism, we will be able to design better therapy for the prevention and treatment of childhood, as well as adult, obesity and T2D.
We have found that IgM exacerbated obesity, enhanced inflammation and altered gut microbiota in an AID mouse model and we identified that IgM-bound gut bacteria were elevated in adolescent patients with obesity and type 2 diabetes (T2D). We hypothesize IgM antibodies and IgM-bound gut bacteria cause obesity and metabolic dysfunction and we will test the hypothesis in mouse and man, in vitro and in vivo, in three specific aims.
