Junqueira_s Basic Histology, Text and Atlas, 14th Edition 2.pdf

C H A P T E R WHITE ADIPOSE TISSUE 6 Adipose Tissue 122 Function of Brown Adipocytes Histogenesis of Brown Adipose T...

C H A P T E R WHITE ADIPOSE TISSUE 6 Adipose Tissue 122 Function of Brown Adipocytes Histogenesis of Brown Adipose Tissue 127 127 Storage & Mobilization of Lipids 123 Histogenesis of White Adipose Tissue 125 SUMMARY OF KEY POINTS 127 BROWN ADIPOSE TISSUE 126 ASSESS YOUR KNOWLEDGE 128 C onnective tissue in which fat-storing cells or adipo- tissue, the more common type specialized for fat storage, cytes predominate is called adipose tissue. These consists of cells each containing one large cytoplasmic drop- large cells are typically found isolated or in small let of whitish-yellow fat. Brown adipose tissue contains cells groups within loose or dense irregular connective tissue but with multiple lipid droplets interspersed among abundant occur in large aggregates in adipose tissue or “fat” in many mitochondria, which helps give this tissue a darker appear- organs and body regions. Adipose tissue normally repre- ance. Brown adipocytes release heat and function to warm sents 15%-20% of the body weight in men, somewhat more the blood. Both types of adipose tissue have a rich blood sup- in women. Besides serving as storage depots for neutral fats, ply and the adipocytes, unlike other cells of connective tissue chiefly triglycerides (long-chain fatty acyl esters of glycerol), proper, are individually surrounded by a thin external lamina adipocytes function as key regulators of the body’s overall containing type IV collagen. energy metabolism. With a growing epidemic of obesity and its associated health problems, including diabetes and heart disease, adipocytes and adipose tissue now constitute a major area of medical research. › WHITE ADIPOSE TISSUE Specialized for relatively long-term energy storage, adipocytes Two properties of triglyceride lipids explain their selection of white adipose tissue are spherical when isolated but are poly- as the preferred form of nutrient storage. Insoluble in water, hedral when closely packed in situ. When completely devel- lipids can be concentrated with no adverse osmotic effects on oped, a white adipocyte is very large, between 50 and 150 μm in cells. Also, the caloric density of triglycerides (9.3 kcal/g) is diameter, and contains a single huge droplet of lipid %lling twice that of proteins or carbohydrates, including glycogen, almost the entire cell. With the single large droplets of triglycer- making these simple lipids the most efficient means of storing ides, white adipocytes are also called unilocular (Figure 6–1). calories. Adipocytes specialize in concentrating triglycerides Because lipid is removed from cells by xylene or other solvents as lipid droplet(s), with other cells normally accumulating used in routine histological techniques, unilocular adipocytes relatively little lipid. are often empty in standard light microscopy. The cells are Adipocytes are active cells metabolically, responding to sometimes said to have a signet-ring appearance, with the lipid both nervous and hormonal stimuli. They release hormones droplet displacing and flattening the nucleus against the cell and various other important substances and adipose tissue is membrane (Figure 6–1d). This membrane and the thin rim of now recognized as an endocrine organ at the center of nutri- cytoplasm that remains after dissolution of the stored lipid may tional homeostasis. With its unique physical properties, tissue shrink, collapse, or rupture, distorting cell and tissue structure. rich in fat conducts heat poorly and provides thermal insu- lation for the body. Adipose tissue also %lls spaces between other tissues, helping to keep some organs in place. Subcuta- › › MEDICAL APPLICATION neous layers of adipose tissue help shape the body surface, and Unilocular adipocytes can generate benign tumors called cushion regions subject to repeated mechanical stress such as lipomas that are relatively common, although malignant the palms, heels, and toe pads. adipose tumors (liposarcomas) occur infrequently. Fetal There are two major types of adipose tissue with different lipomas of brown fat are sometimes called hibernomas. locations, structures, colors, and functions. White adipose 122  White Adipose Tissue 123 FIGURE 6–1 White adipose tissue. C H A P T E R A 6 A Adipose Tissue White Adipose Tissue A a b L * * L * c d White or unilocular adipose tissue is commonly seen in sections of (c) Tissue was fixed here with osmium tetroxide, which preserves many human organs. lipid (L) and stains it black. Many adipocytes in this slide retain at (a) Large white adipocytes (A) are seen in the connective tis- least part of their large