Introduction to Adipose Tissue

Adipose tissue is not merely an organ designed to passively store excess carbon in the form of fatty acids esterified to glycerol (triglycerides). Mature adipocytes synthesize and secrete numerous enzymes, growth factors, cytokines, and hormones that are involved in overall energy homeostasis. Many of the factors that influence adipogenesis are also involved in diverse processes in the body including lipid homeostasis and modulation of inflammatory responses. In addition, a number of proteins secreted by adipocytes play important roles in these same processes. In fact, recent evidence has demonstrated that many factors secreted from adipocytes are pro-inflammatory mediators and these proteins have been termed adipocytokines or adipokines. There are currently over 50 different adipokines recognized as being secreted from adipose tissue. These adipokines are implicated in the modulation of a range of physiological responses that globally includes appetite control and energy balance. Specific metabolic processes regulated by adipose tissue include lipid metabolism, glucose homeostasis, inflammation, angiogenesis, hemostasis, and blood pressure.

White Adipose Tissue

The major form of adipose tissue in mammals (commonly referred to as “fat”) is white adipose tissue (WAT). WAT is composed of adipocytes held together by a loose connective tissue that is highly vascularized and innervated (Figure 45-1). White adipocytes are rounded cells that contain a single large fat droplet that occupies over 90% of the cell volume. The mitochondria within white adipocytes are small and few in number. The mitochondria and nucleus of the white adipocyte is squeezed into the remaining cell volume. Molecular characteristics of white adipocytes include expression of leptin but no expression of uncoupling protein 1, UCP1 (designated UCP1⁻, leptin⁺ adipocytes).

In addition to adipocytes, WAT contains macrophages, leukocytes, fibroblasts, adipocyte progenitor cells, and endothelial cells. The presence of the fibroblasts, macrophages, and other leukocytes along with adipocytes accounts for the vast array of proteins that are secreted from WAT under varying conditions. The highest accumulations of WAT are found in the subcutaneous regions of the body and surrounding the viscera.

Depending on its location, WAT serves specialized functions. The WAT associated with abdominal and thoracic organs (excluding the heart), the so-called visceral fat, secretes several inflammatory cytokines and is thus involved in local and systemic inflammatory processes. WAT associated with skeletal muscle secretes free fatty acids, interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) and as a consequence plays a significant role in the development of insulin resistance. Cardiac tissue associated WAT secretes numerous cytokines resulting in local inflammatory events and chemotaxis that can result in the development of atherosclerosis and systolic hypertension. Kidney associated WAT plays a role in sodium reabsorption and therefore can affect intravascular volume and hypertension.

Brown Adipose Tissue

Specialized adipose tissue that is primarily tasked with thermogenesis, especially in the neonate, is brown adipose tissue (BAT). BAT is so called because it is darkly pigmented due to the high density of mitochondria rich in cytochromes (see Figure 45-1). BAT specializes in the production of heat (adaptive thermogenesis) and lipid oxidation. Brown adipocytes are smaller in overall size compared to white adipocytes. Brown adipocytes are polygonal in shape and contain numerous large mitochondria packed with cristae. Whereas white adipocytes contain a single large fat droplet, brown adipocytes contain several small lipid droplets. Brown adipocytes are molecularly UCP1⁺ and leptin⁻ (UCP1⁺, leptin⁻ adipocytes). BAT is primarily visceral with highest concentrations around the aorta. BAT is highly vascularized and contains a very high density of noradrenergic nerve fibers.

Regulation of Adipogenesis

The process of adipocyte differentiation from a precursor preadipocyte to a fully mature adipocyte follows a precisely ordered and temporally regulated series of events. Adipocyte precursor cells emerge from mesenchymal stem cells (MSCs) that are themselves derived from the mesodermal layer of the embryo. The pluripotent MSCs receive extracellular cues that lead to the commitment to the preadipocyte lineage. Preadipocytes cannot be morphologically distinguished from their precursor MSCs but they have lost the ability to differentiate into other cell types.

The initial step in adipocyte differentiation is referred to as determination and leads to proliferating preadipocytes undergoing a growth arrest. This initial growth arrest occurs coincident with the expression of 2 key transcription factors, CCAAT/enhancer binding protein-α (C/EBPα) and peroxisome proliferator-activated receptor-γ (PPARγ). Following the induction of these 2 critical transcription factors there is a permanent period of growth arrest followed by expression of the fully differentiated adipocyte phenotype. This latter phase of adipogenesis is referred to as terminal differentiation. In the process of adipocyte differentiation PPARγ activates nearly all of the genes required. Although PPARγ and C/EBPα are the most important factors regulating adipogenesis, additional transcription factors influence the events of differentiation. Additional genes regulated by PPARγ in adipocytes are involved in lipid metabolism and/or glucose homeostasis.

