The adipocyte as an endocrine organ in the regulation of metabolic homeostasis

Abstract

Over the past decade and a half it has become increasingly clear that adipose tissue is a much more complex organ than was initially considered and that its metabolic functions extend well beyond the classical actions of thermoregulation and of storage and release of fatty acids. In fact, it is now well established that adipose tissue plays a critical role in maintenance of energy homeostasis through secretion of a large number of adipokines that interact with central as well as peripheral organs such as the brain, liver, pancreas, and skeletal muscle to control diverse processes, such as food intake, energy expenditure, carbohydrate and lipid metabolism, blood pressure, blood coagulation, and inflammation. While many of these adipokines are adipocyte-derived and have a variety of endocrine functions, others are produced by resident macrophages and interact in a paracrine fashion to control adipocyte metabolism. It is also abundantly clear that the dysregulation of adipokine secretion and action that occurs in obesity plays a fundamental role in the development of a variety of cardiometabolic disorders, including the metabolic syndrome, type 2 diabetes, inflammatory disorders, and vascular disorders, that ultimately lead to coronary heart disease. Described herein are the traditional as well as endocrine roles of adipose tissue in controlling energy metabolism and their dysregulation in obesity that leads to development of cardiometabolic disorders, with a focus on what is currently known regarding the characteristics and roles in both health and disease of the adipocyte-derived adipokines, adiponectin, leptin, resistin, and retinol binding protein 4, and the resident macrophage-derived adipokines, tumor necrosis factor-α and interleukin-6.

This article is part of a Special Issue entitled ‘Central Control of Food Intake’.

Introduction

The classical roles of adipose tissue are to insulate and cushion the body, to store free fatty acids (FFA) after food intake, and to release FFAs during periods of fasting to ensure sufficient energy availability (Hajer et al., 2008). Adipocytes are the only cells that are specifically adapted to store lipids without compromising their functional integrity and have all of the enzymatic machinery necessary to synthesize fatty acids, to store triglycerides during periods of abundant energy supply, and to mobilize them via lipolysis when there is a calorie deficit (Fonseca-Alaniz et al., 2007). For example, during the postprandial phase, FFAs are taken up from the blood by adipocytes, after hydrolysis of the triglycerides contained in circulating triglyceride-rich lipoproteins by extracellular lipoprotein lipase (LPL), and are then converted back to triglycerides intercellularly for storage (Hajer et al., 2008). Mobilization of this reserve during periods of fasting occurs through hydrolysis of these intracellular triglycerides by hormone-sensitive lipase (HSL) (Hajer et al., 2008). Insulin is the primary regulator of adipocyte fat content, since it is both a potent inhibitor of HSL and an important activator of LPL (Hajer et al., 2008).

The central nervous system takes part in regulation of these two processes by means of direct or indirect neural activity. The autonomic nervous system acts directly on adipose tissue through both the sympathetic and parasympathetic systems (Fonseca-Alaniz et al., 2007). The sympathetic system promotes catabolic actions (e.g. lipolysis) via β-adrenergic stimulation, which activates HSL (Penicaud et al., 2000), whereas the parasympathetic system promotes anabolic actions by increasing insulin production and increasing tissue glucose and fatty acid uptake (Kreier et al., 2002).

Adipose tissue contains adipocytes as well as many additional cell types, including endothelial cells, fibroblasts, pericytes, monocytes, macrophages, and preadipocytes (Ahima and Flier, 2000). These additional cells, which are collectively termed “stromal vascular cells”, account for a significant portion of the total cell number in adipose tissue, and can be separated from adipocytes using protocols that involve collagenase digestion followed by flotation of the adipocyte fraction using low centrifugal force (Rodbell, 1964). These stromal vascular cells exert a number of important functions for adipose tissue homeostasis. For example, endothelial cells and pericytes make up the vasculature of tissues and enable processes such as adipose tissue growth and development (Brakenhielm et al., 2004; Rupnick et al., 2002), monocytes and macrophages present in adipose tissues are thought to aid in the clearance of necrotic adipocytes, a role of increasing importance in the adipose tissue of obesity (Cinti et al., 2005), and adipose tissue macrophages are responsible for the increased adipose tissue inflammatory cytokine production in obesity (Weisberg et al., 2003; Xu et al., 2003). Adipose tissue is also a reservoir of pluripotent stem cells (Zuk et al., 2002) that contribute to the pools of stromal vascular cells and adipocytes.