Adipose Tissue as an Endocrine Organ

C H A P T E R

14 Adipose Tissue as an Endocrine Organ Nicolas Musi* and Rodolfo Guardado-Mendoza† *Barshop Institute for Longevity and Aging Studies and Geriatric Research, San Antonio, TX, USA, † University of Guanajuato, Leo´n, Mexico

ADIPOSE TISSUE BIOLOGY AND FUNCTION For many years, it was considered that the only function of the adipose tissue was to store energy in the form of fat. However, evidence accumulated over the last two decades has demonstrated that adipose tissue plays other important roles.1 Adipose tissue works as an endocrine organ capable of synthesizing and secreting a large number of substances that regulate energy balance and metabolic homeostasis. In addition to fat cells, adipose tissue also contains a stroma vascular fraction that includes blood cells, endothelial cells, pericytes and adipose precursor cells.2,3 In order for an adipocyte to become a mature cell capable of carrying out its metabolic functions it has to undergo adipogenesis, a highly regulated process involving the coordinated activation of numerous transcription factors (Table 14.1).4 The morphological and functional changes that occur during adipogenesis correspond to a shift in transcription factor expression and activity leading the formation of a mature cell phenotype from an early multipotent state.1

Cellular Endocrinology in Health and Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-408134-5.00014-7

When increased storage requirements are needed, immature cells differentiate into mature adipocytes, facilitating the hyperplasic expansion of adipose tissue. Also, mature adipocytes can expand in size to store more lipids and even become hypertrophic under conditions of overnutrition. The adipose tissue is highly adaptable and is able to modify adipocyte number and morphology in response to alterations in energy balance through changes in free fatty acid (FFA) uptake, esterification, and lipolysis.5,6 In humans, adipose tissue is broadly classified into 2 types, white and brown; some propose that there is a third type, named beige adipose tissue (Figure 14.1).3 White adipose tissue (WAT) is much more abundant than brown adipose tissue (BAT). WAT has extensive distribution in the body, including most of the subcutaneous region, abdominal cavity, mediastinum, and areas between muscle groups. Due to its ability to accumulate and provide energy when needed, WAT is the most important buffering system for lipid energy balance in the body.7 While BAT can also store lipids, it plays an important role for

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Copyright © 2014 Elsevier Inc. All rights reserved.

230 TABLE 14.1 Adipogenesis

14. ADIPOSE TISSUE AS AN ENDOCRINE ORGAN

Transcriptional Regulators of

Negative Regulators

Positive Regulators

Zfp521

EBF1

KLF 2 and 7

Zfp423

PREF-1

AP-1

Wnt 10b

KLF 4 and 6

Wnt 5a

C/EBPs β and δ KLFs 5 and 15 PPARγ C/EBPα STAT 5A SREBP-1

FIGURE 14.1

Types of adipose tissue. Adipose tissue can be functionally classified as white (WAT) and brown (BAT). WAT is largely responsible for the synthesis and storage of triglycerides. WAT also secretes numerous adipokines, such as leptin and adiponectin. BAT is responsible for heat production and energy expenditure due to its high content of uncoupling protein 1(UCP1).

body temperature maintenance. Therefore, BAT is more abundant in infants who are more susceptible to hypothermia, and its mass diminishes as age advances.8 A key function of BAT is heat production secondary to its high content of uncoupling protein 1 (UCP1).9 UCPs are mitochondrial proteins that dissipate the proton gradient before it is used to provide energy for oxidative phosphorylation, generating heat. BAT derives its color from the extensive vascularization and the presence of many densely packed mitochondria. The physiologic

relevance of BAT is underscored by experiments in which transplantation of a small amount of BAT from a lean mouse to a highfat fed mouse causes significant weight loss and improves glucose tolerance.10 It has been assumed for several years that adult humans have a negligible amount of BAT. However, with the advent of new imaging technologies (positron emission tomography (PET) scanning) that can identify BAT in humans in vivo, it is becoming apparent that adult humans have substantial depots of BAT, particularly in the anterior neck and thoracic areas.8 Although the total amount of BAT is much smaller than WAT, its very high metabolic rate and capacity to consume enormous amounts of energy suggests that BAT has important physiologic implications. The origin of beige adipose tissue is less clear compared with WAT and BAT. Initially it was thought that beige adipocytes arise from unique precursor cells,3 although recent evidence suggests that these cells also can arise from white adipocytes through transdifferentiation.2 The function of beige adipose tissue is not well known; it is possible that it has some of the properties of brown adipose tissue, including the ability to dissipate energy.3 In addition to the functional classification (WAT vs. BAT) discussed above, adipose tissue is classified according to its physical location in the body into subcutaneous and visceral. Visceral fat, also known as intraabdominal fat, surrounds the viscera in the abdominal cavity. This physical classification also has important functional implications. For example, visceral fat produces a large amount of pro-inflammatory proteins such as interleukin (IL)-6, tumor necrosis factor (TNF) α and plasminogen activator inhibitor 1 (PAI-1), and harbors a larger amount of inflammatory cells (i.e., monocytes/macrophages) than subcutaneous fat. In contrast, subcutaneous fat produces more adiponectin and leptin, adipokines that play important roles in the regulation of

