Mechanisms of obesity and related pathologies: the macro- and microcirculation of adipose tissue

Abstract

Adipose tissue is an endocrine organ made up of adipocytes, various stromal cells, resident and infiltrating immune cells, and an extensive endothelial network. Adipose secretory products, collectively referred to as adipokines, have been identified as contributors to the negative consequences of adipose tissue expansion that include cardiovascular disease, diabetes and cancer. Systemic blood circulation provides transport capabilities for adipokines and fuels for proper adipose tissue function. Adipose tissue microcirculation is heavily impacted by adipose tissue expansion, some adipokines can induce endothelial dysfunction, and angiogenesis is necessary to counter hypoxia arising as a result of tissue expansion. Tumors, such as invasive lesions in the mammary gland, co-opt the adipose tissue microvasculature for local growth and metastatic spread. Lymphatic circulation, an area that has received little metabolic attention, provides an important route for dietary and peripheral lipid transport. We review adipose circulation as a whole and focus on the established and potential interplay between adipose tissue and the microvascular endothelium.

Figure 1

Interactions between expanding adipose tissue and the endothelium via adipokine secretions. Adipokines induce a reduction in nitric oxide (NO), hindering vasodilation, upregulated adhesion molecules promoting immune infiltration, and increase vessel permeability. Adiponectin, which decreases in expanded adipose, can thus be suggested to have positive effects. (This figure is an adaptation of that appearing in the excellent Chudek and Wiecek review [4].)

Figure 2

Adipose expansion results in tissue hypoxia that necessitates angiogenesis for healthy tissue function. Hypoxia in expanding adipose depots induces the upregulation of an array of adipokines, among them HIF1alpha, MCP1, and VEGF. In early expansion, or in depots in which angiogenesis progresses slowly, the adipose matrix becomes fibrotic and induces further metabolic dysfunction. Angiogenic adipose tissues, however, expand with limited systemic consequence. Paradoxically, a complete inhibition of angiogenesis may completely stop adipose tissue expansion.

Fig 3

Lymphatic circulation is an important transporter of lipids and plays a role in metabolic functions. A) Fluid, macromolecules, and cells enter lymphatic circulation in the periphery through initial lymphatic capillaries and form lymph. Lymph is transported through collecting lymphatic vessels, passes through the lymph nodes, and enters venous circulation at the venous duct. Both collecting lymphatic vessels and lymph nodes are surrounded by adipose tissue such that crosstalk between the two tissues’ functions may occur. B) In the villi of the small intestine, enterocytes package dietary lipids into chylomicrons that are exclusively taken up by lacteals, the lymphatic capillaries of the intestine. Water soluble nutrients are absorbed through the blood. C) Normal lymphatic capillaries drain the interstitium through initial lymphatic “valves”. Dysfunctional lymphatics result in lymph leakage, which stimulates adipogenesis. Adipogenesis may, in turn, further decrease lymphatic capillary quality.