Obesity, Metabolic Syndrome, and Lymphatic Dysfunction

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The relationship between mesenteric lymphatic vessels and surrounding visceral adipose of the mesentery has received increased attention due to observations that imply that dysfunctional lymphatic vessels contribute to adipose deposition in the mesentery. While there has been much work done in rodent models of obesity and metabolic syndrome, there is virtually nothing known about how mesenteric lymphatic vessels are altered both structurally and functionally in humans with metabolic syndrome. To address this important and enormous knowledge gap, novel protocols to study human mesentery and lymphatic vessels derived from organ donors with or without metabolic syndrome have been developed and optimized. The rationale for this approach is that the findings will enable a leap forward in knowledge about the lymphatic-visceral adipose axis that is directly relevant to humans. The central hypothesis to be tested is that metabolic syndrome impairs lymphatic function and that impaired mesenteric lymphatics perpetuate metabolic dysfunction. Guided by robust preliminary data, this hypothesis will be tested in with two specific aims. Specific Aim 1 is to determine mechanisms underlying lymphatic dysfunction in obesity and metabolic syndrome. Specific Aim 2 is to determine how dysfunctional lymphatics contribute to metabolic deficits in mesenteric tissue. These aims will utilize mesenteric tissue from human organ donors, which permits the study of mesenteric lymphatic pump function, permeability, and network structure. The functional studies will be coupled to transcriptomic and proteomic approaches to identify the RNA and protein landscapes in the mesenteric adipose depots surrounding lymphatic vessels. In addition, studies of in vivo lymphatic pumping and permeability in relevant rat and mouse models will help identify causal mechanisms in the two-way communication between lymphatic vessels and visceral adipose tissue. The significance of the proposed research is that it will provide the first comprehensive analysis of human mesentery, including the protein and RNA landscapes, lymphatic vessel networks, lymphatic pump function, and lymphatic permeability that will produce novel information about how human lymphatic vessels interact with visceral adipose tissue in the context of metabolic syndrome. The proposed research is innovative because it opens a new line of investigation focusing on human mesenteric lymphatic structure and function that will provide the first large-scale evaluation of human mesenteric lymphatic pump function and permeability directly related to human health and disease.