ADIPOQUINAS( ADIPOCINAS )

xdAdipose tissue depots

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.

Components 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.

Phenotypic modulation of adipose tissue

ANGPTL2, angiopoietin-like protein 2; CCL2, CC-chemokine ligand 2; CXCL5, CXC-chemokine ligand 5; IL, interleukin; JAK, Janus kinase; NAMPT, nicotinamide phosphoribosyltransferase; RBP4, retinol-binding protein 4; SFRP5, secreted frizzled-related protein 5; STAT, signal transducer and activator of transcription; TNF, tumour necrosis factor.

Sources and functions of key adipokines

Fig 1Adipose tissue: cellular components and molecules produced. Adipose tissue is composed of adipocytes and the stromovascular fraction, which includes macrophages. Left, Adipocytes produce leptin, adiponectin, visfatin, IL-6, MCP-1, and other factors. Macrophages produce TNF-α, IL-5, MCP-1, and other cytokines and chemokines. In human subjects the ultimate cellular source of adipsin and resistin seems to be the macrophage. Right, In obesity leptin and possibly other factors produced by adipocytes, macrophages, or both upregulate adhesion molecules on endothelial cells, leading to transmigration of bone marrow–derived monocytes and thus an increase in WAT-resident macrophages, some of which fuse to generate giant multinucleated cells. Macrophages present in the WAT of obese individuals produce higher levels of TNF-α, IL-6, and chemokines compared with those in lean persons. At the same time, adiponectin production by adipocytes is reduced, possibly through upregulated local TNF-α levels.