ReviewAdipose tissue as an endocrine organ
Introduction
The rapid rise in the rate of obesity is a critically important health issue for the developed world. Obesity is associated with a number of health problems that are often summarized together as the metabolic syndrome and involves the development of insulin resistance, type 2 diabetes, cardiovascular disease and fatty liver disease. Both obesity and type 2 diabetes are causally linked through their association with the development of insulin resistance. Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver (Fig. 1). Adipose tissue plays a crucial role in the regulation of whole-body fatty acid homeostasis. In periods of calorie abundance it stores free fatty acids (FFAs) in the form of triglycerides through their esterification to glycerol and releases them back into the circulation in times of energy shortage. While the role of adipose tissue as a central source of energy has been recognized for centuries it has been just over 50 years since Kennedy (1953) hypothesized about the presence of a circulating, lipostatic, negative feedback signal acting centrally to alter energy expenditure and food intake. The following decade studies involving genetically obese (ob/ob) and diabetic (db/db) mice confirmed the presence of such a circulating factor (Coleman, 1973). While these mutations are on unrelated genes located on separate chromosomes both models were characterized by obesity, hyperphagia, diabetes, infertility and reduced physical activity and thermoregulation. Parabiosis experiments explained the identical syndromes by suggesting the existence of a humoral factor that is absent in the ob/ob mouse and present but ineffective in db/db mice. However, the identity of this lipostatic signal remained elusive. In 1994, using positional cloning in the ob/ob mouse, Zhang et al. (1994) identified and sequenced the ob gene and its protein product, leptin (from leptos, for thin). Shortly thereafter, a cohort of studies (Campfield et al., 1995, Halaas et al., 1995, Pelleymounter et al., 1995) demonstrated that daily injections of ob/ob mice with the 16 kDa peptide leptin rapidly reduced food intake, body mass and percent body fat, while maintaining lean muscle mass. In addition, leptin administration resulted in increased energy expenditure and restored euglycemia and reproductive function, confirming its role as a regulator of energy intake and storage.
Around the same time as the discovery of leptin, Hotamisligil et al. (1993) identified that in addition to proteins involved in metabolic regulation, adipose tissue also secreted tumour necrosis factor-α (TNFα), which they identified to be a negative regulator of insulin signal transduction. Subsequent studies in genetic models of TNFα deficiency confirmed a causal role for this inflammatory cytokine in the development of obesity-induced insulin resistance establishing the now well accepted paradigm that obesity is a chronic condition of low-grade inflammation (Uysal et al., 1997). More recently it has been revealed though that the predominant source of this adipose inflammation is from activated adipose tissue macrophages (Weisberg et al., 2003). These pivotal discoveries established the foundation for the now well accepted idea that adipose tissue is a dynamic endocrine organ that is critical for regulating metabolism in both health and disease, findings, which provided a foundation for the subsequent discovery of many other adipocyte-derived secreted proteins (adipokines) such as adiponectin, resistin, retinol binding protein-4 (RBP4) and interleukin-6 (IL-6). The purpose of this review is to provide a general overview of the above stated adipokines with a focus on their source, whether it is adipose tissue or resident macrophages, structure and function and their effects on whole-body energy metabolism and insulin resistance.
Section snippets
Leptin
In contrast to the ob/ob mouse which lacks leptin, plasma leptin levels increase with weight gain and decrease with weight loss, consistent with leptin's role as a signal of adipose tissue stores (Havel et al., 1996, Maffei et al., 1995). There is a positive linear correlation (r = 0.8) between circulating levels of serum leptin and total body fat mass, which can be explained by increased release of leptin from large compared with small fat cells (Lonnqvist et al., 1997). On average leptin
Adiponectin
Adiponectin is secreted exclusively from adipose tissue and is an abundant plasma protein (Hu et al., 1996). Structurally, adiponectin is related to the complement 1q family and contains a carboxyl-terminal globular domain and an amino-terminal collagenous domain (Scherer et al., 1995) and also shares extensive sequence homology with collagen VIII and X (Hu et al., 1996). Adiponectin circulates in serum as a range of multimers from low-molecular-weight trimers to high-molecular-weight (HMW)
Resistin
The peptide hormone resistin (or FIZZ3) is an adipocyte-derived secretory factor which was first identified as a novel transcript produced exclusively by adipocytes (Steppan et al., 2001) and has been shown to play a significant role in obesity-induced insulin resistance (Steppan et al., 2001). Resistin is expressed within adipocytes of rodents (Steppan et al., 2001) and macrophages of humans (Patel et al., 2003) and its production is increased with feeding and obesity and decreased by PPARγ
Retinol binding protein-4
Retinol binding protein-4 is an approximately 21 kDa protein, that was first reported to be an adipokine by Kahn and co-workers (Yang et al., 2005) when trying to understand the muscle insulin resistance observed in adipose specific Glut 4 null mice. They found that RBP4 expression was increased in insulin resistant adipose tissue specific Glut 4 null mice and reduced in insulin sensitive adipose specific Glut 4 transgenics. Injection of recombinant human RBP4 into lean mice, resulted in insulin
Adipose tissue macrophages
Increased adipose mass associated with obesity has been linked with a low-grade, chronic inflammatory response, characterized by altered production of adipokines and increases in biological markers of inflammation, such as tumour necrosis factor-α, interleukin-6 or monocyte-chemoattractant protein-1 (MCP-1) plasminogen activated inhibitor (PAI-1), colony stimulating factor (CSF) or inducible nitric oxide synthase (iNOS) (Neels and Olefsky, 2006). However, studies in recent years have revealed
Tumour necrosis factor-α (TNFα)
TNFα is synthesised as a 26 kDa transmembrane protein that undergoes cleavage by a metalloproteinase to be released into the circulation as a 17 kDa soluble TNFα molecule (Kriegler et al., 1988). Isolated and differentiated adipocytes are capable of producing TNFα and it was originally suggested that adipocytes are the principal source of elevated TNFα levels in obesity. However, more recently it has been recognized that macrophages from the stromal vascular fraction are the primary source of
Interleukin-6 (IL-6)
Plasma IL-6 levels are increased in type 2 diabetes and are positively correlated with body mass and plasma free fatty acid concentrations (Lazar, 2005). Approximately 1/3 of the IL-6 detected in plasma is attributed to the production from white adipose tissue (Mohamed-Ali et al., 1997). However, most of the adipose derived IL-6 comes from cells of the stromal vascular fraction. In adipocytes and hepatocytes IL-6 has been demonstrated to inhibit the insulin signaling pathway by up-regulating
Conclusion
Adipose tissue is the primary storage site for excess energy. In the past decade it has become increasingly clear that adipose tissue also displays characteristics of an endocrine organ releasing a number of adipocyte-specific factors known as adipokines. Much of the research in this area has focussed on leptin and adiponectin, the two prototypic adipokines, which show beneficial effects on insulin action and lipid metabolism. In obesity leptin concentrations are elevated while adiponectin
Acknowledgement
GRS is a Canadian Research Chair in Metabolism, Obesity and Type 2 Diabetes.
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