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Adipose Tissue and Adipokines in Health and Disease
Giamila Fantuzzi ; Theodore Mazzone (eds.)
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Medicine & Public Health;
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The Adipose Organ
Mammals are provided with an organ that has been neglected by scientists in the past: the adipose organ. This organ is formed by a series of well-defined depots mainly located at two corporal levels: superficial (subcutaneous depots) and deep (visceral depots). In adult rodents, two main depots are the anterior and posterior subcutaneous depots. The first consists of a central body located in the area between the scapulae and several elongated projections abutting toward the cervical region and the axillae. The second is extended from the dorsolumbar area to the gluteal, with an intermediate region located in the inguinal area.
The main visceral depots are tightly connected with viscera. In adult rodents, the main visceral depots are mediastinic, perirenal, perigonadal, mesenteric, and retroperitoneal. The weight of the adipose organ is about 20% of the body weight and therefore it is one of the biggest organs in the body. Its color is mainly white but some areas are brown. In young-adult rodents, maintained in standard conditions, the interscapular region and parts of the cervical and axillary projections of the anterior subcutaneous depot, as well as parts of the mediastinic and perirenal depots, are brown. These two colors correspond to the two tissues: white and brown adipose tissues. The relative amount of the two tissues varies with age, strain, environmental and metabolic conditions, and subsequently, the distribution of the two colors is also variable and implies the ability of reversible transdifferentiation of the two types of adipocytes. During pregnancy and lactation, the subcutaneous depots are transformed into mammary glands.
Each depot of the organ receives its own neurovascular peduncle that is specific for the subcutaneous depots and is usually dependent on the peduncle related to the connected organ in the case of visceral depots. The vascular and nerve supply is much more dense in the brown areas than in the white areas. Their density changes in conjunction with the number of brown adipocytes.
It has been shown that the white adipose tissue of obese mice and humans is infiltrated by macrophages and that the level of infiltration correlates with body mass index and mean size of adipocytes.
This infiltration seems to be an important cause for the insulin resistance associated with obesity. We recently observed that macrophages are mainly located at the level of dead adipocytes in white adipose tissue of obese mice, obese humans, and in transgenic mice, which are lean but have hypertrophic adipocytes (HSL knockout mice). The su
I - Adipose Tissue: Structure and Function | Pp. 3-19
Metabolism of White Adipose Tissue
Triacylglycerols (TAGs) stored in adipose tissue are by far the largest site of energy storage. Adipocytes continuously synthesize and break down these TAGs depending on the body energy status and its hormonal environment. They act as a “buffer” for plasma lipids and also for lipids stored in other tissues. This chapter presents the metabolic pathways used for adipose tissue TAG synthesis and breakdown and the way they are controlled. It points out important recent findings that have modified our conception of these pathways and of their regulation—particularly the role of glyceroneogensis in TAG synthesis—of proteins associated to lipids droplets—particularly perilipins—and of lipases other than the classic hormone-sensitive lipase in TAG hydrolysis.
I - Adipose Tissue: Structure and Function | Pp. 21-33
Malaka B. Jackson; Rexford S. Ahima
Recent evidence has shown that adipose tissue is an active participant in maintaining energy and glucose homeostasis and plays crucial roles in controlling neuroendocrine, autonomic, and immune functions. Leptin is a hormone secreted by adipose tissue. Deficiency of leptin or its receptor results in hyperphagia, morbid obesity, insulin resistance, hyperlipidemia, hypothalamic hypogonadism, and immunosuppression. These abnormalities are reversed by leptin treatment in patients with congenital leptin deficiency or lipodystrophy. In contrast, diet-induced obesity is associated with elevated leptin levels and blunted response to leptin. Leptin resistance has been ascribed to the reduced entry of leptin into the brain or impairment of leptin signal transduction. This chapter focuses on the current understanding of leptin’s actions, with particular emphasis on transport across the blood-brain barrier, signaling via JAK-STAT and PI3-kinase, neuropeptide targets, and electrophysiological effects.
