Obesity has become a global health problem and currently affects ~35% of the US population, with estimated medical costs ranging between $86 and $210 billion per year. Chronic inflammation associated with obesity often leads to insulin resistance and, eventually, type-2 diabetes. Abdominal fat in particular is closely associated with an increased cardiovascular risk of hypertension, atherosclerosis, stroke, and cancer. Surprisingly, very little is known about the initial mechanisms leading to abdominal adipose deposition. Interestingly, dietary lipids are absorbed primarily by lymphatic capillaries in the microvilli and transported to collecting lymphatic vessels in the mesentery, which are normally surrounded by adipose tissue. Despite long- standing associations between lymphatic vessel leakage and adipose tissue deposition, no studies have been performed to determine whether pathophysiological lymphatic leakage can lead to adipose deposition when lymphatic vessels are not genetically deformed or mispatterned (i.e. whether normally developed but leaky lymphatic vessels can cause adipose deposition). The dearth of studies in this area stems from the lack of a method to measure lymphatic permeability to solute. I recently developed a quantitative method that enables rapid, repeatable measurements of collecting lymphatic vessel permeability for the first time, and permits pharmacologic manipulation. Further, I have combined this method with genetic mouse models to identify mechanistic regulators of lymphatic permeability (e.g. nitric oxide, histamine) and to demonstrate that collecting lymphatics from obese, leptin receptor knockout mice have a markedly elevated permeability. The goal of the proposed research is to determine the role of lymphatic vascular permeability in mesenteric adipose deposition, including investigating crosstalk with adipose tissue and dendritic cells. In the mentored phase of this work (Aim 1), I will create a leaky lymphatic vasculature by using an inducible mouse model to delete a crucial regulator of endothelial barrier function, ?-catenin, specifically from lymphatic vessels and not blood vessels. This model will be used to test whether leakage from normally patterned lymphatic vessels is sufficient to lead to significant mesenteric adipose deposition. In the independent phase, I will then determine how inflammatory mesenteric adipose tissue increases collecting lymphatic vessel permeability and whether T-cells that infiltrate the adipose tissue are responsible (Aim 2). Additionally, I will determine whether dendritic cells residing in the lymphatic vessel wall protec against increases in lymphatic permeability, or instead elevate lymphatic permeability (Aim 3). The novel concept of elevated lymphatic permeability as a regulator of adipose deposition will improve the understanding of chronic inflammatory diseases that are associated with adipose tissue (e.g. Crohn's disease, lymphedema). Ultimately, therapeutic targets that tighten the lymphatic endothelial barrier may offer a new approach to prevent adipose deposition in obesity, thereby reducing the incidence of associated cardiovascular diseases.
Obesity affects more than one-third of the US population and leads to chronic inflammation that increases the risk of developing type 2 diabetes, hypertension, heart attack, stroke, and cancer. The early mechanisms leading to adipose deposition are currently unknown, although it is recognized to accumulate around lymphatic vessels. To address this issue, I have developed the only method capable of measuring lymphatic vessel permeability, which will allow me to investigate the interaction between lymphatic vessels, adipose tissue, and immune cells in transgenic mice for the first time.
|Randolph, Gwendalyn J; Ivanov, Stoyan; Zinselmeyer, Bernd H et al. (2017) The Lymphatic System: Integral Roles in Immunity. Annu Rev Immunol 35:31-52|
|Ivanov, Stoyan; Scallan, Joshua P; Kim, Ki-Wook et al. (2016) CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. J Clin Invest 126:1581-91|
|Scallan, Joshua P; Hill, Michael A; Davis, Michael J (2015) Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling. Cardiovasc Res 107:89-97|