Abstract
Obesity is characterized by pathological adipose tissue (AT) expansion. While healthy AT expansion enhances systemic insulin sensitivity, unhealthy AT expansion through increased adipocyte size is associated with insulin resistance, fibrosis, hypoxia, and reduced adipose-derived adiponectin secretion. The mechanisms causing the unhealthy AT expansion are not fully elucidated; yet, dysregulated crosstalk between cells within the AT is an important contributor. Evidence from animal and human studies suggests a crucial role of the crosstalk between vascular endothelium (the innermost cell type in blood vessels) and adipocytes for metabolic homeostasis. Arterial endothelial cells are directly involved in maintaining normal organ functions through local blood flow regulation. The endothelial-dependent regulation of blood flow in AT is hampered in obesity, which negatively affects the adipocyte. Moreover, endothelial cells secrete extracellular vesicles (EVs) that target adipocytes in vivo. The endothelial EVs secretion is hampered in obesity and may be affected by the adipocyte-derived adipokine adiponectin. Adiponectin targets the vascular endothelium, eliciting organ-protective functions through binding to T-cadherin. The reduced obesity-induced adiponectin binding of T-cadherin reduces endothelial EV secretion. This affects endothelial health and cell-cell communication between AT cells and distant organs, influencing systemic energy homeostasis. This review focuses on the current understanding of endothelial and adipocyte crosstalk. We will discuss how obesity changes the AT environment and how these changes contribute to obesity-associated metabolic disease in humans. Particularly, we will describe and discuss the EV-dependent communication and regulation between adipocytes, adiponectin, and the endothelial cells regulating systemic energy homeostasis in health and metabolic disease in humans.
Highlights
Obesity, defined as excessive fat accumulation, is a worldwide epidemic accompanied by an increased risk of developing cardiovascular diseases (CVDs), certain types of cancers, Alzheimer’s disease, non-alcoholic fatty liver disease, and type 2 diabetes mellitus (T2D) [1]
The hyperplastic white adipose tissue (WAT) expansion is characterized by the formation of new adipocytes from adipose progenitor cells, which is associated with enhanced systemic insulin sensitivity
We have recently shown that mice fed an high-fat diet (HFD) developed endothelial dysfunction, which was abrogated in mice with global knockout of the T-type Ca2+ channel Cav3.1 [53]
Summary
Obesity, defined as excessive fat accumulation, is a worldwide epidemic accompanied by an increased risk of developing cardiovascular diseases (CVDs), certain types of cancers, Alzheimer’s disease, non-alcoholic fatty liver disease, and type 2 diabetes mellitus (T2D) [1]. The WAT adapts to the excessive energy intake through two mechanisms 1) an increase in adipocyte number (hyperplasia) and/or 2) size (hypertrophy) [4]. The hyperplastic WAT expansion is characterized by the formation of new adipocytes from adipose progenitor cells, which is associated with enhanced systemic insulin sensitivity. Hypertrophic WAT expansion is, on the other hand, characterized by insulin resistance, dysfunctional prolipolytic action, increased inflammation, fibrosis, and altered adipokine secretion profile, including decreased adiponectin levels [4, 5]. Unhealthy WAT expansion is the sine qua non of metabolic unhealthy obesity, causing ectopic lipid accumulation in peripheral tissues such as the liver and skeletal muscle [4]. We will review and summarize our current understanding of the crosstalk between the adipocytes and the arterial endothelial cells within the WAT and how this communication potentially regulates systemic energy homeostasis in metabolic disorders
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