OBJECTIVES

This chapter should help you to:

· List the structural and functional characteristics of connective tissue that distinguish it from other basic tissue types.
· Know the functions carried out by connective tissues.
· Know the 3 fundamental components found in all connective tissues.
· Know the biochemical cofmpositipn and the sites of synthesis of the extracellular matrix compo-
· Know the structure and function of the cell types found in connective tissue.
· Compare types of connective tissues in terms of the types, relative amounts, and arrangement of cells, fibers, and ground substance.
· Relate the composition of each connective tissue type to its specific functions.
· Name body sites where each connective tissue type may be found and relate location to tissue function .
· Recognize the types of connective tissues and connective tissue cells in a photomicrograph or slide of a tissue or organ and describe their probable function.
· Predict the functional consequences of a given structural defect in a connective tissue.

SYNOPSIS

I. GENERAL FEATURES OF CONNECTIVE TISSUES

A. Functions: The functions of connective tissues, determined chiefly by their mechanical prop erties, include the binding together, compartmentalization , support, and physical and immu nologic protection of other tissues and organs, as well as storage (see also IV.A).

B. Types: The connective tissues described in this chapter (III) are loose and dense collagenous connective tissue (connective tissue proper), reticular connective tissue, elastic connective tissue, and mucous connective tissue. Adipose tissue, cartilage, and bone are specialized con nective tissues and are considered in Chapters 6, 7, and 8, respectively. Integrative multiple choice questions pertaining to all these connective tissues are included after Chapter 8. Blood, often considered a highly specialized type of connective tissue, is discussed in Chapters 12 and 13.

C. Three Fundamental Components: Connective tissue types differ in microscopic appear ance, but all consist of cells, fibers, and ground substance. Connective tissue types and subtypes are classified according to the amounts, types, and proportions of these components.

D. Extracellular Matrix: The fibers and ground substance constitute the extracellular matrix. Connective tissues contain abundant matrix, which largely determines their mechanical proper ties. The fibers are of 2 types, collagen and elastic. The ground substance, in which the fibers and cells are embedded, is composed mainly of glycosaminoglycans (GAGs) dissolved in tissue fluid, Matrix viscosity and rigidity are determined by the amount and types of GAGs, the association of GAGs with core proteins to form proteoglycans, GAG-fiber associations, and GAG-GAG associations. Fiber and ground substance components are synthesized and secreted by connective tissue cells (mainly fibroblasts), and the fibers are assembled in the extracellular space.

E. Embryonic Origin: All connective tissue cell types derive from embryonic mesenchyme. Mesenchyme derives from embryonic mesoderm, except head mesenchyme, which derives from the neural crest (mesectoderm).

II. COMPONENTS OF CONNECTIVE TISSUE

A. Collagen Fibers: Collagen is the most abundant protein in the body. There are many types, some of which form fibers. Collagen fibers often collect to form bundles ranging from 0.5 to 15 um in diameter.