lipid droplets. (X440; Osmium tetroxide) sue associated with small blood vessels. The fat cells are empty (d) In this specimen from a young mammal the smaller adipocytes because lipid was dissolved away in slide preparation. Nuclei at the marked with asterisks are not unilocular, having many lipid drop- cell membranes are visible in some of the fat cells. (X100; H&E) lets of various sizes. Such cells in white fat represent those in which (b) Large (empty) adipocytes predominate in this typical white adi- differentiation is incomplete as well as a small subpopulation of pose tissue, which shows only a small portion of microvasculature. beige cells with brown fat-forming potential. The eccentric nuclei In a single histologic section, nuclei of most very large adipocytes of the unilocular cells are indicated by arrowheads. (X200; PT) are not included. (X100; H&E) Most cytoplasmic organelles in a white adipocyte are near The distribution of white adipose tissue changes signi%- the peripheral nucleus, including mitochondria, a small Golgi cantly through childhood and adult life and is partly regulated apparatus, a few cisternae of RER, and free polyribosomes. by sex hormones controlling adipose deposition in the breasts The thin, submembranous layer of cytoplasm surrounding the and thighs. The color of freshly dissected white adipose tissue lipid droplet contains cisternae of smooth ER (SER) and pino- depends on the diet, varying from white to yellow with the cytotic vesicles. TEM studies reveal that most adipocytes, espe- amount of carotenoids dissolved in the lipid. cially immature cells, contain minute lipid droplets in addition to the large droplet. The lipid droplet-cytoplasm interface is reinforced only by intermediate %laments of vimentin. Storage & Mobilization of Lipids As shown in Figure 6–1 white fat is subdivided into White adipocytes can store triglycerides derived from three incomplete lobules by partitions of connective tissue contain- sources: ing a vascular bed and nerve network. Fibroblasts, macro- phages, and other cells typically comprise about half the total ( Dietary fats brought to the cells via the circulation as cell number in white adipose tissue. Reticular %bers form a chylomicrons, %ne interwoven network that supports individual fat cells and ( Lipids synthesized in the liver and transported in blood binds them together, and the microvasculature between adi- with very-low-density lipoproteins (VLDLs), pocytes may not always be apparent in tissue sections. ( Free fatty acids and glycerol synthesized by the adipocytes. 124 CHAPTER 6 ( Adipose Tissue Chylomicrons (Gr. chylos, juice + micros, small) are par- adipocytes and accelerates its conversion into triglycerides, ticles of variable size, up to 1200 nm in diameter, formed and the production of lipoprotein lipase. from ingested lipids in epithelial cells lining the small intes- When adipocytes are stimulated by nerves or various hor- tine and transported in the blood and lymph. They consist of mones, stored lipids are mobilized and cells release fatty acids a core containing mainly triglycerides, surrounded by a sta- and glycerol. Norepinephrine released in the adrenal gland bilizing monolayer of phospholipids, cholesterol, and several and by postganglionic sympathetic nerves in adipose tissue acti- apolipoproteins. vates a hormone-sensitive lipase that breaks down triglycer- VLDLs are smaller complexes (30-80 nm, providing a ides at the surface of the stored lipid droplets (Figure 6–2). This greater surface-to-volume ratio), of similar lipid and protein lipase activity is also stimulated by growth hormone (GH) from composition to chylomicrons, but are synthesized from lipids the pituitary gland. The free fatty acids diffuse across the mem- in liver cells. Levels of circulating lipoproteins are routinely branes of the adipocyte and the capillary endothelium, and bind measured in clinical tests for blood lipids, after fasting to allow the protein albumin in blood for transport throughout the body. depletion of chylomicrons. Varying levels of apoproteins and The more water-soluble glycerol remains free in blood and is triglycerides in the complexes allow their categorization accord- taken up by the liver. Insulin inhibits the hormone-sensitive ing to density, from VLDL to high-density lipoprotein (HDL). lipase, reducing fatty acid release, and also stimulates enzymes In adipose tissue both chylomicrons and VLDLs are for lipid synthesis. Besides insulin and GH, other peptide hor- hydrolyzed at the luminal surfaces of blood capillaries by lipo- mones also cooperate in regulating lipid synthesis and mobiliza- protein lipase, an enzyme synthesized by the adipocytes and tion in adipocytes. transferred to the capillary cell membrane (Figure 