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Morphology and Development of Adipose Tissue
Adipose-Tissue Metabolism
Adipose Tissue Distribution
Definition and Causes of Obesity
Further Reading

Albright, A.L. and Stern, J.S. (1998). Adipose tissue. In: Encyclopedia of Sports Medicine and Science, T.D.Fahey (Editor). Internet Society for Sport Science: http://sportsci.org. 30 May 1998.

Adipose tissue is specialized connective tissue that functions as the major storage site for fat in the form of triglycerides. Adipose tissue is found in mammals in two different forms: white adipose tissue and brown adipose tissue. The presence, amount, and distribution of each varies depending upon the species. Most adipose tissue is white, the focus of this review.

White adipose tissue serves three functions: heat insulation, mechanical cushion, and most importantly, a source of energy. Subcutaneous adipose tissue, found directly below the skin, is an especially important heat insulator in the body, because it conducts heat only one third as readily as other tissues. The degree of insulation is dependent upon the thickness of this fat layer. For example, a person with a 2-mm layer of subcutaneous fat will feel as comfortable at 15°C as a person with a 1-mm layer at 16°C. Adipose tissue also surrounds internal organs and provides some protection for these organs from jarring.

As the major form of energy storage, fat provides a buffer for energy imbalances when energy intake is not equal to energy output. It is an efficient way to store excess energy, because it is stored with very little water. Consequently, more energy can be derived per gram of fat (9 kcal.gm^-1) than per gram of carbohydrate (4 kcal.gm^-1) or protein (4 kcal.gm^-1). In addition, if terrestrial animals stored their excess energy as carbohydrate, the increased mass would interfere with mobility. The average woman with 20% body fat has about one month of energy stored as fat.

There are some constraints on the use of fat as fuel. Most animals cannot convert lipid into carbohydrate. Tissues that function predominantly anaerobically (e.g.. erythrocytes) must rely on carbohydrate for energy and need to have an ample supply available. Additionally, under normal conditions the brain is dependent upon glucose for energy and does not use fatty acids. In unusual metabolic circumstances, the brain can use ketone bodies (a by-product of incomplete fat metabolism) when they are present in sufficiently high quantities. Finally, a typical diet contains a high proportion of carbohydrate, and the transport of insoluble lipids through blood requires a specific mechanism, so it may be "easier" metabolically for tissues to use glucose under typical dietary conditions.

Brown adipose tissue, which derives its color from rich vascularization and densely packed mitochondria, is found in various locations, depending upon the species and/or age of the animal. In the rat, brown adipose tissue is found primarily in the interscapular region and the axillae, minor amounts are found near the thymus and in the dorsal midline region of the thorax and abdomen. During maturation, in non-hibernating animals, brown adipose tissue is metabolically less active, although cold exposure can activate it. In hibernating animals and neonates, brown adipose tissue is important for regulating body temperature via non-shivering thermogenesis.

Instead of serving as a substrate, the lipid in brown adipose tissue releases energy directly as heat and is, therefore used in heat production for non-shivering thermogenesis and for utilization of excess caloric intake via diet-induced-thermogenesis. The mechanism of heat generation is related to the metabolism of the mitochondria. Mitochondria from brown adipose tissue have a specific carrier called uncoupling protein that transfers protons from outside to inside without subsequent production of ATP.

Morphology and Development of Adipose Tissue

In adult mammals, the major bulk of adipose tissue is a loose association of lipid-filled cells called adipocytes, which are held in a framework of collagen fibers. In addition to adipocytes, adipose tissue contains stromal-vascular cells including fibroblastic connective tissue cells, leukocytes, macrophages, and pre-adipocytes (not yet filled with lipid), which contribute to structural integrity.

Figure 1. White fat cell and brown fat cell. Note the single large lipid vacuole in the white fat cell and the numerous smaller lipid vacuoles in the brown fat cell. LV: lipid vacuole; M: mitochondria; N: nucleus. Artwork courtesy of Dr. John Horwitz, U.C. Davis.

