Chapter 6 Adipose Tissue PDF

 White Adipose Tissue 123 FIGURE 6–1 White adipose tissue....

 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 marked with asterisks are not unilocular, having many lipid drop- the 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 differentiation is incomplete as well as a small subpopulation of adipose tissue, which shows only a small portion of microvascula- beige cells with brown fat-forming potential. The eccentric nuclei ture. In a single histologic section, nuclei of most very large adipo- of the unilocular cells are indicated by arrowheads. (X200; PT) cytes are not included. (X100; H&E) Most cytoplasmic organelles in a white adipocyte are near The distribution of white adipose tissue changes signifi- 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. Transmission electron microscopy (TEM) amount of carotenoids dissolved in the lipid. reveals a great abundance of caveolae in the cell membranes of most adipocytes, especially immature cells, and numerous minute lipid droplets in addition to the large droplet. In this cell type, caveolae are important for lipid trafficking and for- Storage & Mobilization of Lipids mation of the large triglyceride storage droplet. White adipocytes can store triglycerides derived from three As shown in Figure 6–1, white fat is subdivided into sources: incomplete lobules by partitions of connective tissue contain- ing a vascular bed and a nerve network. Fibroblasts, macro- Dietary fats brought to the cells via the circulation as phages, and other cells typically comprise about half the total chylomicrons cell number in white adipose tissue. Reticular fibers form a Lipids synthesized in the liver and transported in blood fine interwoven network that supports individual fat cells and with very low-density lipoproteins (VLDLs) binds them together, and the microvasculature between adi- Free fatty acids and glycerol synthesized by the pocytes may not always be apparent in tissue sections. 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 tine and transported in the blood and lymph. They consist of hormones, stored lipids are mobilized and cells release fatty a core containing mainly triglycerides, surrounded by a sta- acids and glycerol. Norepinephrine released in the adrenal bilizing monolayer of phospholipids, cholesterol, and several gland and by postganglionic sympathetic nerves in adipose apolipoproteins. tissue activates a hormone-sensitive lipase that breaks VLDLs are smaller complexes (30-80 nm, providing a down triglycerides at the surface of the stored lipid droplets greater surface-to-volume ratio), of similar lipid and protein (Figure 6–2). This lipase activity is also stimulated by growth composition to chylomicrons, but are synthesized from lipids hormone (GH) from the pituitary gland. The free fatty acids in liver cells. Levels of circulating lipoproteins are routinely diffuse across the membranes of the adipocyte and the cap- measured in clinical tests for blood lipids, after fasting to illary endothelium, and bind the protein albumin in blood allow depletion of chylomicrons. Varying levels of apoproteins for transport throughout the body. The more water-soluble and triglycerides in the complexes allow their categorization glycerol remains free in blood and is taken up by the liver. according to density, from VLDL to high-density lipoprotein Insulin inhibits the hormone-sensitive lipase, reducing fatty (HDL). acid release, and also stimulates enzymes for lipid synthesis. In adipose tissue both chylomicrons and VLDLs are Besides insulin and GH, other peptide hormones also cooper- hydrolyzed at the luminal surfaces of blood capillaries by lipo- ate in regulating lipid synthesis and mobilization in adipocytes. protein lipase, an enzyme synthesized by the adipocytes and Hormonal activity of white adipocytes themselves transferred to the capillary cell membrane (Figure 6–2). Free includes production of the 16-kDa polypeptide hormone fatty acids then enter the adipocytes by both active transport leptin (Gr. leptos, thin), a “satiety factor” with target cells in and diffusion. Within the adipocytes, the fatty acids combine the hypothalamus, other brain regions, and peripheral organs, with glycerol phosphate, supplied by glucose metabolism, which helps regulate the appetite under normal conditions to again form triglycerides, which are then deposited in the and participates in regulating the formation of new adipose growing lipid droplet. Insulin stimulates glucose uptake by 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 hydro- (Chylo) and VLDLs. In the capillary endothelial cells of adipose lyze the stored triglycerides to free fatty acids and glycerol. These tissue, these complexes are partly broken down by lipoprotein substances diffuse into the capillary, where the fatty acids bind albu- lipase, releasing free fatty acids and glycerol. The free fatty acids min for transport throughout the body for use as an energy source. diffuse from the capillary into the adipocyte, where they are Abundant caveolae in the adipocyte plasmalemma are rich in reesterified to glycerol phosphate, forming triglycerides that are cholesterol and other lipids and appear to mediate endocytosis of stored in the lipid droplet until needed. fatty acids necessary for growth of the lipid storage droplet.  