Adipose Tissue Hormones and Cytokines

Adipose tissue produces and releases a vast array of protein signals including growth factors, cytokines, chemokines, acute phase proteins, complement-like factors, and adhesion molecules (Tables 45-1 and 45-2). In addition to secreted factors, adipose tissue produces several plasma membrane and nuclear receptors that can trigger changes in adipose tissue function. These include receptors for insulin, glucagon, growth hormone, adiponectin, and angiotensin II. Nuclear receptors include those for PPARγ, estrogens, androgens, vitamin D, thyroid hormone, progesterone, and glucocorticoids.

Leptin

Leptin is 16-kDa peptide whose central function is the regulation of overall body weight by limiting food intake and increasing energy expenditure. However, leptin is also involved in the regulation of the neuroendocrine axis, inflammatory responses, blood pressure, and bone mass. The human leptin gene is the homolog of the mouse “obese” gene (symbol OB) that was originally identified in mice harboring a mutation resulting in a severely obese phenotype. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice are obese and exhibit numerous disruptions in energy, hormonal, and immune system balance.

Leptin activates the anorexigenic axis in the arcuate nucleus (ARC) of the hypothalamus by increasing the activity of hypothalamic proopiomelanocortin (POMC) neurons and by reducing their inhibition by NPY neurons. Although it would be expected that the rising leptin levels in obesity would trigger increased anorexigenic responses in the hypothalamus, this is not the case. Elevated serum leptin results in impaired transport of leptin across the blood-brain barrier, referred to as leptin resistance.

Leptin functions by binding to its receptor which is a member of the cytokine receptor family. The leptin receptor mRNA is alternatively spliced resulting in 6 different products. The leptin receptors are named Ob-R, OB-Rb, OB-Rc, Ob-Rd, Ob-Re, and Ob-Rf. The OB-Rb mRNA encodes the long form of the leptin receptor (also called LEPR-B) and is expressed primarily in the hypothalamus but is also expressed in cells of the innate and adaptive immune systems as well as in macrophages. Activation of the receptor leads to increased PI3K and AMPK activity via activation of the Jak/STAT signaling pathway (Figure 45-2). One effect of the activation of the Jak/STAT pathway is activation of suppressor of cytokine signaling 3 (SOCS3), which then inhibits leptin signaling in a negative feedback loop. Leptin binding its receptor also results in the activation of mTOR both in the hypothalamus and in peripheral tissues. The role of leptin in the activation of mTOR function is an important factor in the ability of leptin to activate macrophages. Given that leptin levels rise in the serum of obese individuals and that leptin interaction with macrophages leads to increased macrophage inflammatory processes, it is not surprising that there is a direct correlation between leptin levels and the development of atherosclerosis.

In addition to effects on appetite exerted via central nervous system functions, leptin also exerts effects on inflammatory processes. Leptin modulates peripheral T-cell function, reduces thymocyte apoptosis, and increases thymic cellularity. These actions correlate well with observations of reduced immunologic defense when leptin levels are low. However, too much leptin is not beneficial as high concentrations can result in an abnormally strong immune response which predisposes an individual to autoimmune phenomena.

Adiponectin

Adiponectin was independently isolated by 4 different laboratories leading to different names. However, adiponectin is considered the standard name for this adipose tissue-specific protein. Other names include adipocyte complement–related protein of 30 kDa (ACRP30) because of its homology to complement factor 1q (C1q), adipoQ, gelatin-binding protein of 28 kDa (BGP28), and adipocyte most abundant gene transcript 1 (apM1). The major biological actions of adiponectin are increases in insulin sensitivity and fatty acid oxidation.

Adiponectin contains a C-terminal globular domain which harbors the homology to C1q and an N-terminal collagen-like domain. The globular domain allows for a homotrimeric association of the protein. The association of the subunits is such that 2 trimeric globular domains interact with a single stalk of collagen domains formed from 2 trimers. Within the circulation, adiponectin exists in both a full-length form as well as a globular form that is the result of proteolytic cleavage of the full-length protein. The hormone forms complex structures such that it can be found as a trimer, hexamer, and as the high-molecular-weight oligomer. In addition to the complex structure, adiponectin is glycosylated, a modification that is essential to its activity.

Adiponectin activity is inhibited by adrenergic stimulation and glucocorticoids. Expression and release of adiponectin is stimulated by insulin and inhibited by TNF-α. Conversely, adiponectin exerts inflammatory modulation by reducing the production and activity of TNF-α and IL-6. Adiponectin levels are reduced in obese individuals and increased in patients with anorexia nervosa. In patients with Type 2 diabetes (T2D), levels of adiponectin are significantly reduced.