The lipid droplets in adipose tissue can be unilocular and/or multilocular. Unilocular cells contain a single large lipid droplet which pushes the cell nucleus against the plasma membrane, giving the cell a signet-ring shape (Figure 1). Unilocular cells, characteristic of white adipose tissue, range in size from 25 to 200 microns. Mitochondria are found predominately in the thicker portion of the cytoplasmic rim near the nucleus. The large lipid droplet does not appear to contain any intracellular organelles. Multilocular cells, typically seen in brown adipose tissue, contain many smaller lipid droplets. A cell in brown adipose tissue may reach a diameter of 60 microns and the lipid droplet within the cell may reach 25 microns in diameter. As mentioned above, the brown color of this tissue is derived from the cells' rich vascularization and densely packed mitochondria. These mitochondria vary in size and may be round, oval, or filamentous in shape.

Approximately 60 to 85% of the weight of white adipose tissue is lipid, with 90-99% being triglyceride. Small amounts of free fatty acids, diglyceride, cholesterol, phospholipid and minute quantities of cholesterol ester and monoglyceride are also present. In this lipid mixture, six fatty acids make up approximately 90% of the total, and these are myristic, plamitic, palmitoleic, stearic, oleic, and linoleic. Varying the composition of your diet can vary the fatty acid profile in adipose tissue. The remaining weight of white adipose tissue is composed of water (5 to 30%) and protein (2 to 3%).

White adipose tissue is not as richly vascularized as brown adipose tissue, but each adipocyte in white adipose tissue is in contact with at least one capillary. This blood supply provides sufficient support for the active metabolism, which occurs in the thin rim of cytoplasm surrounding the lipid droplet. Blood flow to adipose tissue varies depending upon body weight and nutritional state, with blood flow increasing during fasting.

Adipocytes are considered to originate from fibroblast-like precursor cells that differentiate into adipocytes under the appropriate stimulatory conditions (described below). The precursor cells do not possess any morphological or enzymatic marker that can be used to determine whether they will become adipocytes. The criteria used to identify adipocytes depends upon lipid accumulation within the cell after proliferation has stopped, making early identification of adipocytes difficult.

The size of adipose tissue mass is a function of both adipocyte number and size. An increase in adipose tissue mass can occur by hyperplastic growth, which is an increase in the number of adipocytes. This increase in number occurs primarily by mitotic activity in precursor cells. Adipose tissue mass can also increase by hypertrophic growth, which is an increase in the size of adipocytes. This increase in size occurs primarily by lipid accumulation within the cell. Growth of this tissue in the rat occurs in well-defined stages. From birth to 4 weeks of age, adipose tissue growth is hyperplastic. Overfeeding a rat during this period can lead to permanent increases in body weight and fat cell number. From 4 to 14 weeks of age both adipocyte hypertrophy and hyperplasia occur. Following 14 weeks of age, adipose tissue growth occurs predominantly by adipocyte hypertrophy.

The developmental sequence of adipose tissue in humans is less well defined. In contrast to most neonates, the human neonate is born relatively fat. Two periods of hyperplastic growth are probably during the third trimester of pregnancy and just prior to and during puberty.

Contrary to earlier belief, hyperplastic growth can also occur in adulthood (in both humans and rats). When adipocytes fill with lipid and get to a critical size, precursor cells are stimulated to differentiate, and an increase in adipocyte number results. This critical size probably does not occur with moderate overfeeding unless the overfeeding is of long duration. In addition, there are probably individual differences in the size that will result in new adipocyte formation. Once new adipocytes are formed, they remain throughout life and only a reduction in size of the cell is possible. This increased number of adipocytes has far-reaching consequences for the treatment and prevention of obesity.

Adipose-Tissue Metabolism

Lipogenesis

Lipogenesis is the deposition of fat. This process occurs in adipose tissue and in the liver at cytoplasmic and mitochondrial sites (Figure 2).

