Review
The autocrine and paracrine roles of adipokines

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Abstract

Obesity, defined by an excess of adipose tissue, is often associated with the development of various metabolic diseases. The increased and inappropriate deposition of this tissue contributes to hyperglycemia, hyperlipidemia, insulin resistance, endothelial dysfunction and chronic inflammation. Recent evidence suggests that factors expressed and secreted by the adipose tissue, adipokines, may contribute to the development of these abnormalities by mechanisms including inhibition of adipogenesis, adipocyte hypertrophy and death, immune cell infiltration and disruption of tissue metabolism. The presence of adipokine receptors in adipocytes renders these cells available to autocrine and paracrine effects of adipokines. In this review the reported local effects of adipokines on adipose tissue structure, inflammation and regulation of metabolic functions, in the face of over-nutrition and consequent obesity, are outlined. Elucidating the local regulation of white adipocyte development and function could help in the design of effective, tissue-specific therapies for obesity-associated diseases.

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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