Targeting lymph-fat interactions to develop new treatments for diabetes

There is a global epidemic of insulin resistance (IR) and associated cardiometabolic diseases such as type 2 diabetes (T2D). Excess fat, particularly abdominal fat, increases the risk of IR and T2D. The expansion of abdominal fat promotes pathogenic inflammatory and metabolic changes in abdominal fat that stimulate IR (1). The intestinal lymphatics flow through abdominal fat (2-4). Recent studies have demonstrated that lymph fluid 'leaks' from lymph vessels and promotes fat expansion and obesity, and that this is enhanced in response to high fat diets (2-4).  Recent studies in our lab further suggest that intestinal lymph fluid promotes not only expansion but also pathogenic changes in fat that promote IR. This project aims:   1. To determine the potential to treat whole-body IR by modulating lymph content and/or lymph access to abdominal adipose.  2. To establish the potential to more effectively treat IR using novel lymph-adipose targeted pro-drugs.  This project will involve interaction with our synthetic chemistry team and metabolic disease specialists. The student will receive extensive training in models of insulin resistance, drug delivery and pharmacokinetics, molecular biology (cell culture, PCR, western blot, flow cytometry), analysis (LC-MS-MS) and confocal imaging.  Figure: Expanded fat cells with lipid droplets in green, nucleus in blue, membrane in pink. References
1. Guilherme et al. Nature reviews Molecular cell biology. 2008;9(5):367-77
2. Sawane et al. Diabetes. 2013;62(6):1970-80
3. Harvey NL. Annals of the New York Academy of Sciences. 2008;1131(1):82-8
4. Harvey NL et al. Nature genetics. 2005;37(10):1072-81