1. Synthesis and assembly a. Intracellular steps. Free polysomes reading collagen mRNA attach to the RER (see Chapter 3), and protocollagen polypeptides are deposited in the cisternae. Each protocollagen or alpha chain, has a molecular mass of about 28,000 daltons and about 250 amino acids: every third amino acid is glycine. Proline and lysine residues within the chains are hydroxylated by proline and lysine hydroxylases (possibly in SER) to form hydroxyproline and hydroxylysine, unusual amino acids present in large amounts in collagen. Core sugars (galactose and glucose) attach to the hydroxylysine residues in the endoplasmic reticulum. With the aid of registration peptides at the ends of the alpha chains, 3 chains coil around one another to form a triple-helical molecule called pro collagen, Further glycosylation may occur in the Golgi complex, where procollagen is packaged for secretion. Golgi vesicles release procollagen into the extracellular space by exocytosis. b. Extracellular steps. In the extracellular space, the enzyme procdlagen peptidase cleaves the registration peptides from procollagen. converting it to tropocollagen, Tro pocollagen molecules align in staggered fashion to form collagen fibrils, possibly under the control of the adjacent cell. The extracellular enzyme lysyl oxidase helps stabilize the nascent fibers by cross-linking lysine and hydroxylysine residues in adjacent tro- pocollagen molecules.
2. Collagen types. Not all collagen types are well characterized. A few, whose biochemical structure, function, and location have been studied in some detail, are described here. a. Type I collagen, the most abundant and widespread, forms large fibers and tiber bun dles. It occurs in tendons, ligaments, bone, dermis, organ capsules, and loose connective tissue. b. Type II collagen is found in adults only in the cartilage matrix (some occurs in the embryonic notochord) and forms only thin fibrils. c. Type III collagen is similar to type I, but is more heavily glycosylated and stains with silver. Often found in association with type I, type III forms networks of thin fibrils that surround and support soft flexible tissues (adipocytes, smooth muscle cells, nerve fibers). It is the major tiber component of hematopoietic tissues leg, bone marrow, spleen) and of the reticular laminae underlying epithelial basal laminae. d. Type IV collagen is the major collagen type in basal laminae. It does not form fibers or fibrils. e. Type V collagen is present in placental basement membranes and blood vessels and in small amounts elsewhere. I, 5pe X collagen is found in the matrix surrounding hypertrophic chondrocytes of de- generating growth plate cartilage in sites of future bone formation (see Chapter 8).
3. Histologic appearance a. Light microscopy. Collagen occurring in large or small bundles of fibrils or as individual fibrils stains pink in H&E-stained sections. In sections stained with Masson's trichrome, collagen fibers stain green. Thin fibers leg, type III) stain darkly with silver stains, but thicker bundles do not. Collagen molecules that do not form fibers or fibrils leg, type IV) cannot be distinguished from the surrounding ground substance except by immu nohistochemistry. b. Electron microscopy All collagen fibrils and fibers have stripes at intervals of 64 nm along their length. This periodicity reflects the staggering of tropocollagen molecules.
4. Mechanical properties. Collagen fibers' most important mechanical property is their tensile strength, which is (weight for weight) greater than that of steel.
5. Location. Collagen fibers are found in all connective tissues and in the reticular laminae of certain basement membranes. In bone, its lacunar regions (spaces between overlapping tropocollagen units) may act as nucleation sites for the hydroxyapatite crystals of bone matrix .

B. Reticular Fibers: Reticular fibers are similar to collagen fibers, but are thinner (0.1-1.5 um), are more highly glycosylated, and form delicate silver-staining networks instead of thick bundles. The networks serve as supportive lattices that allow motile cells to move about in loosely arranged tissues such as hematopoietic tissues. Reticular fibers are composed mainly of type III collagen and some glycoproteins.

C. Elastic Fibers: Elastic fibers consist of an amorphous protein called elastin and numerous protein microfibrils that become embedded in the elastin. They range in diameter from 0. 1 to 10 um.


1. Synthesis and assembly a. Intracellular steps. Microfibrillar proteins and proelastin are synthesized on ribosomes of the RER and secreted separately. Proelastin contains large amounts of the hydrophobic amino acids glycine, proline, and valine, accounting for elastin's insolubility. Micro fibrillar protein contains mostly hydrophilic amino acids. b. Extracellular steps. Proelastin molecules polymerize extracellularly to form elastin chains. Lysyl oxidases then catalyze the conversion of certain lysine residues of elastin to aldehydes, 3 of which condense with a fourth, unaltered lysine residue to form des mosine and isodesmosine. These amino acids, very rare except in elastin, cross-link individual elastin chains. Elastin then associates with numerous microfibrils to form a branching and anastomosing network of elastic fibers. Owing to elastin's unusual com position, its turnover requires the specialized enzyme elastase.
2. Histologic appearance. Elastin contains few charged amino acids, so it stains poorly with standard ionic dyes. Special stains, such as Verhoeff's stain or Weigert's resorcin-fuchsin stain, are used in light microscopic preparations. In EM preparations, both amorphous elastin and microfibrils can be visualized.
3. Mechanical properties. Elastic fibers are very pliable and elastic. They can stretch to 150% of their length without breaking and return to their original length.
4. Location. Elastic tibers occur where their mechanical properties are needed to allow tissues to stretch or expand and return to their original shape, eg, in arterial walls, interalveolar septa, bronchi and bronchioles of the lungs, vocal ligaments, and ligamenta flava of the vertebral column.



D. Ground Substance: The ground substance consists mostly of glycoconjugates of 2 classes, proteoglycans and glycoptoteins. Tissue ffuids and salts are also present.


