Wat

Figure 5 Schematic representation of cell types present in adipose tissue. WAT, white adipose tissue.

preparation dissolve out the lipids, leaving a thin rim of eosinophilic cytoplasm that typically loses its round shape during tissue processing, thus contributing to the sponge-like appearance of WAT in routine preparations for light microscopy (Figure 6 and Figure 7). Owing to the fact that about 90% of the cell volume is a lipid droplet, the small dark nucleus becomes a flattened semilunar structure pushed against the edge of the cell and the thin cytoplasmic rim is also pushed to the periphery of the adipocytes. Mature white adipose cells contain a single large lipid droplet and are described as unilocular. However, developing white adipocytes are transiently multilocular containing multiple lipid droplets before these finally coalesce into a single large drop (Figure 8). The nucleus is round or oval in young fat cells, but is cup-shaped and peripherally displaced in mature adipocytes. The cytoplasm is stretched to form a thin sheath around the fat globule, although a relatively large volume is concentrated around the nucleus. A thin external lamina called basal lamina surrounds the cell. The smooth cell membrane shows no microvilli but has abundant smooth micropinocytotic invaginations that often fuse to form small vacuoles appearing as rosette-like configurations (Figure 9). Mitochondria are few in number with loosely arranged membranous cristae. The Golgi zone is small and the cytoplasm is filled with free ribosomes, but contains only a limited number of short profiles of the granular endoplasmic reticulum. Occasional lyso-somes can be found. The coalescent lipid droplets contain a mixture of neutral fats, triglycerides, fatty acids, phospholipids, and cholesterol. A thin interface membrane separates the lipid droplet from the cytoplasmic matrix. Peripheral to this membrane is a system of parallel meridional thin filaments. Because of the size of these cells, relative to the thickness of the section, the nucleus (accounting for only one-fortieth of the cell volume) may not always be present in the section. Unilocular adipo-cytes usually appear in clumps near blood vessels, which is reasonable since the source and dispersion of material stored in fat cells depends on transportation by the vascular system.

Brown fat is a specialized type of adipose tissue that plays an important role in body temperature regulation. In the newborn brown fat is well developed in the neck and interscapular region. It has a limited distribution in childhood, and occurs only to a small degree in adult humans, while it is present in significant amounts in rodents and hibernating animals. The brown color is derived from a rich vascular network and abundant mitochondria and lysosomes. The individual multilocular adipocytes are frothy appearing cells due to the fact that the lipid, which does not coalesce as readily as in white fat cells and is normally stored in multiple small droplets, has been leached out during tissue

Figure 6 (A) Human subcutaneous white adipose tissue with Masson trichrome staining (10x; bar = 100mm). (B) Same tissue at a higher magnification (40x; bar = 25 mm). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra, Spain.)

Figure 6 (A) Human subcutaneous white adipose tissue with Masson trichrome staining (10x; bar = 100mm). (B) Same tissue at a higher magnification (40x; bar = 25 mm). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra, Spain.)

processing (Figure 10). The spherical nuclei are centrally or eccentrically located within the cell. Compared to the unilocular white adipocytes, the cytoplasm of the multilocular brown fat cell is relatively abundant and strongly stained because of the numerous mitochondria present. The mitochondria are involved in the oxidation of the stored lipid, but because they exhibit a reduced potential to carry out oxidative phosphorylation, the energy produced is released in the form of heat due to the uncoupling activity of UCP and not captured in adenosine triphosphate (ATP). Therefore, brown adipose tissue is extremely well vascularized so that the blood is warmed when it passes through the active tissue.

Figure 7 (A) Human omental white adipose tissue with Masson trichrome staining (10x; bar = 100mm). (B) Same tissue at a higher magnification (40x; bar = 25mm). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra, Spain.)

