Lymphatic-adipocyte interactions in obesity and lymphedema

Project Summary/Abstract Adipose tissue homeostasis and expansion requires the coordination of multiple cell types to accommodate increases in tissue volume and metabolic requirements. An important component of adipose tissue regulation is the lymphatic vascular system, which is responsible for the removal of extracellular fluid and for immune cell trafficking from the tissue to lymph nodes. In obesity, the relationship between fat and lymphatics becomes dysregulated, resulting in lymphatic vessel dysfunction, including decreased vessel formation, increased permeability, and diminished contractility. Conversely, in conditions of impaired lymphatic function, such as after lymph node resection, adipose tissue is dysregulated and experiences accelerated expansion in the affected area. Given the increasing prevalence of obesity and its complications, as well as the burden of lymphedema in millions of post-surgical patients, the mechanisms which regulate the relationship between adipose tissue and lymphatics are of significant interest. Broadly, this proposal will investigate cell-type specific interactions which govern this relationship. The lab’s single-nucleus RNA sequencing data revealed that lymphatic endothelial cells express the leptin receptor, indicating a role for leptin—an adipocyte-produced hormone which regulates organismal energy balance—in lymphatic function. Preliminary studies have demonstrated that leptin augments lymphatic tube formation and impacts gene expression, and Aim 1 of this proposal describes a plan to further define leptin’s role in lymphatic function. Aim 2 proposes to study the adipocyte-lymphatic relationship from an alternative direction by performing single-nucleus RNA sequencing on adipose tissue associated with lymphedema in human subjects, thereby revealing changes in cellular composition and transcriptional profiles after disruption of local lymphatics. This five-year career development program will build on and expand the candidate’s skills and experience in studying adipocyte biology, animal models of metabolic dysfunction, and single-cell RNA sequencing, while also employing a number of new techniques to evaluate lymphatic vessel function. By assembling a mentorship team and collaborators who are well-equipped to facilitate these studies, in addition to supplementary didactic work, this project will enable the candidate’s transition to an independent career as a physician-scientist in the fields of adipose tissue biology and metabolism.