1. Proteoglycans are composed of a core protein to which GAGs are attached. The GAGs of proteoglycans are straight-chain polymers of repeating sugar heterodimers made up of hex osamine (glucosamine or galactosamine) and uronic acid (glucuronic or iduronic acid). Five major classes of GAGs, differing in their sugars, exist in connective tissues: hyaluronic acid (which does not form proteoglycans), chondroitin sulfate, dermatan sulfate, keratan sul fate, and heparan sulfate, Proteoglycans are discussed further in Chapter 7.
2. Glycoproteins are proteins to which shorter, branched oligosaccharide chains are covalently bound. Glycoproteins of ground substance are much smaller than proteoglycans. Examples: fihronectin, which mediates the attachment of cells to the extracellular matrix, and laminin, a component of basal laminae that mediates attachment of epithelial cells.

E. Cells: Connective tissue cells can be grouped into 2 classes, fixed and wandering.

1. Fixed cells are native to the tissue in which they are found. a. Mesenchymal cells are the precursors of most connective tissue cells. Embryonic mesenchyme comprises a loose network of stellate cells and abundant intercellular tluid. Some mesenchymal cells remain undifferentiated in adult connective tissue and con stitute a reserve population of stem cells called adventitial cells, which are difficult to distinguish from some fibroblasts. b. Fibroblasts are the predominant cells in connective tissue proper (III.A). They synthe size, secrete, and maintain all the major components of the extracellular matrix. Structurally, fibroblasts are of 2 types, one of which resembles mesenchymal cells. This type is stellate, with long cytoplasmic processes and a large, ovoid, pale-staining nucleus. The cytoplasm is mitotically active and contains abundant RER and Golgi complexes. This cell type is important in producing collagen and other matrix components. Cells of the second type are less active and ate sometimes termed fibrocytes, because they are believed to be more mature. Fibrocytes are smaller and spindle-shaped, with a dark, elongated nucleus and fewer organelles. They may revert to the fibroblast state and participate in tissue repair. c. Reticular cells make up a functionally diverse yet morphologically similar group. They produce the reticular fibers (II.B) that form the netlike stroma of hematopoietic and iymphoid tissues (III.B). Some apparently can phagocytose antigenic material and cellular debris. Others (antigen-presenting cells) collect antigens on their surfaces and help activate immunocompetent cells to mount an immune response. Reticular cells are typ ically stellate with long, thin cytoplasmic processes. Each has a central, pale, irregularly rounded nucleus and a prominent nucleolus. In the cytoplasm, the number of mitochondria and the degree of development of the Golgi complex and RER are variable. Some reticular cells, particularly those with less developed organelles, may be stem cells of various blood types. d. Adipose cells or adipocytes are mesenchymal derivatives specialized as storage depots for lipids (see Chapter 6).
2. Wandering cells are immigrant cells, usually from blood or bone marrow (Chapters 12-14). Some retain their original characteristics and may eventually leave the connective tissue; others differentiate and take up permanent residence there. a. Mast cells. These large (20-30-Clm) cells derive from bone marrow precursors and are characterized by abundant basophilic cytoplasmic granules that appear electron-dense at the EM level. Other features of mast cells include many small plasma membrane folds and a well-developed Golgi complex. The granules, which often obscure the small central nucleus, contain heparin, histamine, and eosinophil chemotactic factor of anaphylaxis (ECF-A). Mast cells have surface recepton for the IgE antibodies that trigger degranulation, the exocytosis of granule contents that initiate the local inflammation commonly associated with allergic reactions. b. Macrophages are large, stellate cells derived from cells of the blood monocyte lineage that infiltrate connective tissue and develop into phagocytes. Resident macrophages can proliferate and form additional macrophages. Dye particles injected into the body are engulfed by these cells and accumulate in cytoplasmic granules. Otherwise, these cells may be difficult to detect in H&E-stained sections. Macrophages contain many lyso somes, which aid in digesting phagocytosed materials, and a well-developed Golgi complex. They help maintain the integrity of connective tissues by removing foreign substances and cellular debris, and they participate in the immune response by presenting phagocytosed antigens to lymphocytes. To remove large foreign objects such as splinters, macrophages may fuse to form multinuclear giant cells. Monocyte-derived phagocytes, which together constitute the mononuclear phagocyte system, include the macrophages (lymphoid organs, lungs, serous cavities, and connective tissue), as well as Kupffer cells (liver), osteoclasts (bone), and microglial cells (central nervous system). c. plasma cells differentiate from antigen-stimulated B lymphocytes. As the primary producers of circulating antibodies, they are the main effecters of the humoral immune response. They are sparsely distributed throughout the body but are abundant in areas susceptible to penetration by bacteria. Plasma cells are large and ovoid, with an eccentric nucleus and abundant RER. The characteristic "clock face" nucleus results from a large, central nucleolus and several large heterochromatin clumps regularly spaced around the inner surface of the nuclear envelope. These cells usually exhibit a clear juxtanuclear area (cytocenter) containing a well-developed Golgi complex and centrioles. d. Other blood-derived connective tissue cells. Many wandering cell types originate in the bone marrow and are carried to connective tissue by the blood and lymph. Blood-derived cells found in connective tissues include the leukocytes (white blood cells, ie, lympho cytes, monocytes, neutrophils, eosinophils, and basophils), which have roles in the immune response and are described in detail in Chapters 12-14.

