Chapter 50 ANATOMY AND HISTOLOGY OF THE FAT COMPARTMENTS OF THE BODY

10.1055/b-0038-149586

Chapter 50 ANATOMY AND HISTOLOGY OF THE FAT COMPARTMENTS OF THE BODY

Andrea Sbarbati, Maria Rosaria Marinozzi, Giamaica Conti

Adipose tissue is a specialized connective tissue involved in the synthesis and storage of fat. It is mainly composed of specialized cells (adipocytes) that are enmeshed in a structural network of collagen fibers. The fat stored in adipose tissue comes from dietary fats or is produced in the body. Adipose tissue includes numerous anatomic depots. In adults it is located beneath the skin (subcutaneous fat), around internal organs (visceral fat), in bone marrow (yellow bone marrow), and in breast tissue, but it is also present in deposits between the muscles and in other organs.

In humans, the distribution of adipose tissue varies as a function of genetics, age, sex, race, and, for some depots, sensitivity to hormones and glucocorticoids.

The first fat lobule begins to develop between the fourteenth and sixteenth weeks of gestation, with cranial-to-caudal and proximal-to-distal gradients. By 28 weeks, fat lobules can be detected in all presumptive visceral and subcutaneous locations. ¹

Mammals have two different types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). Recently, a third potential class of adipose tissue called brite (“brown-in-white”), also known as beige, inducible brown, or recruitable brown, has been identified. It is formed by a “mysterious” type of adipocyte. It is morphologically indistinguishable from its neighboring white adipocytes in the basal or unstimulated state. However, when stimulated by chronic cold exposure (or other mechanisms that mimic beta-adrenergic stimulation), it becomes multilocular and begins thermogenesis. ²

Brown Adipose Tissue: A Thermogenic Tissue

BAT is mainly located in the visceral area, and brown adipocytes represent the major part of BAT. Brown adipocytes contain multiple smaller (multilocular) lipid droplets. Brown adipocytes are rich in mitochondria and reside in depots that are highly innervated and vascularized.

BAT is a thermogenic tissue. ³ Thermogenesis is mediated by an oxidative phosphorylation of free fatty acids, regulated by expression of tissue-specific mitochondrial brown fat uncoupling protein 1 (UCP1). ⁴ BAT activation depends on sympathetic (noradrenergic) stimulation. Thermogenesis can be vital in neonates exposed to the cold, because they are unable to shiver and require this process to keep warm. However, with aging, the BAT disappears and sets up an unilocular lipid deposit. In this case, it strongly resembles WAT, but it maintains the capability to respond after physiologic stimuli. The interest in BAT function has increased in the past 20 years, because hypofunction or hyperfunction of BAT is involved in the pathogenesis of obesity ⁵ and in other pathologic conditions. ⁶ The biochemistry and cell biology of BAT have been extensively investigated, and excellent descriptions are available. ⁷

White Adipose Tissue: A Heterogeneous Tissue

The major part of human adipose tissue is composed of WAT. It forms pads between organs and has different functions. Its primary purpose is energy storage in the form of triglycerides. It can also act as a thermal insulator and can protect other organs from mechanical damage. ⁸ WAT’s functions are regulated by endocrine signals and the sympathetic nervous system. In particular, energy metabolism in adipocytes is controlled by hormones such as insulin, catecholamines, and glucocorticoids produced by other organs. These hormones bind to adipocytes and trigger the hydrolysis of triacylglycerol, resulting in the release of energy-rich fatty acids and glycerol, the process known as lipolysis.

WAT is also involved in the immune response, antiinflammatory blood pressure control, blood clotting, and thyroid and reproductive functions. These processes are coordinated mainly through the synthesis and release of bioactive peptides called adipokines (such as adiponectin, leptin), which act locally and distally through autocrine, paracrine, and endocrine effects. ⁹

Two main cellular components may be identified in the WAT: white adipocytes and the stromal vascular fraction (SVF). They are morphologically different but functionally related. The remaining part of the adipose tissue is composed of water (5% to 30%) and protein (3% or less).

White adipocytes represent 90% of the mass of the WAT, and 60% to 85% of their weight is represented by lipids—for the most part triglycerides and free fatty acids, diglycerides, cholesterol, phospholipids, and small amounts of cholesterol esters. The principal fatty acids are myristic, palmitic, palmitoleic, stearic, oleic, and linoleic acids.

White adipocytes are large, spherical, and tightly packed and are supported by richly vascularized loose connective tissue. The size of adipocytes is based on the cells’ lipid content, ranging from 80 to 130 µm in diameter; their volume varies in relation with their activity. They contain a unique, large droplet surrounded by a phospholipid monolayer enhanced by a cagelike structure of vimentin network, perilipin, and proteins. ¹⁰ The nucleus is flattened and located on the periphery, and its nuclear lamina is coupled to the vimentin network. ¹¹ Near the nucleus the cytoplasm gets thicker and contains a Golgi apparatus, smooth and rough endoplasmic reticulum, free ribosomes, and large, elongated mitochondria with densely packed transverse cristae. ¹² The amount of mitochondria and their enzymatic equipment varies between different fat depots, contributing to the diverse physiology of the adipose tissue. ¹³ White adipocytes have a profound actin cortical network. ¹¹ The cytoplasm of white adipocytes contains also lipid structures, called lipid droplets, lipid bodies, or adiposomes. They are highly intracytoplasmic organelles composed of a core of neutral lipids surrounded by a phospholipid monolayer and associated proteins that regulate their size and lipid traffic. ¹⁴

The plasma membrane is specialized in fatty acid protein-mediated transport. ¹⁵ It contains various types of receptors for hormones, neurotransmitters (mainly noradrenaline), cytokines, and other signaling molecules. ¹⁶ Adipocytes express toll-like receptors, which are responsible for the recognition of pathogen-associated molecular patterns and other signaling molecules of innate and adaptive immunity. ¹⁷ The plasma membrane is covered by glycocalyx. ¹²

SVF consists of multipotent stem cells, preadipocytes, fibroblasts, pericytes, endothelial cells of blood and lymphatic vessels, macrophages, mast cells, and other infiltrating immune cells. ¹⁶ Lymphoid cells are also present. ¹⁸ SVF cellular compartments and their role are summarized in Table 50-1.