Distribution

White adipose tissue may represent the largest endocrine tissue of the whole organism, especially in overweight and obese patients. The anatomical distribution of individual fat pads dispersed throughout the whole body and not connected to each other contradicts the classic organ-specific localization. WAT exhibits clear, regional differences in its sites of predilection (Table 1). The hypodermal region invariably contains fat, except in a few places such as the eyelids and the scrotum. Adipocytes also accumulate around organs like the kidneys and adrenals, in the coronary sulcus of the heart, in bone marrow, mesentery, and omentum. Unilocular fat is

Adipose Tissue Masson Trichrome Stain
Figure 8 Paraffin section of rat abdominal white adipose tissue with a hematoxylin and eosin stain showing the simultaneous presence of uni- and multilocular adipocytes (40x; bar = 25 mm). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra, Spain.)

widely distributed in the subcutaneous tissue of humans but exhibits quantitative regional differences that are influenced by age and sex. In infants and young children there is a continuous subcutaneous fat layer, the panniculus adiposus, over the whole body. This layer thins out in some areas in adults but persists and grows thicker in certain other regions. The sites differ in their distribution among sexes, being responsible for the characteristic body form of males and females, termed android and ginecoid fat distribution. In males, the main regions include the nape of the neck, the subcutaneous area over the deltoid and triceps muscles, and the lumbosacral region. In females, subcutaneous fat is most abundant in the buttocks, epitrochanteric region, anterior and lateral aspects of the thighs, as well as the breasts. Additionally, extensive fat depots are found in the omentum, mesenteries, and the retroperitoneal area of both sexes. In well-nourished, sedentary individuals, the fat distribution persists and becomes more obvious with advancing age with males tending to deposit more fat in the visceral compartment. Depot-specific differences may be related not only to the metabolism of fat cells but also to their capacity to form new adipo-cytes. Additionally, regional differences may result from variations in hormone receptor distribution as well as from specific local environmental characteristics as a consequence of differences in innervation and vascularization.

Regional distribution of body fat is known to be an important indicator for metabolic and cardiovascular alterations in some individuals.

Figure 9 (A) Transmission electron micrographs with the characteristically displaced nucleus to one side and slightly flattened by the accumulated lipid. The cytoplasm of the fat cell is reduced to a thin rim around the lipid droplet (7725x). (B) The cytoplasm contains several small lipid droplets that have not yet coalesced. A few filamentous mitochondria, occasional cisternae of endoplasmic reticulum, and a moderate number of free ribosomes are usually visible (15000x). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra, Spain.)

Figure 9 (A) Transmission electron micrographs with the characteristically displaced nucleus to one side and slightly flattened by the accumulated lipid. The cytoplasm of the fat cell is reduced to a thin rim around the lipid droplet (7725x). (B) The cytoplasm contains several small lipid droplets that have not yet coalesced. A few filamentous mitochondria, occasional cisternae of endoplasmic reticulum, and a moderate number of free ribosomes are usually visible (15000x). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra, Spain.)

(A)

Figure 10 (A) Paraffin section of rat brown adipose tissue with a hematoxylin and eosin stain (20x; bar = 50mm). (B) Same tissue at a higher magnification (40x; bar = 25mm). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra.)

Figure 10 (A) Paraffin section of rat brown adipose tissue with a hematoxylin and eosin stain (20x; bar = 50mm). (B) Same tissue at a higher magnification (40x; bar = 25mm). (Courtesy of Dr. M A Burrell and M Archanco, University of Navarra.)

The observation that the topographic distribution of adipose tissue is relevant to understanding the relation of obesity to disturbances in glucose and lipid metabolism was formulated before the 1950s. Since then numerous prospective studies have revealed that android or male-type obesity correlates more often with an elevated mortality and risk for the development of diabetes mellitus type 2, dyslipidemia, hypertension, and atherosclerosis than gynoid or female-type obesity. Obesity has been reported to cause or exacerbate a large number of health problems with a known impact on both life expectancy and quality of life. In this respect, the association of increased adiposity is accompanied by important pathophysiological

Table 1 Distribution of main human adipose tissue depots

Subcutaneous (approx. 80%; deep l superficial layers)

Truncal

- Cervical

- Dorsal

- Lumbar Abdominal Gluteofemoral Mammary

Visceral (approx. 20%; thoracic-abdominal-pelvic)

Intrathoracic (extra-intrapericardial) Intra-abdominopelvic

- Intraperitoneal

Omental (greater and lesser omentum) Mesenteric (epiplon, small intestine, colon, rectum) Umbilical

- Extraperitoneal

Peripancreatic (infiltrated with brown adipocytes) Perirenal (infiltrated with brown adipocytes)

- Intrapelvic

Gonadal (parametrial, retrouterine, retropubic) Urogenital (paravesical, para-retrorectal)

Intraparenchymatous (physiologically or pathologically)

Inter-intramuscular and perimuscular (inside the muscle fascia) Perivascular

Paraosseal (interface between bone and muscle) Ectopic (steatosis, intramyocardial, lypodystrophy, etc.)