White Adipose Tissue 125 › › MEDICAL APPLICATION FIGURE 6–3 Development of white and brown C H A P T E R fat 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 expression have been noted between visceral deposits (in the Fibroblast Preadipocytes 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 Like other connective tissue, skeletal and muscle cells, adipocytes smaller number of so-called beige adipocytes with cytologi- develop from mesenchymal stem cells. Adipose development cal features and gene expression patterns of both white and first produces preadipocytes, which look rather like larger brown adipocytes. White adipocytes are unilocular, with one large lipid droplet occupying most of the cytoplasm. The white fibroblasts with cytoplasmic lipid droplets (Figure 6–3). Initially, adipocyte is usually much larger than that shown here in rela- the droplets of white adipocytes are isolated from one another tion to the 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) with numerous mitochondria (not shown here). Mitochon- which remain within white adipose tissue and have histological drial metabolism of lipid in brown adipocytes releases heat and metabolic features generally intermediate between white rather than ATP. Cells functioning as brown adipocytes can and brown adipocytes. With adaptation to cold temperatures also develop from beige adipocytes during adaptation to cold beige adipocytes change reversibly, forming many more small temperatures. lipid droplets, adopting a gene expression profile more like that of brown fat, and begin to release heat (see as follows). Humans are born with stores of white adipose tissue, › › MEDICAL APPLICATION which begin to accumulate by the 14th week of gestation. Both In addition to leptin, white adipose tissue secretes numerous visceral and subcutaneous fat is well-developed before birth. other cytokines and other factors with paracrine and auto- Proliferation of progenitor cells diminishes by late gestation, crine activity, including many proinflammatory cytokines. It is and adipose tissue increases mainly by the filling of existing not clear whether these are produced by adipocytes or other adipocytes until around age 10, followed by a period of new cells of the tissue such as macrophages or fibroblasts. With its fat cell differentiation that lasts through adolescence. New increased amounts of white adipose tissue, obesity is charac- adipocyte formation occurs around small blood vessels, where terized by a state of chronic mild inflammation. Proinflamma- undifferentiated mesenchymal cells are most abundant. tory factors released from visceral fat are being investigated Excessive adipose tissue accumulation, or obesity, for links to the inflammation-related disorders associated occurs when nutritional intake exceeds energy expendi- with obesity, such as diabetes and heart disease. ture, an increasingly common condition in modern, seden- tary lifestyles. Although adipocytes can differentiate from 126 CHAPTER 6 Adipose Tissue mesenchymal stem cells throughout life, adult-onset obesity mainly involves increasing the size of existing adipocytes › BROWN ADIPOSE TISSUE (hypertrophy). Childhood obesity, in contrast, often involves Brown adipose tissue constitutes 2%-5% of the newborn body increases in both adipocyte size and numbers due to the dif- weight, located mainly in the back, neck, and shoulders, but ferentiation of more preadipocytes from mesenchymal cells it is greatly reduced during childhood and adolescence. In (hyperplasia). Weight loss after dietary changes is due to adults, it is found only in scattered areas, especially around the reductions in adipocyte volume, but not their overall number. kidneys, adrenal glands, aorta, and mediastinum. The color of brown fat is due to both the very abundant mitochondria (containing cytochrome pigment) scattered among the lipid › › MEDICAL APPLICATION droplets of the fat cells and the large number of blood capillar- Adult-onset obesity is very often associated with age- ies in this tissue. Brown adipocytes contain many small lipid related metabolic changes and may involve reduced activity inclusions and are therefore called multilocular (Figure 6–3). of the hormone-sensitive lipases of adipocytes, causing less The small lipid droplets, abundant mitochondria, and rich effective fat mobilization out of the cells. The increased num- vasculature all help mediate this tissue’s principal function of ber of adipocytes produced during childhood obesity pre- heat production and warming the blood. disposes an individual to obesity in later life. Despite claims Cells of brown fat are polygonal and generally smaller of various fad diets, there is no evidence that any particular than white adipocytes; their smaller lipid droplets allow the type of caloric restriction is more effective than others; rather, nucleus to be more centrally located (Figure 6–4). Brown adi- any intake of calories that is lower than the energy expendi- pocytes are often closely packed around large capillaries and ture will result in loss of adipose tissue. the tissue is subdivided by connective tissue partitions into lobules that are better delineated than the lobules of white FIGURE 6–4 Brown adipose tissue. BV a b (a) Brown adipose tissue with closely packed cells is shown here (b) A diagram of a single brown, multilocular adipocyte show- around a small blood vessel (BV), with adjacent white adipose tis- ing the central nucleus, many small lipid droplets (yellow), and sue at the top of the photo. Brown adipocytes are slightly smaller very numerous mitochondria. Also shown is a sympathetic and characteristically contain many small lipid droplets and cen- nerve ending that releases norepinephrine to stimulate mito- tral spherical nuclei. If the lipid has been dissolved from the cells, chondrial production of heat, the principal function of brown as shown here, the many mitochondria among the lipid spaces are adipose tissue. retained and can be easily discerned. (X200; PT)  Brown Adipose Tissue 127 adipose tissue. Cells of this tissue receive direct sympathetic from the intermembranous space to the matrix without pass- innervation, which regulates their metabolic activity. ing through ATP synthetase complexes. Instead of producing C H A P T E R ATP, the energy associated with this proton flow dissipates Function of Brown Adipocytes as heat. The main function of these multilocular adipose cells is to produce heat by nonshivering thermogenesis. The physi- Histogenesis of Brown Adipose Tissue ology of brown fat is best understood