III. CONNECTIVE TISSUE TYPES

A. Connective Tissue Proper: Connective tissue proper, found in most organs, is characterized by a predominance of fibers (mainly type I collagen) in the extracellular matrix. Its varied functions chiefly relate to binding cells and tissues into organs and organ systems. Its subclasses are based on the type, density, and orientation of its fibers.


1. Loose connective tissue (areolar tissue) appears disorganized. It consists of a loose network of different types of fibers, upon which many kinds of fixed and wandering cells are sus pended. The abundant ground substance is only moderately viscous. (The types of cells and fibers and the composition of the ground substance are summarized in Table 5-1.) This flexible yet delicate tissue surrounds and suspends vessels and nerves as they traverse most organs, underlies and supports most epithelia, and fills spaces between other tissues leg, between muscle fibers and their dense connective tissue sheaths). It also supports the serous membranes (mesothelia) of the pleura, pericardium, and peritoneum. Always well vas cularized, areolar tissue conveys oxygen and nutrients to avascular epithelia. Its cells func tion in immune surveillance for foreign substances entering the body through the blood or epithelia.
2. Dense connective tissue. Collagen fibers are the predominant component of dense connec tive tissue. Nearly all are of type I collagen. The cells are predominantly mature fibroblasts (fibrocytes). The ground substance is essentially identical to that of areolar tissue but is less abundant (Table 5-1). There are 2 types of dense connective tissue: regular, with a ropelike arrangement of fiber bundles, and irregular, with a fabriclike arrangement. a. Dense regular connective tissue. The fibers of this tissue are tightly packed into parallel bundles, between which are a few attenuated, spindle-shaped fibroblasts. The small, cigar-shaped nuclei of the fibroblasts are oriented parallel to the fibers; the cytoplasm is difficult to distinguish with the light microscope. There is little room for ground substance, which nevertheless permeates the tissue. The tensile strength of the packed collagen fibers makes them ideal for transmitting mechanical force over long distances while using a minimum of material and space. This tissue serves to transmit the force of muscle contraction, to attach bones to one another, and to protect other tissues and organs. It is found in tendons, ligaments, periosteum, perichondrium, deep fascia, and some organ capsules. b. Dense irregular connective tissue. The components of this tissue are identical to those in dense regular connective tissue (Table 5-1). At first glance, dense irregular connective tissue seems poetly organized, but its collagen bundles have a complex woven pattern that resists tensile stress from any direction. Its functions include covering fragile tissues and organs and protecting them from multidirectional mechanical stresses. It occurs in the reticular layer of the dermis and in most organ capsules.

B. Reticular Connective Tissue: Reticular fibers (type III collagen) form a delicate, netlike scaffolding upon which cells, the predominant element, are suspended. Reticular cells attach to the fibers, which may be mostly covered by the long, thin reticular cell processes. Other cell types, such as lymphocytes, are suspended in the spaces of the network (Table 5-1). There is very little ground substance. Reticular connective tissue supports motile cells and filters body fluids. It is found mainly in hematopoietic tissues such as bone marrow spleen, and lymph nodes.

C. Elastic Connective Tissue: In H&E-stained sections, elastic tissue resembles dense regular (collagenous) connective tissue. Fibers predominate; most are elastic, while some are collagen. Elastic fibers are collected in thick, wavy, parallel bundles. The bundles are separated by loose collagenous tissue and occasional fibroblasts with attenuated cytoplasm and condensed, oblong nuclei. Other connective tissue cells may be present in small numbers (Table 5-1). The ground substance is sparse and similar to that of other dense connective tissues. Elastic connective tissue provides flexible support and predominates in the ligamenta flava of the vertebral column and the suspensory ligament of the penis.

