Adipokines in inflammation and metabolic disease

Abstract

The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.

Figure 1. Adipose tissue depots

Adipose tissue is mainly found in subcutaneous and visceral depots. Under conditions of obesity, adipose tissue expands in these and other depots throughout the body. Common sites of adipose tissue accumulation include the heart, the kidneys and the adventitia of blood vessels. Differential adipokine secretion by various adipose tissue depots may selectively affect organ function and systemic metabolism.

Figure 2. Components of adipose tissue

a Adipocytes are the main cellular component of adipose tissue, and they are crucial for both energy storage and endocrine activity. The other cell types that are present are precursor cells (including pre-adipocytes), fibroblasts, vascular cells and immune cells, and these cells constitute the stromal vascular fraction of adipose tissue. Vascular cells include both endothelial cells and vascular smooth muscle cells, which are associated with the major blood vessels. The blood vessels in adipose tissue are required for the proper flow of nutrients and oxygen to adipocytes, and they are the conduits that allow for the distribution of adipokines. Vascular cells also secrete, and are responsive to, adipose tissue-secreted proteins. Other active adipose tissue components include macrophages and T cells, which have major roles in determining the immune status of adipose tissue. The fibroblast-derived extracellular matrix functions to provide mechanical support, and excess matrix can lead to adipose tissue dysfunction. Factors that are secreted by these different cellular components are critical for maintaining homeostasis in adipose tissue and throughout the body. b Examples of intercellular communication between different adipose tissue cell types include the counter-regulation between adiponectin and tumour necrosis factor (TNF), and between secreted frizzled-related protein 5 (SFRP5) and WNT5a. Under conditions of obesity the pro-inflammatory factors (TNF and WNT5a) predominate.

Figure 3. Phenotypic modulation of adipose tissue

Adipose tissue can be described by at least three structural and functional classifications: lean with normal metabolic function, obese with mild metabolic dysfunction and obese with full metabolic dysfunction. As obesity develops, adipocytes undergo hypertrophy owing to increased triglyceride storage. With limited obesity, it is likely that the tissue retains relatively normal metabolic function and has low levels of immune cell activation and sufficient vascular function. However, qualitative changes in the expanding adipose tissue can promote the transition to a metabolically dysfunctional phenotype. Macrophages in lean adipose tissue express markers of an M2 or alternatively activated state, whereas obesity leads to the recruitment and accumulation of M1 or classically activated macrophages, as well as T cells, in adipose tissue. Anti-inflammatory adipokines, including adiponectin and secreted frizzled-related protein 5 (SFRP5), are preferentially produced by lean adipose tissue. In states of obesity, adipose tissue generates large amounts of pro-inflammatory factors, including leptin, resistin, retinol-binding protein 4 (RBP4), lipocalin 2, angiopoietin-like protein 2 (ANGPTL2), tumour necrosis factor (TNF), interleukin-6 (IL-6), IL-18, CC-chemokine ligand 2 (CCL2), CXC-chemokine ligand 5 (CXCL5) and nicotinamide phosphoribosyltransferase (NAMPT). Obese individuals with adipose tissue in a metabolically intermediate state have improved metabolic parameters, diminished inflammatory marker expression and better vascular function compared with individuals that have metabolically dysfunctional adipose tissue. Metabolically dysfunctional adipose tissue can be associated with higher levels of adipocyte necrosis, and M1 macrophages are arranged around these dead cells in crown-like structures.