Energy ingested as fat beyond that needed for current energy demands is stored in adipose tissue. In addition, carbohydrate and protein consumed in the diet can be converted to fat. Energy ingested as carbohydrate can be stored as glycogen in the liver and muscle. Carbohydrate can also be converted to triglycerides primarily in the liver and transferred to adipose tissue for storage. Amino acids from ingested proteins are used for new protein synthesis or they can be converted to carbohydrate and fat.

Fatty acids, in the form of triglycerides or free fatty acids bound to albumin, are ingested in the diet or synthesized by the liver (described above). Very little synthesis of free fatty acids occurs in the adipocytes. Triglycerides are the most significant source of fatty acids, because this is the form in which dietary lipids are assembled by the gut and liver. Triglycerides made up of long chain fatty acids, in the form of chylomicrons (from intestinal absorption) or lipoproteins (from hepatic synthesis), are hydrolyzed to glycerol and free fatty acids by an enzyme called lipoprotein lipase (LPL). Lipoprotein lipase is synthesized in adipocytes and secreted into adjacent endothelial cells. Chylomicrons and lipoproteins (very low density lipoproteins) contain C-ll apoprotein, which activates LPL. Free fatty acids are taken up by adipocytes in a concentration-dependent manner by a transmembrane transport protein. Once inside the adipocyte, fatty acids enter a common pool made up of both incoming and outgoing fatty acids. Fatty acids that are stored in the adipose tissue must first combine with coenzyme A to form a thioester and then they are re-esterified in a stepwise manner to triglycerides. Glucose is the primary source of glycerol for this re-esterification process. Only a small amount of glycerol released, when triglycerides are hydrolyzed by LPL, can be reused by adipocytes to form alpha glycerol phosphate to be used for trigyceride assembly. Most glycerol is returned to the circulation.

Insulin, a hormone secreted by the beta cells of the pancreas, plays a predominant role in the lipogenic process. The net effect of insulin is to enhance storage and block mobilization and oxidation of fatty acids. Insulin exerts its effect by stimulating LPL formation, so that circulating triglycerides are hydrolyzed and free fatty acids can enter the adipocyte. Insulin is also required for the transport of glucose, which is needed for re-esterification of the triglycerides once inside the adipocyte. Finally, the conversion of glucose to fatty acids is accomplished by insulin's activation of several enzymes.

Lipolysis

Lipolysis is the chemical decomposition and release of fat from adipose tissue. This process predominates over lipogenesis when additional energy is required (Figure 2). The triglycerides within the adipocyte are acted upon by a multi-enzyme complex called hormone sensitive lipase (HSL), which hydrolyzes the triglyceride into free fatty acids and glycerol. These lipases act consecutively on triglycerides, diglycerides, and monoglycerides. Triglyceride lipase regulates the rate of lipolysis, because its activity is low.

Once triglycerides are hydrolyzed to fatty acids and glycerol, fatty acids enter the common free fatty acid pool where they may be re-esterified, undergo beta-oxidation (metabolic degradation), or be released into the circulation as substrates for skeletal muscle, cardiac muscle, and liver. If the fatty acids are to undergo beta-oxidation for ATP production, fatty acids move from the adipocytes into the blood and are carried to the tissues that can use them as an energy source. Long-chain fatty acids enter the cells of these tissues by passive diffusion, and their rate of uptake is proportional to their difference in concentration inside and outside of the cell. Once inside the cells, beta-oxidation begins with "activation", that is, the formation of thioesters with coenzyme A. This activation step converts the fatty acids to a form that is more amenable to the successive biochemical changes that ultimately result in ATP formation.