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ADIPOKINE SECRETION AND INTERACTION WITH OTHER TISSUES

glucose and lipid metabolism, energy balance, and appetite. The discovery of leptin in 1994 was the initial demonstration that the adipose tissue functions as an endocrine organ that synthesizes and secretes proteins that affect other tissues/ organs. Many of the proteins secreted by adipose tissue are synthesized by the adipocyte per se, which composes approximately 80% of adipose tissue. Yet, other cell types present within adipose tissue, including pericytes, endothelial cells, monocytes, macrophages, preadipocytes, and stem cells, can also produce and secrete proteins. The humoral products of adipose tissue are involved in various processes such as inflammation, lipid metabolism, energy balance, vascular tone, glucose homeostasis, insulin sensitivity, and atherosclerosis. The expression of different receptors and the production of a variety of substances allow the adipose tissue to cross-talk with other tissues and regulate systemic energy balance and metabolism.11

ADIPOKINE SECRETION AND INTERACTION WITH OTHER TISSUES The list of newly discovered adipocytederived factors is rapidly growing.12,13 Below, some of the better characterized proteins secreted by fat are discussed (Table 14.2).

Leptin This adipokine is a small peptide (16 kDa) that belongs to the IL-6 family of cytokines and is encoded by the ob gene. Plasma leptin concentration directly correlates with the amount of adipose tissue present in the body. Leptin is an anorexigenic peptide that interacts with its receptor in the central nervous system to regulate food intake and energy expenditure.14 The leptin receptor also is expressed in

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hematopoietic and immune cells where it has immunomodulating properties. Plasma leptin is increased by glucocorticoids, acute infection and proinflammatory cytokines, and it is reduced by cold exposure, adrenergic stimulation, growth hormone, thyroid hormone, melatonin, smoking and thiazolidinediones.

Adiponectin This adipokine circulates in three isoforms: a trimer of low molecular weight, a hexamer of medium molecular weight, and a multimeric of high molecular weight. Two adiponectin receptors have been identified, AdipoR1 and AdipoR2; skeletal muscle contain both type of receptors whereas liver primarily expresses AdipoR2. Adiponectin improves insulin sensitivity and stimulates fatty acid oxidation in skeletal muscle, liver, and adipose tissue. The cellular effects of adiponectin are mediated, in part, through the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). In addition to its effect on the liver and muscle, adiponectin regulates energy expenditure through activation of AMPK in the hypothalamus, where AdipoR1 and AdipoR2 co-localize with the leptin receptor.15,16

TNFα TNFα is a 26 kDa transmembrane protein that undergoes cleavage by a metalloproteinase to be released into the circulation as a 17-kDa soluble protein. Although adipocytes produce some TNFα, it is thought that macrophages from the stromal vascular fraction are the primary source of adipose-derived TNFα. TNFα impairs insulin signaling in liver, adipose tissue and skeletal muscle17 by activation of serine kinases such as the c-Jun-N-terminal kinase (JNK) and inhibitor of NF-kB kinase (IKK), which serine phosphorylate insulin receptor substrate 1 (IRS1).18 In hepatocytes

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232 TABLE 14.2

14. ADIPOSE TISSUE AS AN ENDOCRINE ORGAN

Proteins Secreted by Adipose Tissue

Molecule

Cellular Communication Mechanism

Leptin Adiponectin

Tumor necrosis factor α

Target Tissue/Organ

Biological Effect

Endocrine

Hypothalamus/central nervous system

Food intake and energy expenditure regulation

Endocrine

Hypothalamus

Energy expenditure

Paracrine

Skeletal muscle

Glucose uptake/insulin action

Adipose tissue

Fatty acid oxidation

Endocrine

Liver

Reduces insulin signaling and fatty acid oxidation

Paracrine

Skeletal muscle Adipose tissue

Interleukin-6

Plasminogen activator inhibitor 1 (PAI-1)