Adiponectin functions by interaction with specific cell-surface receptors and at least 2 receptors have been identified. AdipoR1 is expressed at highest levels in skeletal muscle and AdipoR2 in primarily expressed in the liver. Expression of adiponectin receptors is also seen in various regions of the brain. AdipoR1 is highly expressed in the medial prefrontal cortex, hippocampus, and the amygdala. AdipoR2 expression in the brain is restricted to the hippocampus and specific hypothalamic nuclei. AdipoR1 is a high-affinity receptor for globular adiponectin and has low affinity for the full-length adiponectin. In contrast, AdipoR2 has intermediate affinity for globular and full-length adiponectin. Activation of adiponectin receptors results in the phosphorylation and activation of AMPK. The adiponectin-mediated activation of AMPK results in increased glucose uptake, increased fatty acid oxidation, increased phosphorylation, and inhibition of acetyl-CoA carboxylase (ACC) in muscle. In the liver, the result is reduced glucose output as a consequence or reduced activity of gluconeogenic enzymes.

Adiponectin also plays an important role in hemostasis and inflammation by suppressing TNF-α–and IL-6–mediated inflammatory changes in endothelial cell responses and inhibiting vascular smooth muscle cell proliferation. Activation of AMPK activity in endothelial cells results in increased fatty acid oxidation and activation of endothelial NO synthase (eNOS).

Inflammatory Functions of Adipose Tissue

The significance of inflammatory responses elicited via secretion of adipose tissue–derived (WAT) cytokines relates to the fact that their production and secretion is increased in obese individuals. There is a direct link between the changes in adipose tissue function in obesity and the development of T2D and the metabolic syndrome. One key change in adipose tissue during obesity is an increase in the percentage of macrophages resident within the tissue. Macrophages are a primary source of pro-inflammatory cytokines secreted by adipose tissue.

As the level of macrophages increases in adipose tissue the level of pro-inflammatory cytokine secretion by the tissue increases. Circulating levels of both TNF-α and IL-6 increase as adipose tissue expands in obesity and these changes are directly correlated with insulin resistance and the development of T2D. Adiponectin normally exerts an important anti-inflammatory role; however, as the level of macrophage infiltration increases in obesity there is suppression of adiponectin production and secretion.

Adipose tissue-derived IL-6 accounts for approximately 30% of the circulating level of this pro-inflammatory cytokine. Visceral WAT secretes a higher percentage of the circulating IL-6 than subcutaneous WAT and this fact correlates with the negative effects of a pro-inflammatory status on the organs in obesity. As WAT density increases there is an associated increase in IL-6 secretion, which is correlated to an increase in the circulating levels of acute-phase proteins such as CRP.

In addition to the negative effects of TNF-α on adiponectin, production of the cytokine also directly decreases insulin sensitivity by inhibiting insulin receptor signaling. TNF-α also decreases endothelial nitric oxide synthase (eNOS), resulting in decreased levels of NO as well as decreased expression of mitochondrial oxidative phosphorylation genes. This leads to increased oxidative stress, accumulation of reactive oxygen species (ROS), and increased endoplasmic reticulum stress.

Lymph tissue is surrounded by pericapsular adipose tissue which increases in density with increasing obesity. This close association allows for 2-way paracrine interactions between the lymph and adipose tissues. One important interaction between lymph tissue and WAT involves leptin. Pro-inflammatory cytokine production and release from T cells is increased as a result of leptin action. Leptin effects on the vascular endothelium are also pro-inflammatory. Expression of adhesion molecules is increased by leptin binding its receptor on endothelial cells. This results in an increased ability of neutrophils and other leukocytes to adhere to the endothelium leading to increased local intravascular inflammatory processes.

Metabolic Functions of Brown Adipose Tissue

Although significant in density in newborns, adults do retain some metabolically active BAT deposits that respond to cold and sympathetic nervous system activation. Within BAT, norepinephrine interacts with all types of adrenergic receptors (α₁, α₂, and β), each of which activates distinct signaling pathways in the brown adipocyte.

Signal transduction events triggered by adrenergic stimulation of BAT result in the activation of adenylate cyclase resulting in increased cAMP production and activation of PKA. PKA phosphorylates and activates HSL leading to increased release of fatty acids. The fatty acids are taken up by the mitochondria; however, in BAT they interact with and activate the proton gradient uncoupling activity of uncoupling protein 1 (UCP1, also known as thermogenin). Uncoupling the proton gradient releases the energy of that gradient as heat. In addition to stimulating heat production in BAT, norepinephrine promotes the proliferation of brown preadipocytes, promotes the differentiation of mature brown adipocytes, inhibits apoptosis of brown adipocytes, and regulates the expression of the UCP1 gene (Figure 45-3).

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