Insulin reduces mobilization of fatty acids from adipose tissue by inhibiting triglyceride lipase. The mechanism of this inhibition may be through a decrease in cyclic AMP which in turn results in an inhibition of cyclic-AMP-dependent protein kinase. This suppression of lipolysis lowers the rate of fatty acid delivery to the liver and to peripheral tissues. The consequence of fewer fatty acids to the liver is a reduction in the formation of ketoacids (e.g., ketones). Insulin also stimulates the use of ketoacids by peripheral tissues, preventing an accumulation of these acids in the blood.

Adipose Tissue Distribution

Figure 3: Representation of "pear" or lower body fat distribution and "apple" or upper body fat distribution. Artwork courtesy of Wendy M. Garcia, Davis, CA.

Even the most casual observer will note that everyone does not carry their adipose tissue in the same anatomical locations. Adipose tissue that is located predominantly on the upper body has been termed android, male, central, upper-body segment, or "apple" distribution (Figure 3).

This distribution pattern is found more frequently in men; consequently the terms android and male. When adipose tissue accumulates predominantly in the lower body, the terms gynoid, female, lower-body segment , or "pear" distribution are used (Figure 3). As the terms gynoid and female imply, this fat pattern is found more frequently in women than in men.

What factors determine fat distribution? A primary factor is genetic background, which can often be seen by looking at the similarity in fat distribution within same-sex family members. As mentioned earlier, gender is also known to affect body fat location. Women usually show greater lower body fat distribution and men show more upper body fat distribution. As an individual ages body fat distribution may change. For example, after the menopause a change towards upper body fat distribution is observed. This change may be due to a relative decrease in LPL activity in the lower body region. Finally, extreme weight gain and weight cycling ("yo-yo dieting") may increase upper body fat.

Upper body fat distribution is correlated with the development of various health problems, including cardiovascular disease, hypertension, and non-insulin dependent diabetes. Excess visceral fat rather than excess upper body subcutaneous fat is associated with increased risk. A quick test to see if you are at risk for complications associated with upper body fat distribution is to calculate your waist-to-hip-ratio by measuring the circumference of your waist and dividing it by the circumference of your hips. Women are at risk if the ratio exceeds 0.85; for men the ratio is 0.95.

Definition and Causes of Obesity

Obesity is not a single disorder. A variety of methods and criteria are used to diagnose the presence of obesity. It is the quantity of adipose tissue and not just total body weight that defines obesity. Several factors contribute to the development of obesity: genetics, environment, physiology, psychology, and undetermined.

Work from experimental animals shows clear genetic anomalies as one basic cause of obesity. Genes for obesity can be recessive, dominant, or polygenic. Recessive alleles that influence the development of obesity have been identified in various rodents.

In the human population, obesity is a feature of several recessive syndromes, including Bardet-Biedl, Lawrence-Moon, and Prader-Labhart-Willi, as well as, triglyceride storage diseases. These syndromes are relatively rare. A single genetic anomaly in the absence of other concurrent genetic syndromes has yet to be identified in humans. It is possible that alleles at particular loci exert a small effect that is not easily detectable by themselves. If these alleles exist at a large number of loci, collectively they may exert a substantial impact on obesity. Genes clearly influence body size and body fat distribution, and are likely to be involved in modulating human obesity.

In humans, it is difficult to separate genetic and environmental factors and assign the relative contribution of each to the development of obesity. Several familial, twin, and adoption studies have provided a means to study the contributions of heredity and environment. These studies provide strong suggestive data for a genetic component to obesity, as well as modulation of genes by environmental factors.

Environmental influences on obesity include food intake and degree of physical activity. Overeating relative to energy needs is a component of obesity development. However, from studies with experimental animals it is clear that many animals that develop obesity are energetically more efficient than lean animals; that is, for a given amount of food, the obesity-prone animals deposit more fat than do the obesity-resistant animals. In fact, when genetically obese rodents are not allowed to overeat from birth, they are still considerably fatter than their lean brothers and sisters.

The study of food intake in humans is confounded by the fact that some obese individuals under-report the amount of food they eat. The composition of the diet can also influence obesity. Overweight individuals have been shown to consume more high-fat foods than normal-weight individuals.