Endocrine

Liver

Reduces insulin signaling

Paracrine

Skeletal muscle

Increases fatty acid oxidation and glucose uptake

Islet of Langerhans

A-cell proliferation and survival

Vascular/endothelial cells

Fibrinolysis

Endocrine

Liver

Decreases insulin signaling

Paracrine

Adipose tissue

Autocrine Paracrine Endocrine

Resistin

Skeletal muscle Visfatin

Endocrine

Liver

Increases production of TNFα and IL-6

Paracrine

Adipose tissue

Insulinomimetic?

Skeletal muscle Angiotensin

Endocrine

Vascular cells

Blood pressure regulation

Paracrine

Adipocytes

Adipocytogenesis

and muscle, TNFα also can inhibit AMPK, consequently reducing fatty acid oxidation.19,20

Interleukin-6 In humans, approximately 30% of circulating IL-6 originates from adipose tissue. Whether IL-6

is beneficial or detrimental to glucose metabolism is controversial. Data from some studies indicate that IL-6 impairs insulin action, whereas other studies have shown that IL-6 stimulates fatty acid oxidation and glucose uptake in skeletal muscle.21,22 There is also evidence indicating that IL-6 increases pancreatic

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α cell proliferation and survival with a consequent increase in glucagon secretion.23

cytokine that activates leukocytes and stimulates production of TNFα and IL-6.27

Plasminogen Activator Inhibitor 1 (PAI-1)

Angiotensin

Endothelial and vascular smooth muscle cells are important sources of PAI-1, but other cells such as adipocytes, macrophages, monocytes, fibroblasts, mesangial cells, hepatocytes, and platelets also secrete PAI-1. The plasma level of PAI-1 directly correlates with adipose tissue mass. PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, fatty acids, TNFα, and transforming growth factorβ, while catecholamines reduce its production.24 PAI-1 functions as a serine protease inhibitor that lowers tissue plasminogen activator (tPA). tPA activates plasminogen to promote fibrinolysis. Consequently, increases in PAI-1 level enhance clotting and contributes to the remodeling of vascular architecture and atherosclerosis.

Resistin Resistin shares structural similarities with adiponectin. However, in contrast to adiponectin, resistin is associated with insulin resistance. Resistin inhibits insulin signaling and promotes insulin resistance by increasing hepatic gluconeogenesis. Pre-adipocytes express more resistin compared with mature adipocytes, suggesting a role in adipogenesis.25

Visfatin Visfatin is mainly produced by visceral tissue adipocytes, but macrophages and subcutaneous fat also secrete this adipokine to a lesser degree. Visfatin has a mimetic insulin effect and it is capable of lowering glucose levels.26 Visfatin also works as a pro-inflammatory

Adipose tissue expresses all of the components of the renin angiotensin system. Adipose tissue angiotensinogen mRNA and protein levels are regulated by nutrition, with decreased levels at fasting and increased levels after feeding. Angiotensin II stimulates prostacyclin synthesis, adipocyte differentiation, and lipogenesis. It is possible that adipocytederived components of this system play a role in the cardiovascular alterations of obesity and type 2 diabetes.

ADIPOSE TISSUE DYSFUNCTION DURING OBESITY An important biological property of adipose tissue is its capacity to rapidly respond to fluctuations in nutrient and energy supply through adipocyte hypertrophy and hyperplasia. In most obese subjects, the expansion/ remodeling of the adipose tissue is thought to be pathological because it leads to a metabolic phenotype that promotes metabolic alterations and cardiovascular disease. However, not all the adipose tissue expansion is necessarily pathological. For example, there is an obese phenotype that is “metabolically healthy;” these are obese individuals who have normal or near-normal insulin sensitivity and lipid metabolism. The molecular basis that underlies the difference between a pathological versus a non-pathological form of obesity is not known. An interesting observation regarding adipose tissue expansion is the role of macrophage infiltration. Macrophage infiltration into adipose tissue may occur through different mechanisms:28 1) macrophage infiltration in order to phagocytose dead adipocytes;

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14. ADIPOSE TISSUE AS AN ENDOCRINE ORGAN