I - Adipose Tissue: Structure and Function | Pp. 35-46
Aimin Xu; Yu Wang; Karen S. L. Lam
Adiponectin is a glycosylated adipokine selectively secreted from adipocytes. The native adiponectin forms several oligomeric complexes, including trimer, hexamer, and high-molecular-weight (HMW) 12–18 multimers. In the past 5 yr, numerous clinical studies have demonstrated a close association between low plasma levels of adiponectin (hypoadiponectinemia) with obesity-related diseases, including dyslipidemia, atherosclerotic cardiovascular diseases, type II diabetes, hypertension, fatty liver, and certain types of cancers. Mounting experimental evidence shows that adiponectin is an endogenous insulin sensitizer with potent antidiabetic, anti-atherogenic, and anti-inflammatory properties. It also has profound protective actions against hepatic and cardiac injury. Different oligomeric forms of adiponectin might act on different tissue targets and stimulate distinct cellular pathways. Two putative adiponectin receptors (adipoR1 and adipoR2) have recently been cloned. In vitro studies indicate that adipoR1 and adipoR2 mediate the metabolic actions of adiponectin via activation of AMP-activated protein kinase. Although the pathophysiological relevance of adiponectin and its receptors need to be further investigated, this adipokine may represent a novel target for the prevention and treatment of obesity-related pathologies.
I - Adipose Tissue: Structure and Function | Pp. 47-59
Vasoactive Factors and Inflammatory Mediators Produced in Adipose Tissue
In the search for mechanisms of obesity-mediated vascular pathology, attention has been focused on the role played by adipose tissue, a multifunctional organ involved not only in fat storage but also in the production of numerous hormones, growth factors, and cytokines with pleiotropic features. In the last decade the list of adipose-derived factors shown to be implicated either directly or indirectly in the regulation of vascular homeostasis through effects on blood pressure, inflammation, atherogenesis, coagulation, fibrinolysis, angiogenesis, proliferation, apoptosis, and immunity has increased at a phenomenal pace. By definition, adipocytokines are cytokines produced by adipocytes. Although adipose tissue secretes a wide variety of factors, strictly speaking, not all of them can be contemplated as cytokines. Interleukin-6, tumor necrosis factor-α, leptin, adipsin, resistin, adiponectin, and visfatin fall within the category that satisfies the stricter requirements to be properly classified as adipocytokines. However, the less strict term of adipokines has been coined to include a wider range of factors such as PAI-1, C-reactive protein, monocyte chemoattractant protein-1, serum amyloid A, and vascular endothelial growth factor, among others. Adipokines are known to contribute to the low-grade inflammation state observed in obese patients at the same time as participating in the development of obesity-related comorbidities, such as insulin resistance, metabolic syndrome, and atherogenesis. The molecular mechanisms linking the adiposity-inflammation-immunity cluster are complex. The triad of obesity-insulin resistance-cardiovascular disease is interwoven in a setting of inflammation, endothelial dysfunction and atherosclerosis in which adipokines act as markers of the acute phase reaction at the same time as being directly involved as causative factors in an extensive crosstalk between adipocytes and elements of the stroma vascular fraction. The current knowledge in this field is reviewed with a broad perspective approach.
II - Adipokines as Regulators of Immunity and Inflammation | Pp. 63-77
Regulation of the Immune Response by Leptin
Víctor Sánchez-Margalet; Patricia Fernández-Riejos; Carmen González-Yanes; Souad Najib; Consuelo Martín-Romero; José Santos-Alvarez
Adipose tissue is no longer considered as a mere energy store, but an important endocrine organ that produces many signals in a tightly regulated manner. Leptin is one of the most important hormones secreted by the adipocyte, with a variety of physiological roles related with the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. Leptin’s modulation of the immune system is exerted at the development, proliferation, anti-apoptotic, maturation, and activation levels. The role of leptin in regulating the immune response has been assessed in vitro as well as in clinical studies. Both the innate and adaptive immune responses are regulated by leptin. Every cell type involved in immunity can be modulated by leptin. In fact, leptin receptors have been found in neutrophils, monocytes, and lymphocytes, and the leptin receptor belongs to the family of class I cytokine receptors. Moreover, leptin activates similar signaling pathways to those engaged by other members of the family. The overall leptin action in the immune system is a proinflammatory effect, activating proinflammatory cells, promoting T-helper 1 responses, and mediating the production of other proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-2, or IL-6. Leptin receptor is also upregulated by proinflammatory signals. Thus, leptin is a mediator of the inflammatory response, and could have also a permissive role in the development of autoimmune diseases.