D. Mucous Connective Tissue: This tissue has few cells and fibers distributed randomly in the abundant ground substance, which has a syrupy to jellylike consistency and is composed chiefly of hyaluronic acid (Table 5-1). Mucous tissue yields readily to pressure but returns to its original shape, so it is useful for protecting underlying structures from excess pressure. It is the predominant component (Wharton's jelly) of the umbilical cord, of the nucleus pulposis of the intervertebral disks, and of the pulp of young teeth.

IV. HISTOPHYSIOLOGY OF CONNECTIVE TISSUE

A. Functions:


1. Support. Structural support is the major function of connective tissue, which forms the framework upon which all other body tissues are assembled. Its physical properties allow it to bind, to fill spaces, and to separate functional units of other tissues and organs. It thus maintains functional units in their proper 3-dimensional relationships, allowing maintenance and coordination of all body functions.
2. Defense a. Physical. The viscosity of the extracellular matrix, which is due largely to hyaluronic acid, slows the progress of many bacteria and foreign particles. Sheets of tightly packed and often interwoven collagen fibers, as in organ capsules, help to confine local infec tions. However, some bacteria secrete enzymes that break down matrix components; eg, staphylococci, clostridia, streptococci, and pneumococci secrete hyaluronidase, and Closrridium perfringens secretes cdiagenase. b. Immunologic. Foreign bodies that penetrate epithelia are intercepted by immunorespon sive cells that inhabit the underlying connective tissue (II.E.2). These cells not only activate local immune responses (inflammation) but also mobilize the immune system to supply additional cells via the bloodstream. Recruited cells migrate through capillary and venule walls into the connective tissue, a process called diapedesis,
3. Repair. Rapidly closing any breaches in the body's protective barriers is an important function of connective tissue. Injury stimulates invasion of the site by immunocompetent cells and the proliferation of fibroblasts. Macrophages remove clotted blood, damaged breach. Rapidlyformed collagenous matrices that close wounds are often less well organized tissue, and foreign material, while fibroblasts secrete extracellular matrix materials to fill the than the original tissues and form scars. Small scars may eventually be completely re- modeled; larger scars are only partially remodeled.
4. Storage. Reserves of water and electrolytes, especially sodium, are stored in the extracellu lar matrix, owing to the high polyanionic charge density of glycosaminoglycans. Energy reserves in the form of lipids are stored in adipocytes.
5. Transport. Except in the central nervous system, most blood and lymphatic vessels are surrounded by loose connective tissue, which is thus a crossroads for transporting substances to and from other tissues.

B. Edema: The water in tissue fluid comes from the anerial ends of capillaries in capillary beds, forced out by hydrostatic pressure (arterial pressure). Loss of fluid to the tissues increases the blood solute concentration at the venous end of the capillary; this increased colloid osmotic pressure, along with the lower hydrostatic pressure at the venous end, draws most of the lost fluid back into the blood. Any excess fluid remaining in the tissue is normally drained away by lymphatic capillaries, so that there is no net change in the amount of blood or tissue fluid. Edema, or accumulation of excess tissue fluid, accompanies pathologic conditions that cause the following:


1. Increased hydrostatic pressure in capillaries by obstructing venous blood flow (eg, congestive heart failure);
2. Dereased colloid osmotic pressure in the blood caused by lack of blood proteins (eg, starvation);
3. Increased hydrostatic pressure in the tissue caused by blockage of lymphatic drainage by parasites or tumor cells; and
4. Increased colloid osmotic pressure in the tissue caused by excessive accumulation of glycosaminoglycans in the matrix. Edema caused by this condition is called myxedema.

C. Hormonal Effects: Cortisol (hydrocortisone), produced by the adrenal glands under the ~ inffuence of pituitary adrenocorticotropic hormone (ACTH), inhibits connective tissue fiber synthesis by fibroblasts and retards local inflammatory and immune responses by other connec tive tissue cells. Cortisol or synthetic cortisone therefore reduces local heat, redness, and tenderness but delays and impairs wound healing. Insufficient levels of thyroid hormone (hypo thyroidism) cause accumulation of excess glycosaminoglycans in the connective tissue matrix, leading to myxedema.

