Obesity, Adipose Tissue and Vascular Dysfunction

Abstract

Cardiovascular diseases are the leading cause of death worldwide. Overweight and obesity are strongly associated with comorbidities such as hypertension and insulin resistance, which collectively contribute to the development of cardiovascular diseases and resultant morbidity and mortality. Forty-two percent of adults in the United States are obese, and a total of 1.9 billion adults worldwide are overweight or obese. These alarming numbers, which continue to climb, represent a major health and economic burden. Adipose tissue is a highly dynamic organ that can be classified based on the cellular composition of different depots and their distinct anatomical localization. Massive expansion and remodeling of adipose tissue during obesity differentially affects specific adipose tissue depots and significantly contributes to vascular dysfunction and cardiovascular diseases. Visceral adipose tissue accumulation results in increased immune cell infiltration and secretion of vasoconstrictor mediators, whereas expansion of subcutaneous adipose tissue is less harmful. Therefore, fat distribution more than overall body weight is a key determinant of the risk for cardiovascular diseases. Thermogenic brown and beige adipose tissue, in contrast to white adipose tissue, is associated with beneficial effects on the vasculature. The relationship between the type of adipose tissue and its influence on vascular function becomes particularly evident in the context of the heterogenous phenotype of perivascular adipose tissue that is strongly location dependent. In this review, we address the abnormal remodeling of specific adipose tissue depots during obesity and how this critically contributes to the development of hypertension, endothelial dysfunction, and vascular stiffness. We also discuss the local and systemic roles of adipose tissue derived secreted factors and increased systemic inflammation during obesity and highlight their detrimental impact on cardiovascular health.

Keywords: adipose tissue; cardiovascular diseases; hypertension; obesity.

Conflict of interest statement

Disclosures:

None of the authors have any financial, personal or professional relationships with other people or organizations that could reasonably be perceived as conflicts of interest or as potentially influencing or biasing this work.

Figures

Figure 1.. Obesity, vascular stiffness and cardiovascular disease (CVD): genetic/epigenetic and environment interactions.

A food desert refers to an area with limited access to nutritious, affordable food.

Figure 2.. Prenatal programming and epigenetics in the genesis of obesity and cardiovascular disease (CVD) in offspring.

(Illustration credit: Ben Smith)

Figure 3.. Function and localization of different adipose tissue depots.

Comparison of white, beige and brown adipocytes in regard to their localization in specific depots in human and mice. Their major functions and progenitor cells are depicted. Major changes occurring during adipose tissue remodeling in obesity are highlighted. PVAT, Perivascular adipose tissue; CD, Cluster of differentiation; PDGFRα: Platelet-derived growth factor receptor alpha; Pax7, Paired box 7; En-1, Engrailed-1; Myf5, Myogenic factor 5;Ucp-1, Uncoupling protein-1; AT, Adipose tissue.

Figure 4.. Changes in different adipose tissue depots in homeostasis and during obesity.

In states of normal body weight (left), thermogenic brown and beige adipocytes are found surrounding the thoracic aorta (PVAT) and can be detected in the cervical, supraclavicular, axillary, paraspinal, renal and epicardial area and in infants in the interscapular depot. These cells have a multilocular appearance and due to the high density of mitochondria appear brown. The abdominal aorta and mesenteric vasculature are surrounded by white adipocytes. These unilocular adipocytes are also found in visceral and subcutaneous adipose depots. Adiponectin and angiotensin 1–7 are secreted by adipocytes and have a vasodilating effect on the vasculature. In the lean state, adipose tissue is populated with different immune cells important for homeostasis, that change dramatically during obesity. During obesity (right), T regulatory cells (Treg) are lost in visceral adipose tissue and inflammatory CD8 T cells and macrophages infiltrate the visceral, mesenteric and to a lesser extent subcutaneous adipose depot. Thermogenic adipose tissue in proximity to the heart and the aorta downregulates thermogenic gene expression and becomes infiltrated with immune cells. Classical brown adipose tissue is potentially protected against obesity-induced immune cell infiltration. Secretion of vasodilatory factors from adipocytes are downregulated whereas leptin and angiotensin II (ANGII) are predominantly secreted, resulting in elevations in blood pressure. PVAT, Perivascular adipose tissue; WAT, white adipose tissue; ANG II, Angiotensin II; ANG 1–7, Angiotensin 1–7; CD, Cluster of differentiation. (Illustration credit: Ben Smith)

Figure 5.. Effects of obesity on the vasculature which promote dysfunctional remodeling and stiffness of the vasculature.

EC, endothelial cell; VSMC, vascular smooth muscle cell; MMPs, matrix metalloproteinase; TG2, tissue transglutaminase; Ang II, angiotensin II; MR, mineralocorticoid receptor; TxA2, thromboxane A2; ENaC, epithelial Na+ channel; IL, interleukin; TNF, tumor necrosis factor; NO, nitric oxide; MCP-1, monocyte chemotactic protein-1; CRP, C- reactive protein; TGF-β, transforming growth factor-β. (Illustration credit: Ben Smith)