Heart and Metabolism

Physiology and pathophysiology of energy storage

G. Frühbeck
Department of Endocrinology and Metabolic Research Laboratory,
Clínica Universitaria de Navarra, Pamplona, Spain
Correspondence: Dr Gema Frühbeck, Department of Endocrinology, Clínica Universitaria de Navarra, 31008 Pamplona, Spain. Tel: +34 948 255400, fax: +34 948 296500, e-mail: gfruhbeck@unav.es

Abstract

Studies of adipose tissue metabolism and body weight regulation are increasing our understanding of the intricate balance of energy homeostasis. Fat cells actively secrete a large number of growth factors, hormones, and cytokines, which influence fuel storage, mobilization, and utilization in both central and peripheral systems. Adipocytes display a wide repertoire of metabolic processes to guarantee continuous availability of energy despite a highly variable supply. This article reviews the sophisticated integrated mechanisms that operate in an orchestrated manner in adipose tissue on several physiological levels, enabling the organism to adapt to a wide range of metabolic challenges. Heart Metab. 2002;17:35–39.

Keywords: Obesity, adipokines, leptin, tumor necrosis factor-a, interleukins, resistin

Introduction
The ability to ensure continuous availability of energy despite a highly variable supply is a major determinant of the survival of all species. In this sense, the primary role of adipocytes was thought to be fat storage. Unlike protein or glycogen, which require water, the hydrophobic nature of fat results in the advantage of highly efficient storage. In addition, oxidation of fat yields twice as much energy as that of carbohydrate or protein. Adipose tissue, considered to lack any specific metabolic activity, therefore received little attention.
Until the 1990s adipose tissue had been largely considered to be an inert storage depot with access to stored triacylglycerols being regulated mainly by adrenergic stimulation [1, 2]. This view remained prevalent until research focused attention on the relevant role of adipose tissue as a source of metabolic fuel [3]. In recent years, interest in the biology of adipose tissue has emerged in relation to the discovery of a host of adipocyte-derived factors that contribute to energy homeostasis [4–6]. It is now well established that several growth factors and cytokines secreted by adipose tissue play a key role in cell differentiation, energy metabolism, and insulin resistance. The physiological relevance of this endocrine organ is evident from the fact that the absence of adipose tissue, as observed in lipodystrophy, is as detrimental as an excess of body fat [7].
In order to store triacylglycerol during periods of caloric excess and to mobilize this reserve when expenditure exceeds energy intake, adipocytes dispose of a whole range of enzymes for both lipolysis and de novo lipogenesis reactions [8]. In fat cells, the regulation of these processes is exquisitely responsive to hormones, cytokines, and other factors that are involved in energy metabolism [3, 5]. Preadipocytes first appear late in embryonic life, although major expansion of the white adipocyte population is delayed until shortly after birth [9].

Adipocyte-derived factors
In a dynamic view of the adipocyte a wide range of signals emanates from white adipose tissue to impinge on the function of several organs (Figure 1).

Figure 1. Production of adipocyte-derived factors exerts a role on both the central nervous system and the periphery.

White adipose tissue is actively involved in cell function regulation through a complex network of endocrine, paracrine, and autocrine signals, which influence the response of many tissues, including the hypothalamus, as well as mainly metabolic organs such as pancreas, liver, skeletal muscle, kidneys, adrenal glands, or the cardiovascular system. Adipocytes act as endocrine secretory cells [10, 11]; numerous hormones, growth factors, and cytokines are expressed in white adipose tissue, such as leptin, tumor necrosis factor-a (TNFa), interleukin-6 (IL-6), and their respective soluble receptors [3, 5]. White adipose tissue also secretes important regulators of lipoprotein metabolism such as lipoprotein lipase, apolipoprotein E, and cholesteryl ester transfer protein. The increasing number of products secreted by adipocytes also includes angiotensinogen, plasminogen activator inhibitor-1, tissue factor, transforming growth factor-b, and inducible nitric oxide synthase (iNOS). The role of insulin-like growth factor-I, glucocorticoids, and sex steroids in adipose tissue proliferation, heterogeneity, and distribution is beginning to be better understood. However, the influence of acylation stimulating protein, adipophilin, adipoQ, adipsin, monobutyrin, agouti protein, and factors related to proinflammatory and immune processes remains to be fully elucidated [5]. These relationships show that white adipose tissue can no longer be considered to be a passive bystander in whole body pathophysiology, since it lies at the heart of a network of signals leading to important health complications in case of faulty functioning (Figure 2).

Figure 2. Pathophysiological complications associated with adipose tissue dysfunction.

More recently, identification of a series of new molecules implicated in obesity and adipose tissue development has been published. The gene Lpin1 has been shown to encode a novel nuclear protein, which has been named lipin [12]. The discovery of lipin has revealed a new factor required for normal adipose tissue development and metabolism. Elucidation of the molecular function of lipin will likely lead to new insights into these processes [13]. This novel family of nuclear proteins contains at least three members in mammalian species. The human ortholog LPIN1 is a potential candidate gene for lipodystrophy.
The discovery of a novel hormone, which researchers named resistin (for resistance to insulin), was reported in 2001 [14, 15]. The knocking out of the glucose transporter gene GLUT4 in mice resulted in normal growth and adipose tissue mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes [16]. Although GLUT4 expression was preserved in muscle, these rodents developed insulin resistance in muscle and liver, as shown by decreased biological responses and impaired activation of phosphoinositide-3-OH kinase. Therefore, adipose-selective depletion of GLUT4 in mice led to impaired glucose tolerance and insulin resistance with preserved adipose mass. Consequently, insulin resistance occurred secondarily in muscle and liver, as evidenced by defective proximal signaling and reduced physiological responses. Moreover, the insulin resistance could not be accounted for by changes in circulating free fatty acids, triglycerides, or leptin, or by changes in TNFa expression in adipose tissue. Thus, selective downregulation of GLUT4 and glucose transport in adipose tissue can cause insulin resistance and, thereby, increase the risk of developing diabetes.
Acetyl-coenzyme A carboxylase 2 has been shown to be a key metabolite in the regulation of energy homeostasis [17]. The absence of this enzyme resulted in higher fatty acid oxidation rates in heart and skeletal muscle followed by a marked decrease in fat storage despite increased food intake.