D. Nutritional Factors: As a co-factor of proline hydroxylase (II.A. I.a), vitamin C (ascorbic acid) is required for normal collagen synthesis. Vitamin C deficiency leads to a condition called scurvy, characterized by weakening of all connective tissue. Proline hydroxylase activity also requires iron, molecular oxygen, and alpha-ketoglutarate, The importance of vitamins to connective tissues is also discussed in Chapter 8.

E. Collagen Renewal: Collagen is avery stable protein, and its turnover is quite slow--slowest in tendons and other dense connective tissues, fastest in loose connective tissue. Macrophages and neutrophils release collagenase, which breaks down old collagen, and new collagen is synthesized by fibroblasts. With age, extracellular collagen becomes increasingly cross-linked and its turnover slows in all connective tissues.

OBJECTIVES

This chapter should help you to:

· Relate the functions of adipose tissue to its structural characteristics.
· Describe adipose tissue as a connective tissue in terms of the relative amount and types of its cells, fibers, and ground substance.
· Know the differences and similarities between the Z types of adipose tissue.
· Recognize the type of adipose tissue present in a photomicrograph or slide of a tissue or organ.

SYNOPSIS

I. GENERAL FEATURES OF ADIPOSE TISSUE

A. A Tissue and an Organ: Adipose tissue, or fat, is a connective tissue specialized to store fuel. Were we unable to store fuel, all of our time would have to be spent obtaining food. The cytoplasm of fat cells, or adipocytes, contains large triglyceride deposits in the form of one or more lipid droplets with no limiting membranes. Together, the clusters of adipocytes scattered throughout the body constitute an important metabolic organ that varies widely in size and distribution, depending on such factors as age, sex, and nutritional status.

B. General Organization: Clusters of adipocytes are divided into robes and lobules by septa of collagenous connective tissue of variable density. Individual cells are surrounded by a network of reticular fibers. The ground substance is sparse.

C. TwoTypes: There are 2 basic types of adipose tissue, termed white adipose tissue, or white fat, and brown adipose tissue, or brown fat. A white adipocyte has a single large lipid droplet; a brown adipocyte has many small droplets.

II. WHITE ADIPOSE TISSUE

A. Distinguishing Features: White adipose tissue, the more abundant of the 2 types, is also termed unilocular adipose tissue, a reference to the single fat droplet in each of its cells. In mature adipocytes, the droplet is so large that itdisplaces the nucleus and remaining cytoplasm to the cell periphery. Cell diameter varies from 50 to 150 um Adipocytes in histologic sections have a signet-ring appearance because most of the lipid is washed away during preparation, leaving only a ffanened nucleus and a thin rim of cytoplasm. The cytoplasm near the nucleus contains a Golgi complex, mitochondria, a small amount of RER, and free ribosomes. The cytoplasm in the thin rim contains SER and pinocytotic vesicles. This tissue is sometimes termed yellow adipose tissue or yellow fat; dietary carotenoids accumulate in the lipid droplets, making the tissue yellow. White fat is richly vascularized, but not as richly as brown fat.

B. Distribution:


1. Subcutaneous fat (hypodermis) is the layer of white adipose tissue found just beneath the skin except in the eyelids, penis, scrotum, and most of the external ear. (There is some fat in the earlobe.) In infants, it forms a thermal insulating layer of uniform thickness covering the entire body and is termed the panniculus adiposus, In adults it becomes thicker or thinner in selected areas, depending upon the person's age, sex, and dietary habits. Where it thins, it takes on the appearance of areolar tissue. In males, the fat layer thickens over the nape of the neck, deltoids (shoulders), triceps brachii (back of the upper arm), lumbosacral region (lower back), and buttocks. In females, additional fat is deposited in the breasts, buttocks, and hips and over the anterior aspect of the thighs.
2. Intraabdominal fat. Fat deposits of variable size surround blood and lymphatic vessels in the omentum and mesenteries suspended in the abdominal cavity. Additional accumulations occur in retroperitoneal areas, such as around the kidneys.
3. Other locations. Other prominent accumulations of fat are found within the eye orbits, surrounding major joints leg. knees), and forming pads in the palms and soles.

C. Functional Characteristics: Adipocytes store fatty acids in triglycerides testers of glycerol and 3 fatty acids). The triglycerides stored in both white and brown fat undergo continuous turnover. Released fatty acids serve as a source of chemical energy for cells (the predominant source in resting muscle) and as raw materials for making phospholipids (the predominant component of biologic membranes). Turnover is regulated by several histophysiologic factors, which shift the equilibrium toward fat uptake or mobilization, depending on the body's level of, and need for, circulating fatty acids.