II - Adipokines as Regulators of Immunity and Inflammation | Pp. 79-90
Leptin in Autoimmune Diseases
Over the last few years, a series of molecules known to play a function in metabolism have also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response both in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of pro-inflammatory pathogenic cytokines. In this context, leptin could represent the “missing link” between immune response, metabolic function, and nutritional status. Strategies aimed at interfering with the leptin axis could represent innovative therapeutic tools for infections and autoimmune disorders. This chapter reviews the most recent advances in the role of leptin in autoimmune responses.
II - Adipokines as Regulators of Immunity and Inflammation | Pp. 91-100
Leptin and Gastrointestinal Inflammation
Arvind Batra; Britta Siegmund
Leptin is a 16-kDa protein, predominantly produced by adipose tissue with serum leptin concentrations correlating to body fat mass. Initially described as a regulator of appetite, it is now well established that this mediator exerts pro-inflammatory effects on various immune as well as nonimmune cells. In vitro as well as in vivo studies suggest an involvement of leptin in the regulation of intestinal inflammation. The data leading to this finding are the subject of discussion in this chapter. In particular, the various effects of leptin on different cell populations that are involved in the induction and persistence of intestinal inflammation, i.e., T-cells, antigen presenting cells, and epithelial cells, are outlined in detail. In addition, we propose a significant role for the potential interaction of the adipose tissue and the mucosal immune system in the pathophysiology of inflammatory bowel disease.
II - Adipokines as Regulators of Immunity and Inflammation | Pp. 101-110
Adiponectin and Inflammation
Adipose tissue has been recognized as the organ not only storing excess energy but also secreting a variety of bioactive substances named adipocytokines. Adipocytokines include tumor necrosis factor-α and interleukin-6, which are secreted from adipose tissue and may induce inflammatory response in various tissues including vascular walls and muscles. We found a novel adipocytokine named adiponectin, which has a strong ability of anti-inflammation. Adiponectin inhibits several inflammatory responses in macrophages and endothelial cells. This chapter presents a variety of anti-inflammatory functions and also discusses the mechanism of antidiabetic, anti-atherogenic, and anti-oncogenic properties of adiponectin.
II - Adipokines as Regulators of Immunity and Inflammation | Pp. 111-117
Macrophages, Adipocytes, and Obesity
Anthony W. Ferrante
Obesity induces an inflammatory response, which is implicated in the pathogenesis of obesity-associated complications. Adipose tissue is an important, perhaps an initiating, site in the development of obesity-induced inflammation. Macrophages are present in adipose tissue and their number and activation status correlate with measures of adiposity. Production of pro-inflammatory molecules and activation of intracellular pathways that regulate inflammatory responses in adipose tissue macrophages implicate these cells in development of obesity-induced complications, including insulin resistance.
More clearly elucidating the physiology of macrophages associated with adipose tissue and their contribution to obesity-induced inflammation will provide important insights into the physiology of adipose tissue and the pathophysiology of obesity and its complications. A detailed characterization of obesity-induced alterations in monocytes and macropahges will likely identify new therapeutic strategies to combat obesity-induced complications, such as atherosclerosis, non-alcoholic fatty liver disease and diabetes.
III - Interactions Between Adipocytes and Immune Cells | Pp. 121-131