Hyperlipidemia

Cardiovascular disease

Cancer Obstructive sleep apnea Hyperuricemia

Atherosclerosis/ inflammation

Hyperlipidemia sleep apnea Hyperuricemia

Atherosclerosis/ inflammation

^ Psychosocial distress

Others

Figure 11 Main comorbidities associated with increased adiposity.

Metabolic syndrome Infertility

^ Psychosocial distress

Osteoarthritis

Gastrointestinal alterations

Others

Figure 11 Main comorbidities associated with increased adiposity.

alterations, which lead to the development of a wide range of comorbidities (Figure 11).

Function

Although many cell types contain small reserves of carbohydrate and lipid, the adipose tissue is the body's most capacious energy reservoir. Because of the high energy content per unit weight of fat as well as its hydrophobicity, the storage of energy in the form of triglycerides is a highly efficient biochemical phenomenon (1 g of adipose tissue contains around 800 mg triacylglycerol and only about 100 mg of water). It represents quantitatively the most variable component of the organism, ranging from a few per cent of body weight in top athletes to more than half of the total body weight in severely obese patients. The normal range is about 10-20% body fat for males and around 20-30% for females, accounting approximately for a 2-month energy reserve. During pregnancy most species accrue additional reserves of adipose tissue to help support the development of the fetus and to further facilitate the lactation period.

Energy balance regulation is an extremely complex process composed of multiple interacting homeostatic and behavioral pathways aimed at maintaining constant energy stores. It is now evident that body weight control is achieved through highly orchestrated interactions between nutrient selection, organoleptic influences, and neuroendocrine responses to diet as well as being influenced by genetic and environmental factors. The concept that circulating signals generated in proportion to body fat stores influence appetite and energy expenditure in a coordinated manner to regulate body weight was proposed almost 50 years ago. According to this model, changes in energy balance sufficient to alter body fat stores are signaled via one or more circulating factors acting in the brain to elicit compensatory changes in order to match energy intake to energy expenditure. This was formulated as the 'lipostatic theory' assuming that as adipose tissue mass enlarges, a factor that acts as a sensing hormone or 'lipostat' in a negative feedback control from adipose tissue to hypothalamic receptors informs the brain about the abundance of body fat, thereby allowing feeding behavior, metabolism, and endocrine physiology to be coupled to the nutritional state of the organism. The existing body of evidence gathered in the last decades through targeted expression or knockout of specific genes involved in different steps of the pathways controlling food intake, body weight, adiposity, or fat distribution has clearly contributed to unraveling the underlying mechanisms of energy homeostasis. The findings have fostered the notion of a far more complex system than previously thought, involving the integration of a plethora of factors.

The identification of adipose tissue as a multifunctional organ as opposed to a passive organ for the storage of excess energy in the form of fat has been brought about by the emerging body of evidence gathered during the last few decades. This pleiotro-pic nature is based on the ability of fat cells to secrete a large number of hormones, growth factors, enzymes, cytokines, complement factors, and matrix proteins, collectively termed adipokines or adipocy-tokines (Table 2, Figure 12), at the same time as expressing receptors for most of these factors (Table 3), which warrants extensive cross-talk at a local and systemic level in response to specific external stimuli or metabolic changes. The vast majority of adipocyte-derived factors have been shown to be dysregulated in alterations accompanied by changes

Table 2 Relevant factors secreted by adipose tissue into the bloodstream

Molecule

Function/effect

Adiponectin/ACRP30/AdipoQ/

apM1/GBP28 Adipsin

Angiotensinogen

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