The amount of energy that an individual expends will also influence the development of obesity. Increased level of activity is associated with leanness. Other than the energy deficit that occurs with exercise, metabolic changes with training also impact fat utilization and storage. Trained individuals have an increased lipolytic capacity compared to sedentary persons. Both basal and catecholamine-stimulated lipolysis are higher in fat cells from trained individuals. In rats that are obesity-prone, prior to the onset of obesity, catecholamine-stimulated lipolysis is lower in their fat cells than in fat cells from obesity-resistant rats. An important benefit of exercise during weight loss is that it results in preservation of fat-free mass and allows fat loss that is equivalent to or greater than weight loss.

Several physiological factors may be involved in the development of obesity. These include altered adipose tissue metabolism, hormonal changes, and changes at sites in the brain that control satiety, particularly in the hypothalamus. There may be some kind of abnormal signal that affects adipose tissue metabolism and alters fuel partitioning, directing increased storage in adipose tissue instead of use in muscle. This abnormal signal has not been identified. However, lipoprotein lipase has been found to be increased in obesity, and this enzyme can increase the storage of triglycerides in adipose tissue. Hormonal changes that may affect obesity include hyperinsulinemia and changes in pituitary or adrenal function. Hormonal changes during pregnancy promote fat deposition. If weight gain is excessive, it can result in lifelong obesity.

The role of psychological variables in the development of obesity is difficult to define. There is no unifying theme. Some obese individuals have eating disorders. Other obese individuals may eat in response to stress or depression. Still other obese individuals may eat large meals or may eat rapidly. It has also been suggested that some obese individuals may be restrained eaters, and when there is a break in their usual routine, they respond by excessive eating.

Although a number of mechanisms have been identified for the development of obesities, the exact picture is far from clear. For many individuals, there may be an underlying biological defect. When this individual comes into contact with a plentiful, good-tasting, high-fat food in an environment that promotes inactivity, obesity results. Also important is the fact that while many people may lose weight, there is little success in keeping the weight off. The reasons for this recidivism and possible solutions are the focus of current research.

Further Reading

1. Bouchard C., A. Tremblay, A. Nadeau, J. Dussault, J.-P. Despres, G. Theriault, P.J. Lupien, O. Serresse, M.R. Boulay, and G. Fournier. Long-term exercise training with constant energy intake. 1: Effect on body composition and selected metabolic variables. Int. J. Obesity 14:57-73, 1990.

2. Greenwood, M.R.C. and P.R. Johnson. Genetic differences in adipose tissue metabolism and regulation. Ann. N.Y. Acad. Sci. 676:253-269, 1993.

3. Johnson, P.R. and M.R.C. Greenwood. The adipose tissue. In: "Cell and Tissue Biology: A Textbook of Histology." (ed. by L. Weiss), 6th edition, Urban and Schwarzenberg, Baltimore, MD. pp. 191-209, 1988.

4. Johnson, P.R., J.S. Stern, M.R.C. Greenwood, L.M. Zucker, and J. Hirsch. Effect of early nutrition on adipose cellularity and pancreatic insulin release in the Zucker rat. J. Nutrition. 103:738-743, 1973.

5. Knittle, J.L. and J. Hirsch. Effect of early nutrition on the development of rat epididymal pads: cellularity and metabolism. J. Clin. Invest. 47:2091-2098, 1968.

6. St. Jeor, S.T. The role of weight management in the health of women. J. Amer. Dietetic Assoc. 93:1007-1012, 1993.

7. Stunkard, A.J., J.R. Harris, N.L. Pederson, and G.E. McClearn. The body-mass index of twins who have been reared apart. N. Engl. J. Med. 322:1483-1487, 1990.

8. Wadden T.A., and T.B. Van Itallie, Treatment of the seriously obese patient. The Guilford Press, New York, 524 pp, 1992.