6–2). Free Hormonal activity of white adipocytes themselves includes fatty acids then enter the adipocytes by both active transport production of the 16-kDa polypeptide hormone leptin and diffusion. Within the adipocytes, the fatty acids combine (Gr. leptos, thin), a “satiety factor” with target cells in the hypo- with glycerol phosphate, supplied by glucose metabolism, thalamus, other brain regions, and peripheral organs which to again form triglycerides, which are then deposited in the helps regulate the appetite under normal conditions and par- growing lipid droplet. Insulin stimulates glucose uptake by ticipates in regulating the formation of new adipose tissue. FIGURE 6–2 Lipid storage and mobilization from adipocytes. Nerve ending Adipocyte Capillary with norepinephrine Albumin transporting Free fatty free fatty acids acids Albumin Glycerol Hormone-sensitive Glucose lipase cAMP Nucleus Glycerol phosphate Chylo VLDL Triglyceride droplet Lipoprotein lipase (storage) Triglyceride Free fatty acids Triglycerides are transported by blood and lymph from the intes- Norepinephrine from nerve endings stimulates the cyclic AMP tine and liver in lipoprotein complexes known as chylomicrons (cAMP) system, which activates hormone-sensitive lipase to (Chylo) and VLDLs. In the capillary endothelial cells of adipose hydrolyze the stored triglycerides to free fatty acids and glycerol. tissue, these complexes are partly broken down by lipoprotein These substances diffuse into the capillary, where the fatty acids lipase, releasing free fatty acids and glycerol. The free fatty acids bind albumin for transport throughout the body for use as an diffuse from the capillary into the adipocyte, where they are energy source. reesterified to glycerol phosphate, forming triglycerides that are stored in the lipid droplet until needed.  White Adipose Tissue 125 › › MEDICAL APPLICATION FIGURE 6–3 Development of white and brown fat C H A P T E R cells. Leptin was discovered and is well studied in genetically obese mice, but such studies have not yet led to new treat- ments for human obesity. In most obese humans adipocytes produce adequate or excess quantities of leptin, but target Mesenchymal cell cells are not responsive due apparently to insufficient or defective receptors or post-receptor signal transduction. 6 Adipose Tissue White Adipose Tissue Although white adipose tissue associated with differ- ent organs appears histologically similar, differences in gene Fibroblast Preadipocytes expression have been noted between visceral deposits (in the abdomen) and subcutaneous deposits of white fat. Such dif- ferences may be important in the medical risks of obesity; it is well established that increased visceral adipose tissue raises the risk of diabetes and cardiovascular disease whereas increased subcutaneous fat does not. The release of visceral fat products directly to the portal circulation and liver may also influence the medical importance of this form of obesity. In response to body needs, lipids are mobilized rather uni- formly from white adipocytes in all parts of the body, although adipose tissue in the palms, soles, and fat pads behind the eyes Brown adipocytes Beige adipocytes White adipocytes resists even long periods of starvation. During starvation adi- pocytes can lose nearly all their fat and become polyhedral or Mesenchymal stem cells differentiate as progenitor cells for all spindle-shaped cells with only very small lipid droplets. types of connective tissue, including preadipocytes. These are initially of at least two types. Preadipocytes developing within Histogenesis of White Adipose Tissue the lateral mesoderm of the embryo produce large number of white adipocytes (forming white adipose tissue) and a smaller Like other connective tissue, skeletal and muscle cells, adipocytes number of so-called beige adipocytes with cytological features develop from mesenchymal stem cells. Adipose development and gene expression patterns of both white and brown adi- %rst produces preadipocytes, which look rather like larger pocytes. White adipocytes are unilocular, with one large lipid %broblasts with cytoplasmic lipid droplets (Figure 6–3). Initially droplet occupying most of the cytoplasm. The white adipocyte is usually much larger than that shown here in relation to the the droplets of white adipocytes are isolated from one another other cell types. but soon fuse to form the single large droplet (Figure 6–1). Brown adipocytes differentiate from another population As shown in Figure 6–3 white adipocytes develop together of preadipocytes located in paraxial embryonic mesoderm with a smaller population of cells termed beige adipocytes, and remain multilocular (having many small lipid droplets) which remain within white