The lymphatic system, including lymphatic vessels and lymph nodes (LNs), crucially regulates fluid balance, nutrient absorption, and immunity. Blind-ended lymphatic capillaries take up fluid and immune cells in all organs. These vessels coalesce into so-called lymphatic collecting vessels that drain to and from LNs. Collecting vessels, surrounded by specialized muscle cells, control the rate and magnitude of lymph transport throughout the lymphatic system. Both collecting vessels and LNs are inevitably surrounded by adipose tissue. Interestingly, the adipose tissue surrounding prominent LNs and lymphatic collecting vessels in rodents is "beige" fat -subcutaneous fat depots that can undergo adaptive thermogenesis, a transition from a character consisting predominantly of white, energy-storing unilocular adipocytes to those of brown multilocular adipocytes that express UCP-1. Brown adipocytes generate heat using the mitochondrial uncoupling protein 1 (UCP-1), and UCP-1 is essential for its thermo genic properties. Importantly, beige adipose tissue has been discovered in adult humans and whole body images show depots of brown fat in adults that colocalize with classic locations of LNs, resembling beige subcutaneous depots of the mouse, which inevitably encase LNs. Indeed, recent histological analysis confirms that adipose depots containing brown adipocytes colocalize with LNs in humans, as they do in mice. Beige fat is also found around the human heart and major arteries, as observed in mice as well. While the function of brown fat in generating heat under conditions of cold stress is well appreciated, only a few studies have addressed whether the anatomical locations of brown or beige fat are important. That is, does the location of heat-generating fat provide essential local thermogenesis to maintain particular functions? Perhaps the primary role of brown fat as a thermogenic organ is key and that increasing local temperature through UCP-1 induction would improve lymphatic transport, since lymphatic transport in intact vessels is known to increase substantially with fever-range elevations in temperature. Thus, we hypothesize that thermogenesis in beige fat plays a key role in supporting the lymphatic system, including transport of cargo through the lymphatic vasculature (such as HDL-cholesterol, or antigens) and overall functionality of the adjacent lymph node.
In aim 1, we will investigate whether thermogenesis around lymph nodes and surrounding lymphatic vessels supports lymphatic transport to lymph nodes and maintains immune responses, particularly in the context of cold challenge.
In aim 2, we will investigate the functional consequences that loss of UCP-1-generated heat has on local lymphatic transport, including an analysis of implications for cardiovascular disease considering that lymphatic vessels mediate the movement of cholesterol out of the aortic wall.

Public Health Relevance

In aging, declines are seen in immunity, cardiovascular health, and in the ability to generate extra heat through a process called nonshivering thermogenesis to keep core body temperature stable while supporting other demands of the body, such as demands to fight infections and move nutrients and waste products such as cholesterol into and out tissues. The lymphatic system includes specialized vessels and nodes that sustain immunity as well as transport nutrients and waste products. This system is surrounded by a type of fat that can generate heat and this proposal will test the idea that the fat's ability to generate heat is critical to maintaining immunity and cardiovascular health.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG046743-01A1
Application #
8701500
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Finkelstein, David B
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ivanov, Stoyan; Paget, Christophe; Trottein, Fran├žois (2014) Role of non-conventional T lymphocytes in respiratory infections: the case of the pneumococcus. PLoS Pathog 10:e1004300