2) chemokine-induced macrophage mobilization from bone marrow; 3) local hypoxia, which induces release of chemoattractant cyokines;29 and 4) FFA activation of toll-like receptor 4 (TLR4) that causes a local inflammatory state and macrophage infiltration/ activation.30,31 In obesity, multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines, decreases in protective factors (adiponectin), and cross-talk between inflammatory and metabolic cells (Figure 14.2). Upon stimulation, macrophages assume a classical pro-inflammatory activation state (M1) that generates a Th1 response. On the other hand, Th2 cytokines such as IL-4 and IL-3 generate an alternative macrophage activation state (M2) that attenuates the classical NF-kB-dependent pathway. Adipose tissue macrophages assume different states along the M1/M2 spectrum depending on fat depot location and nutritional status; adiposity results in a shift toward a pro-inflammatory signaling pathway where classically activated M1 cells predominate.32 34 This specific adipose tissue network and cross-talk indicates that maintaining metabolic homeostasis requires a balanced immune response and integrated signals of multiple cell types. Adipose tissue insulin resistance and dysfunctional lipid storage play a key role in the progression toward metabolic dysregulation in obesity. Visceral adipose tissue has a higher capacity to secrete pro-inflammatory cytokines and to become a hypertrophic cell prone to macrophage infiltration. With the prevalent inflammatory status, this causes endoplasmic reticulum (ER) stress, adipose tissue hypoxia and adipocyte death.29,35 Similar to the effects in adipose tissue, liver is also affected by this inflammatory response. The steatotic liver is characterized by an elevation of many of the signaling pathways involved in both inflammation and metabolism (JNK, TLR4, ER

stress). In the skeletal muscle of obese patients, there is activation of inflammatory signals through TLR4 and downstream pathways.36 During adipose tissue expansion, also there is activation of hypothalamic signaling pathways that induce food intake and nutrient storage.37,38 This effect may be mediated by saturated fatty acids, which activate neuronal JNK and NF-kB signaling pathways with direct effects on leptin and insulin signaling.39 In addition to the inflammatory state that occurs in insulin target tissues (muscle, liver, fat), during obesity also there is an increase in cytokine production and macrophage accumulation in the islets of Langerhans, which promote β cell dysfunction.40,41

ADIPOSE TISSUE AS A THERAPEUTIC TARGET AND FUTURE PERSPECTIVES Adipose tissue plays a key role in maintaining energy balance and metabolic homeostasis through its ability to store energy and to secrete a large number of substances (FFA, adipokines, etc.). Accordingly, adipose tissue is an attractive target for pharmacological treatment of obesity, diabetes, and other metabolic diseases. Examples of strategies that could be employed include: 1) regulation of transcriptional factors that control adipogenesis to promote the development of “healthy” adipocytes; 2) modification of the adipokine secretion profile to favor beneficial factors (adiponectin) and decrease release of potentially deleterious ones (TNFα, IL-1, resistin); 3) inhibition of intracellular pathways activated by adipokines (TNFα receptor, IKKβ/NF-kB, JNK); 4) increasing WAT lipolysis; 5) WAT transdifferentiation to BAT, which promotes energy expenditure; and 6) activation of BAT. Targeting the adipose tissue to treat metabolic diseases is a reality; for example, the

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FIGURE 14.2 Role of adipose tissue expansion on metabolic and cardiovascular disease. The interplay between genetic and environmental factors (sedentary lifestyle, high caloric intake) leads to obesity, characterized by adipocyte hyperplasia and hypertrophy. Obesity also is characterized by the development of a pro-inflammatory state in adipose tissue, leading to macrophage infiltration, hypoxia, and macrophage polarization (M1/M2). During obesity, there is also an increase in the production and secretion of pro-inflammatory cytokines that impair glucose homeostasis and promote cardiovascular disease, including TNFα, IL-1, IL-6, and resistin, whereas cytokines that improve glucose metabolism and promote cardiovascular health such as adiponectin are decreased. Aging also induces inflammation and promotes adiposity, further worsening cardiometabolic diseases.

antidiabetic agents thiazolidenediones (TZDs) promote differentiation of preadipocytes into white adipocytes and decrease the expression of TNFα, IL-1, and resistin while increasing adiponectin. Currently, major efforts are underway to develop novel strategies to prevent and treat metabolic diseases by targeting the adipose tissue and its products.42,43 Consequently, it is likely that in the near future new agents will be available for the management of obesity, type 2 diabetes, and associated cardiovascular diseases.

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