1. Factors enhancing lipid uptake (lipogenic influences) a. Dietary abundance. Dietary fats are absorbed by intestinal epithelial cells and carried, in particles called chylomicrons, by lymphatic vessels to the blood (see Chapter 15). Chylomicron triglycerides are hydrolyzed by lipoprotein lipases in the capillaries of adipose tissue; the released fatty acids are absorbed by adipocytes and resynthesized into triglycerides for storage. Dietary glucose can be converted in the liver to fatty acids, which the blood then carries to adipocytes in the triglycerides of very low density lipoproteins (VLDL), Glucose can also be directly absorbed from the blood and con verted into triglycerides or glycerol by the adipocytes themselves. b. Hormones. Insulin increases the uptake of glucose by adipocytes and enhances the synthesis of triglycerides from carbohydrates.
2. Factors enhancing lipid mobilization (lipolytic inllnences). When the blood levels of fatty acids and glucose fall below homeostatic levels, eg, during starvation or prolonged exercise, adipocytes break down triglycerides and release stored fatty acids and glycerol into the blood. Lipid mobilization occurs first from subcutaneous, mesenteric, and retroperitoneal adipose tissue and last from deposits in the hands, feet, and retro-orbital fat pads. a. Hormone-sensitive lipases. Peptide hormones and norepinephrine increase cyclic AMP levels (see Chapter 20) in adipocytes. Hormone-sensitive lipases in the adipocyte cytoplasm are activated by cyclic AMP and cleave fatty acids from stored triglycerides. b. Hormones. Adrenocorticotropic hormone (ACTH), released by the anterior pituitary, stimulates the release of free fatty acids from adipocytes. Other hormones with various degrees of lipolytic ability are glucagon, growth hormone, and thyroid hormone. A sex dependent regional sensitivity of adipose tissue to circulating androgens and estrogens exerts a major influence on sex-dependent differences in the uptake and mobilization of fatty acids by adipocytes. c. Innervation. Interruption of the autonomic nerve supply to adipose tissue decreases fat loss from the affected region, so it would appear that the autonomic nervous system is important in fatty acid mobilization. Autonomic fibers to white fat terminate only on the walls of blood vessels, but in brown fat they also make direct contact with theadipocytes. Exogenous norepinephrine can double the blood levels of free fatty acids by its effect on adipose tissue.

D. Histogenesis: Unilocular adipocytes derive from mesenchymal precursor cells that resemble fibroblasts. The appearance of numerous small lipid droplets in the cytoplasm signals the transformation of these cells into lipoblasts. As lipid accumulation continues, the small droplets fuse until a single lipid droplet forms.

III. BROWN ADIPOSE TISSUE

A. Distinguishing Features: Brown fat is called multilocular adipose tissue because of the multiple small lipid droplets in its adipocytes. Brown adipocytes are smaller than white adipocytes and have a spheric, centrally located nucleus. They contain many mitochondria; the tan to reddish-brown tissue color is due chiefly to mitochondrial cytochromes. Loose connective tissue septa give brown adipose tissue a lobular appearance like that of a gland in histologic section. The vascular supply (partly responsible for the color) is very rich, as is the autonomic nerve supply. Many unmyelinated nerve fibers contact the adipocytes.

B. Distribution: Brown fat is less abundant than white at all ages. Young and middle-aged adults have little or none, but fetuses, newborns, and the elderly have accumulations in the axilla, in the posterior triangle of the neck (near the carotid artery and thyroid gland), and around the renal

C. Functional Characteristics: Brown fat has many of the same functional capabilities as white, but its metabolic activity is more intense and can lead to generation of heat. Under conditions of excessive cold, autonomic stimulation can cause oxidative phosphorylation in the numerous mitochondria to uncouple from adenosine triphosphate (ATP) synthesis, and the released energy dissipates as heat. The numerous vessels supplying this tissue carry the heat to the body. Brown fat is important in hibernating animals and in human infants before other thermoregulatory mechanisms are well developed.

D. Histogenesis: The multilocular adipocytes of brown fat derive from mesenchymal precur sors that assume an epithelial shape and arrangement. The multiple small fat droplets that appear during development do not coalesce during maturation.

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