Energy metabolism
Throughout the 2.5-million-year history of human development the principal threat to survival has been recurrent famine. The evolution of adipocytes provided a means for coping with the cycles of undernutrition by enabling the preloading of calories for subsequent use. During the 20th century, however, an unprecedented change in the pattern of caloric availability took place in many developed countries. Recurrent undernutrition was replaced by unending overnutrition, the consequences of which were greatly amplified by the permanent state of physical inactivity imposed by sedentary occupations and immobilizing technologies of modern life [18]. Obesity results from an energy imbalance, where energy intake exceeds energy expenditure over a sustained period of time [19]. Body weight increases when more energy is taken in than is burnt off. Maintenance of energy balance is a complex phenomenon affected by nutritional, endocrine, nervous, physical, and psychosocial factors, as depicted in Figure 3.

Figure 3. Schematic representation of the multi- factorial factors influencing the development of obesity.

Genetic as well as environmental factors affect appetite, food choices, metabolism, activity, and how the body fine-tunes the balance between energy intake and expenditure, affecting everything from food intake to how fat is stored in the body.

Insulin resistance
Although it is well known that the increased storage of triglycerides in adipocytes promotes insulin resistance, how this exerts a detrimental impact in muscle, liver, and elsewhere in the body has not been completely elucidated. A variety of adipocyte-derived molecules have been proposed as potential mediators of the resistance to insulin associated with obesity. Among the numerous peptides secreted by fat cells that may lead to insulin resistance TNFa and leptin stand out [5, 20]. Both are overexpressed in adipocytes from obese individuals and can cause insulin resistance through their effects on insulin-mediated cellular signaling pathways. Hotamisligil’s group [21] was the first to report a close relationship between increased adipose TNFa expression and features of insulin resistance in rodent models of obesity and type 2 diabetes mellitus. Furthermore, it has been reported that TNFa induces phosphorylation of the insulin receptor substrate (IRS)-1 at serine residues and that serine-phosphorylated IRS-1 operates as an inhibitor of insulin receptor activity [22]. Leptin is not only a central regulator of body fat mass, by decreasing food intake and increasing energy expenditure, but could also be involved in the induction of insulin resistance, possibly via peripheral mechanisms of action [6]. Recent reports suggest complex interactions between the leptin and insulin signaling pathways. In fact, leptin can act through some components of the insulin signaling cascade, such as IRS-1 and IRS-2, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo [20, 23, 24]. A divergence of leptin effects on insulin-stimulated IRS-1- and IRS-2-mediated signaling and downstream kinases suggests a complex and multidimensional interaction between these two hormonal signaling systems. Leptin rapidly activates signaling pathways directly at the level of insulin-sensitive tissues through the functional leptin receptor, and these pathways overlap with, but are distinct from, those engaged by insulin. Thus, evidence suggests that other factors are also required for the development of insulin resistance.
Resistin may be an important link between increased fat mass and insulin resistance since its concentrations are decreased in a mouse model of insulin-deficiency diabetes, and insulin administration rapidly normalizes resistin levels in adipose tissue [25, 26]. Therefore, insulin apparently modulates its own activity through the regulation of resistin.
Recently, compelling evidence has been reported that a mitochondrial anion carrier called uncoupling protein-2 is a critical modulator of insulin secretion and that an increase in this protein may cause b-cell dysfunction [27–29]. Another knockout model, the targeted disruption of the gene encoding iNOS, provides evidence for the involvement of iNOS in the development of muscle insulin resistance in diet-induced obesity [30]. Moreover, rodents lacking IL-6 developed obesity, displayed decreased glucose tolerance and increased triglyceride concentrations. Furthermore, endogenous IL-6 has been shown to exert a tonic suppression of fat mass at the central nervous system in mice, probably due to stimulation of energy expenditure in addition to inhibition of feeding [31].

Summary
The above scientific evidence has transformed our thinking about the adipocyte. It can no longer be regarded as a passive depot tissue for storing excess energy in the form of triglyceride but has to be considered as an extremely active cell that regulates the pathways responsible for energy homeostasis and whose activity is exquisitely regulated by a complex network of autocrine, paracrine, and neuroendocrine signals.

REFERENCES

1: J Lipid Res 1993 Jul;34(7):1057-91

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Fat cell adrenergic receptors and the control of white and brown fat cell function.

Lafontan M, Berlan M.

Institut National de la Sante et de la Recherche Medicale, INSERM, Unite 317, Institut Louis Bugnard, Faculte de Medecine, CHU Rangueil, Toulouse, France.

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Publication Types:

Review
Review, Academic

PMID: 8371057 [PubMed - indexed for MEDLINE]

2: Cell 1995 Jan 13;80(1):15-8