ReviewThe autocrine and paracrine roles of adipokines
Introduction
Obesity, affected by the expanding adipose tissue mass, has necessitated the study and understanding of this organ. It is now accepted that the adipose tissue is an important, dynamic participant in regulating whole-body metabolism and is crucial for glucose and energy homeostasis (Rosen and Spiegelman, 2006). Various diseases are closely associated with increased adipose tissue mass, including type 2 diabetes, atherosclerosis, hypertension, osteoarthritis and certain cancers (Greenberg and Obin, 2006). Obesity-associated changes in the structure and function of adipose tissue and its distribution are affected by and effect changes in the adipokine secretory repertoire and profoundly influence the susceptibility of an individual to the associated pathologies (Björntorp, 1991).
Obesity has been described as a low grade inflammatory condition, with both the cellularity and the secretions of adipose tissue reflecting these changes. Current evidence suggests that over-nutrition leads to adipocyte hypertrophy, followed by cell death, which may act as a stimulus for immune cell infiltration into the tissue (Strissel et al., 2007, Murano et al., 2008). Monocyte infiltration and differentiation in particular has been shown to correlate with adipocyte hypertrophy, as well as body mass (Weisberg et al., 2003). These macrophages, in response to the endocrine and metabolic milieu prevalent in the obese adipose tissue, switch their phenotype from one of a non-inflammatory resident macrophage to that of a lipid engorged foam cell, expressing dendritic cell markers, such as CD11c (Lumeng et al., 2007). The secretions of these macrophages, such as IL-6 and TNFα, along with those from the hypertrophied adipocyte, such as MCP-1 and leptin, regulate the pathological changes of obesity, like insulin resistance and endothelial dysfunction (Fig. 1). These autocrine/paracrine effects augment the endocrine changes mediated by the molecules in other organs such as liver, heart and skeletal muscle. All the signals released from or expressed by the adipose tissue are referred to as adipokines here, even though these include cytokines, chemokines and products of tissue enzyme activity (Table 1).
Section snippets
Adipokines, adipose tissue structure and regional distribution
Two histologically and functionally distinct types of adipose tissue have been identified: white (WAT) and brown adipose tissue (BAT). In mice, BAT exists throughout adulthood, while in humans it was thought to exist mainly in the neonatal period, having largely disappeared within the first years after birth. However, recent evidence suggests that adults retain metabolically active BAT depots that can be cold-induced and respond to sympathetic nervous system activation (Frühbeck et al., 2009).
Adipokine receptors and signal transduction
The presence of several of the adipokine receptors in adipocytes from both subcutaneous and visceral depots potentially renders these cells available to autocrine/paracrine regulation by adipokines. It has been demonstrated that human adipocytes express leptin receptors, both the long form (huOb-R), as well as the short forms B219.1–B219.3 (Kielar et al., 1998, Apran-Husmann et al., 2001). The IL-6 receptor, together with the signal-transducing gp130 unit, is also present in isolated mature
Adipokine regulation of adipose mass and blood flow
During adipogenesis, fibroblast-like preadipocytes differentiate into lipid-laden and insulin-responsive adipocytes. This process occurs in several stages and involves a cascade of transcription factors, among which peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs) are considered the crucial determinants of adipocyte fate. The involvement of additional factors, including Krupel-like factors (KLFs), Wingless and INT-1 proteins (Wnts), and
Role of adipokines in inflammation
The secretory function of adipocytes can also be modulated by adipokines, as shown mainly in in vitro models. TNFα is known to suppress adiponectin production by adipocytes, while it induces a number of proinflammatory mediators like IL-6, MCP-1 and PAI-1 (Cawthorn and Sethi, 2008), primarily via activation of Foxo1 (Ito et al., 2009). Treatment of differentiated human adipocytes with TNFα also significantly decreased the expression of angiotensinogen and haptoglobin (B. Wang et al., 2005, M.
Autocrine/paracrine regulation of glucose and lipid metabolism
Deposition of energy in adipose tissue occurs primarily via hydrolysis of circulating triglycerides by lipoprotein lipase (LPL), uptake of fatty acids and re-esterification to glycerol within the cell or via de novo lipogenesis. Interestingly, ASP is a potent stimulator of triglyceride synthesis in adipocytes in vitro (Baldo et al., 1993) and is released by adipose tissue in vivo in the postprandial period, when net fatty acid uptake by the tissue occurs (Saleh et al., 1998). TNFα has opposing
Conclusion
There is accumulating evidence that in obesity, adipose tissue expands, through adipocyte hypertrophy that is facilitated by inhibition of adipogenesis and adipocyte death. These areas of cell death form focal points for macrophage infiltration into the tissue. The infiltrating macrophages switch from a non-inflammatory phenotype to form foam cells. Continued accumulation of body fat is accompanied by adipocyte hyperplasia and hypertrophy, along with further increases in macrophage numbers. All
Acknowledgements
Aspects of this work were funded by grants from Heart Research UK (RG 2580/09/11), European Commission (EXGENESIS: LSHM-CT-2004-005272) and The Wellcome Trust (grant number GR078055MA).
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