adipose tissue and have histo- with numerous mitochondria (not shown here). Mitochondrial metabolism of lipid in brown adipocytes releases heat rather logical and metabolic features generally intermediate between than ATP. Cells functioning as brown adipocytes can also develop white and brown adipocytes. With adaptation to cold temper- from beige adipocytes during adaptation to cold temperatures. atures beige adipocytes change reversibly, forming many more small lipid droplets, adopting a gene expression pro%le more like that of brown fat, and begin to release heat (see below). Humans are born with stores of white adipose tissue, which begin to accumulate by the 14th week of gestation. Both › › MEDICAL APPLICATION visceral and subcutaneous fat is well-developed before birth. In addition to leptin, white adipose tissue secretes numerous Proliferation of progenitor cells diminishes by late gestation, other cytokines and other factors with paracrine and auto- and adipose tissue increases mainly by the %lling of existing crine activity, including many proinflammatory cytokines. It is adipocytes until around age 10, followed by a period of new not clear whether these are produced by adipocytes or other fat cell differentiation which lasts through adolescence. New cells of the tissue such as macrophages or fibroblasts. With its adipocyte formation occurs around small blood vessels, where increased amounts of white adipose tissue, obesity is charac- undifferentiated mesenchymal cells are most abundant. terized by a state of chronic mild inflammation. Proinflamma- Excessive adipose tissue accumulation, or obesity, occurs tory factors released from visceral fat are being investigated when nutritional intake exceeds energy expenditure, an increas- for links to the inflammation-related disorders associated ingly common condition in modern, sedentary lifestyles. with obesity, such as diabetes and heart disease. Although adipocytes can differentiate from mesenchymal stem cells throughout life, adult-onset obesity mainly involves 126 CHAPTER 6 ( Adipose Tissue increasing the size of existing adipocytes (hypertrophy). Childhood obesity, in contrast, often involves increases in › BROWN ADIPOSE TISSUE both adipocyte size and numbers due to the differentiation of Brown adipose tissue constitutes 2%-5% of the newborn body more preadipocytes from mesenchymal cells (hyperplasia). weight, located mainly in the back, neck, and shoulders, but Weight loss after dietary changes is due to reductions in adipo- it is greatly reduced during childhood and adolescence. In cyte volume, but not their overall number. adults it is found only in scattered areas, especially around the kidneys, adrenal glands, aorta, and mediastinum. The color of brown fat is due to both the very abundant mitochondria › › MEDICAL APPLICATION (containing cytochrome pigment) scattered among the lipid Adult-onset obesity is very often associated with age- droplets of the fat cells and the large number of blood capillar- related metabolic changes and may involve reduced activity ies in this tissue. Brown adipocytes contain many small lipid of the hormone-sensitive lipases of adipocytes, causing inclusions and are therefore called multilocular (Figure 6–3). less effective fat mobilization out of the cells. The increased The small lipid droplets, abundant mitochondria, and rich number of adipocytes produced during childhood obesity vasculature all help mediate this tissue’s principal function of predisposes an individual to obesity in later life. Despite heat production and warming the blood. claims of various fad diets, there is no evidence that any Cells of brown fat are polygonal and generally smaller particular type of caloric restriction is more effective than than white adipocytes; their smaller lipid droplets allow the others; rather, any intake of calories that is lower than the nucleus to be more centrally located (Figure 6–4). Brown adi- energy expenditure will result in loss of adipose tissue. pocytes are often closely packed around large capillaries and the tissue is subdivided by connective tissue partitions into FIGURE 6–4 Brown adipose tissue. BV a b (a) Brown adipose tissue is shown here around a small blood ves- (b) A diagram of a single multilocular adipocyte showing the central sel (BV) and adjacent white adipose tissue at the top of the photo. nucleus, numerous small lipid droplets (yellow), and many mito- Brown adipocytes are slightly smaller and characteristically contain chondria. Also shown is a sympathetic nerve ending that releases many small lipid droplets and central spherical nuclei. If the lipid norepinephrine to stimulate mitochondrial production of heat. has been dissolved from the cells, as shown here, the many mito- chondria among