from studies of the Brown adipose tissue also develops from mesenchyme but tissue in hibernating species. In animals ending their hiber- involves preadipocytes in a different embryonic location 6 nation period, and in newborn humans, nerve impulses lib- (paraxial) from those producing white adipose tissue. Brown Adipose Tissue Brown Adipose Tissue erate norepinephrine into brown adipose tissue. As in white adipocytes also emerge earlier than white fat during fetal fat, this neurotransmitter activates the hormone-sensitive development. In humans, the amount of brown fat is maximal lipase of adipocytes, promoting hydrolysis of triglycerides relative to body weight at birth, when thermogenesis is most to fatty acids and glycerol. However, unlike the process in needed and partially disappears by involution and apoptosis white fat, liberated fatty acids of multilocular adipocytes during childhood. In adults, the amount and activity of brown are not released but are quickly metabolized, with a con- fat are higher in lean individuals. sequent increase in O2 consumption and heat production. The number of brown adipocytes increases during cold This raises the temperature within the tissue and warms the adaptation, usually appearing as clusters of multilocular cells locally circulating blood, which then distributes the heat in white adipose tissue. As indicated earlier, this increase 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 defining 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 unilocular), causing the nucleus and remaining cytoplasm to be in 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 produced when nutrients are needed and carried throughout the body on in the liver and circulating as VLDLs; and from fatty acids synthe- plasma proteins such as albumin. sized 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 fibers, 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 White Adipose Tissue and contain primarily many small lipid droplets (they are multi- White adipose tissue is found in many organs throughout the locular) in cytoplasm containing many mitochondria and a central body, typically forming about 20% of the body weight in adults. nucleus. Adipocytes of white fat are typically very large cells, ranging in Fatty acids released in adipocytes of brown fat are metabolized in diameter from 50 to 150 μm. mitochondria of these cells for thermogenesis rather than ATP syn- thesis, using uncoupling protein-1. 128 CHAPTER 6 Adipose Tissue Adipose Tissue ASSESS YOUR KNOWLEDGE 1. White adipocytes are derived developmentally from what precur- 8. Fully differentiated white adipocytes are large cells, typically having sor cells? diameters of approximately what size? a. Monocytes a. 5 μm b. Fibroblasts b. 10 μm c. Mesenchymal cells c. 100 μm d. Brown adipocytes d. 500 μm e. Mast cells e. 1000 μm 2. What are the relatively large particles formed in the intestinal 9. Ten days after birth, a full-term newborn boy develops firm, ery- epithelial cells and rich in ingested lipids? thematous nodules, and plaques over his trunk, arms, buttocks, a. Fatty acids thighs, and cheeks. His mother’s pregnancy was complicated by b. Chylomicrons placenta previa, and his airway was cleared of aspirated meconium c. Glycerols immediately after birth. A biopsy of subcutaneous tissue shows d. Very low-density lipoproteins necrosis within the brown adipose tissue. What metabolic activity is e. Adipocytes liable to be affected in this patient? a. Export of fatty acids from fat 3. What substance, released from the adrenal gland and some b. Thermal insulation autonomic neurons, increases lipolytic activity in white adipocytes? c. Oxidation of fatty acids for thermogenesis a. Leptin d. Activation of the adenylate cyclase system b. Insulin e. Initiation of shivering c. Norepinephrine d. Glycogen 10. A 44-year-old woman of African ancestry visits her family physi- e. Triglyceride cian for a physical examination at the urging of her husband. She has no current complaints and is taking no medications. She is allergic 4. What is the most important form of lipid storage in both white and to erythromycin. She works as a software developer and lives with brown adipocytes? her 52-year-old husband and 12-year-old daughter. She is a non- a. Free fatty acids smoker and drinks an occasional glass of wine when she and her b. Cholesterol husband go out to dinner. She is involved in no regular exercise. Her c. Chylomicrons mother is 66 and suffers from type 2 diabetes, hyperlipidemia, and d. Glycerol hypertension and had a myocardial infarction last year. The patient’s e. Triglycerides father died of a stroke last year at the age of 72. On examination, the patient’s blood pressure is 155/100 mm Hg, pulse 84 beats/min, weight 5. Important target cells of leptin are found in which organ? 215 lb (increased from 180 lb 3 years ago), and height 5 ft 7 in. In this a. Small intestine patient, during the period of weight gain, which one of the following b. White adipose tissue responses would be most likely in her white fat? c. Large intestine a. Increased synthesis of growth hormone d. Hypothalamus b. Decreased synthesis of leptin e. Brown adipose tissue c. Increased release of chylomicrons to the blood 6. The hormone-sensitive lipase in the cells of adipose tissue acts d. Decreased conversion of beige adipocytes to unilocular white primarily on what substrate? adipocytes a. Glucose e. Increased incorporation of fatty acids into triglycerides b. Free fatty acids c. Glycerol d. Triglycerides e. Very low-density lipoproteins 7. Applied to adipocytes, the term “multilocular” refers to which of the following? a. The large number of small cytoplasmic lipid droplets b. The proliferation of the cells in an obese individual c. The large number of mitochondria in the cells d. The high density of nerves supplying the tissue e. The type of mesenchymal cells also present Answers: 1c, 2b, 3c, 4e, 5d, 6d, 7a, 8c, 9c, 10e