**Table 50-1 Cellular Components of the Stromal Vascular Fraction**
Stem Cells	Mast Cells	Preadipocytes	Lymphocytes	Macrophages
Multipotency (can differentiate in bone, cartilage, muscle, adipose cells)	Related to inflammatory processes, remodeling processes, and obesity	Different proliferative potentials, depending on the fat pad of origin	CD8+ T cells, INFgamma+, CD4+ T cells, and beta 2 cells, and regulatory T cells (Tregs) as antiinflammatory cells	Are bone marrow– derived cells that have an active role in starting inflammation, apoptosis and recruitment of inflammatory cells.
Largely employed in regenerative and reconstructive surgery, particularly for skin regeneration, scar correction, and breast reconstruction	Involved in cytokine secretion in adipose tissue, insulin resistance mechanisms, and oxidative metabolism regulation	Differentiate in adipocytes or adipocyte precursors that could stimulate the adhesion mechanism in neoplastic cells	Their presence in adipose tissue is related to obesity, a high leptin level, Treg downregulation, and susceptibility to autoimmune diseases	Their numbers increase in pathologic conditions such as obesity. This process is led by paracrine activation of macrophages and other cell types and involves several mechanisms such as angiogenesis, modulation, and differentiation of adipocyte precursors.

VISCERAL ADIPOSE TISSUE

Visceral adipose tissue (vWAT) is associated with internal organs. It can be divided into three major depots. The first is the omental fat that is associated with the intestines; the second is the mesenteric fat that is more deeply buried around the intestines and the retroperitoneal fat, which is located near the kidneys, at the dorsal side of the abdominal cavity. Third, smaller amounts of vWAT are localized in the mediastinum (intrathoracic or pericardial fat) and around specific organs, such as the heart (epicardial fat), stomach (epigastric fat), and blood vessels (perivascular fat). ¹⁹ The fat lobules of vWAT, especially in the greater omentum, are large, irregular, and not surrounded by collagen septa. In fact this adipose depot is composed in prevalence by mature unilocular adipocytes. ²⁰

vWAT accumulation has been closely related to a cluster of metabolic alterations, including insulin resistance, hyperinsulinemia, elevated triglyceride levels, low high-density lipoprotein (HDL) cholesterol, and hypertension. ²¹ The adipocytes of the vWAT show high lipogenic and lipolytic activities and produce proinflammatory cytokines. In addition, molecules involved in innate immunity, acute phase response, and in complement factors are overexpressed in vWAT.

SUBCUTANEOUS ADIPOSE TISSUE

Subcutaneous adipose tissue (sWAT) is distributed over the body’s surface in the hypodermal layer of the skin and it is sandwiched between dermis and deep fascia. Fat lobules of the sWAT layer are generally organized in a regular fashion. Connective scaffolding of sWAT varies according to anatomic site and function. ²²

Classification of the Subcutaneous Adipose Tissue

sWAT appears structurally homogeneous, but actually the differences in the morphology among the various fat depots are qualitative and quantitative. The structure of sWAT can vary, depending on the body location, age, sex, weight, race, and nutrition. For instance, elderly patients have a larger amount of collagen in the connective mesh of the sWAT than younger individuals, and there is a moderate thickening of vascular walls during aging. In the abdomen and hips, the deep layer appears rich in fibrous components.

**Table 50-2 Subcutaneous Adipose Tissue Classification**
Deposit sWAT	Structural sWAT	Fibrous sWAT	Lobular sWAT	Nonlobular sWAT
Poor collagenic component	More stroma is present	Fibers are thick and abundant	Fibers are very abundant and thick	Present in tissue characterized by a maximum degree of fibrosis
Unilocular adipocytes of 90-100 µm	Adipocytes of 80 µm embedded in muscular tissue	Adipocytes of 80 µm in diameter embedded in a dense collagen matrix	Well-vascularized tissue with capillaries characterized by thick endothelium	The presence of capillaries and vessels is variable but generally not abundant
Extracellular space very slim; thin-walled capillaries and rare stem niches	Observed in particular in depots subjected to mechanical stress	Observed in particular in trochanter, suprapubic area, arm pits, inner face of knee, thighs, arms, pectoral and mammary areas	Adipocytes of 90-100 µm organized in clusters surrounding collagen fibers	Adipocytes are characterized by very scarce lipid content

It is evident that this heterogeneity is related to the different roles played by each single district. This leads us to realize that a more appropriate term would be subcutaneous sWATs rather than sWAT. The heterogeneity of sWAT could be connected to the functional specializations of the depots in the various sites. ²¹ Lipids are mobilized at a slower rate but are synthesized at a higher rate in the femoral area than in the abdominal region. Fasting is accompanied by an increased rate of fat mobilization and a decreased rate of fat synthesis in all fatty depots. There are also regional differences in the hormonal regulation of fat metabolism in obesity. The action of insulin is most pronounced in the femoral region, whereas the activity of catecholamines is most marked in the abdominal area.

Actually, sWAT is classified as a large subfamily. Based on their structural and ultrastructural features, there are three kinds of WAT: deposit WAT (dWAT), structural WAT (stWAT), and fibrous WAT (f WAT). ²³ However, it must be emphasized that the individual depots could be made by mixtures of different types of sWAT.

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