the lipid spaces are retained and can be easily discerned. (X200; PT)  Brown Adipose Tissue 127 lobules that are better delineated than the lobules of white from the intermembranous space to the matrix without pass- adipose tissue. Cells of this tissue receive direct sympathetic ing through ATP synthetase complexes. Instead of producing C H A P T E R innervation, which regulates their metabolic activity. ATP, the energy associated with this proton flow dissipates as heat. Function of Brown Adipocytes The main function of these multilocular adipose cells is to Histogenesis of Brown Adipose Tissue produce heat by nonshivering thermogenesis. The physiol- Brown adipose tissue also develops from mesenchyme, but ogy of brown fat is best understood from studies of the tissue involves preadipocytes in a different embryonic location 6 in hibernating species. In animals ending their hibernation (paraxial) from those producing white adipose tissue. Brown Adipose Tissue Brown Adipose Tissue period, and in newborn humans, nerve impulses liberate nor- adipocytes also emerge earlier than white fat during fetal epinephrine into brown adipose tissue. As in white fat, this development. In humans the amount of brown fat is maximal neurotransmitter activates the hormone-sensitive lipase of relative to body weight at birth, when thermogenesis is most adipocytes, promoting hydrolysis of triglycerides to fatty acids needed and partially disappears by involution and apoptosis and glycerol. However, unlike the process in white fat, liber- during childhood. In adults the amount and activity of brown ated fatty acids of multilocular adipocytes are not released fat are higher in lean individuals. but are quickly metabolized, with a consequent increase in O2 The number of brown adipocytes increases during cold consumption and heat production. This raises the tempera- adaptation, usually appearing as clusters of multilocular cells ture within the tissue and warms the locally circulating blood, in white adipose tissue. As indicated earlier this increase which then distributes the heat throughout the body. involves the reversible shift of beige cells to functional brown Heat production in brown adipocytes is greater than that adipocytes, but may also include proliferation and differen- of other cells because their inner mitochondrial membranes tiation of new adipocytes from preexisting progenitor cells. have greatly upregulated levels of the transmembrane pro- Besides stimulating thermogenic activity, autonomic nerves tein uncoupling protein-1 (UCP1) or thermogenin. In the also promote brown adipocyte differentiation and prevent presence of free fatty acids, UCP1 permits the flow of protons apoptosis in mature brown fat cells. Adipose Tissue SUMMARY OF KEY POINTS ( The de%ning cells of adipose tissue (fat), adipocytes, are very large ( These cells each contain primarily one large lipid droplet (they are cells derived from mesenchyme and specialized for energy storage in unilocular), causing the nucleus and remaining cytoplasm to be lipid droplet(s) with triglycerides. pushed against the plasmalemma. ( Adipocytes store lipids from three sources: from dietary fats pack- ( Fatty acids are released from white adipocytes by lipase activity aged as chylomicrons in the intestine; from triglycerides pro- when nutrients are needed and carried throughout the body on duced in the liver and circulating as very-low-density lipoproteins plasma proteins such as albumin. (VLDLs); and from fatty acids synthesized locally. ( Leptin is a polypeptide hormone with target cells in the hypothala- ( Lipids are mobilized from adipocytes by hormone-sensitive lipase mus that is released from white adipocytes and helps regulate eating activated by norepinephrine released from the adrenal gland and behavior. various peptide hormones. ( Cells of adipose tissue are supported by reticular %bers, with con- Brown Adipose Tissue nective tissue septa dividing the tissue into lobules of various sizes. ( Brown fat comprises up to 5% of the newborn body weight but ( There are two types of adipose tissue: white fat and brown fat. smaller amounts in adults. ( Adipocytes of this tissue are typically smaller than those of white fat and contain primarily many small lipid droplets (they are multi- White Adipose Tissue locular) in cytoplasm containing many mitochondria and a central ( White adipose tissue is found in many organs throughout the body, nucleus. typically forming about 20% of the body weight in adults. ( Fatty acids released in adipocytes of brown fat are metabolized in ( Adipocytes of white fat are typically very large cells, ranging in mitochondria of these cells for thermogenesis rather than ATP syn- diameter from 50 to 150 μm. thesis, using uncoupling protein-1.