Subcutaneous Fat: Anatomy, Physiology, and Treatment Indications

Introduction

Although it is well accepted by dermatologists that subcutaneous fat is an essential component of the skin, the basic science of fat physiology is still a poorly understood ‘black hole’ in the field of dermatology. Medical disorders related to fat such as panniculitis, lipodystrophies, localized adiposity, and atrophy are commonly treated by dermatologists either by medications or surgical pro­cedures. The demand for procedures that manipulate fat especially for cosmetic enhancement is becoming increasingly popular.

Multiple conditions affect fat distribution in the human body. Studies have shown the association between severe obesity and mortality due to increased rates of cardiovascular disease and diabetes. The type of regional adipose tissue with excess body fat in the upper mid-section of the body called android or male-type obesity represents the entity called visceral obesity. The type of fat distribution associated with accumulation in the lower part of the body or gluteofemoral region is known as gynoid or female type obesity, the excess of which is associated with higher grades of cellulite.

General adiposity (assessed by body mass index [BMI] which is determined by weight/height ) and abdominal adiposity are associated with a higher risk of death. However, abdominal obesity, which is determined by waist/hip ratio, may be a stronger indicator of obesity than BMI. Visceral and subcutaneous fat have distinct features and excess of either of these may result in a variety of health-related and/or aesthetic concerns.

Subcutaneous fat and gluteofemoral (cellulite) fat

The topographic anatomy of fatty tissue includes two layers that are separated by a superficial fascia. The more external layer or areolar layer consists of vertically oriented globular large adipocytes. The deeper layer, known as the lamellar layer, has horizontally arranged smaller cells with larger and more numerous blood vessels. Women and children tend to have a thicker areolar layer, which, in turn, is thicker in the gluteofemoral regions. Fatty tissue development during puberty is more robust in women than in men. This may be explained by the influence of estrogen as 17β-estradiol stimulates the replication of adipocytes ( Fig. 5.1 ). The adipocytes in the gluteofemoral region are larger and are influenced by female sex hormones These adipocytes are also metabolically more stable and resistant to lipolysis. In addition, estrogen increases the response of the adipocytes to antilipolytic α ₂ -adrenergic receptors (α ₂ -ARs).

The only hormones that are able to affect lipolysis in human adipocytes are catecholamines (epinephrine and norepinephrine, which are lipolytic) and insulin (antilipolytic). Functionally, there are marked regional differences in both hormonal responsiveness and metabolic activity of human adipose tissue. Catecholamine-induced lipolytic responsiveness is greater in viscera than in abdominal subcutaneous tissue and gluteofemoral fat cells. The regulation of lipolysis by catecholamines involves AR stimulation of adenylate cyclase via β-ARs (β ₁ , β ₂ , and β ₃ -ARs) and inhibition by α ₂ -ARs ( Fig 5.1 ). Abdominal and gluteal adipocyte cell size correlates directly with α ₂ -AR density (p < 0.1). The fact that the ratio of α ₂ -AR to β-AR is higher in the gluteal region than in abdominal adipocytes accounts for some of the enhanced responsiveness of abdominal fat cells compared with gluteal fat cells to mixed AR agonists, such as epinephrine and norepinephrine. In addition, abdominal adipocytes have a greater sensitivity to pure β-AR agonists such as isoproterenol. These factors are responsible for enhanced lipolysis of abdominal adipocytes secondary to catecholamine stimulation as compared to gluteal adipose tissue.

Adipose tissue lipoprotein lipase (LPL) directly correlates with the adipose cell size and its affinity for β-AR. Catecholamine-induced lipolysis, as measured by localized LPL release, suggests that abdominal adipocytes have an abundance of β-AR with greater central obesity seen in post-menopausal women as opposed to gynoid feminine type obesity, which is more prevalent in pre-menopausal women. Exogenous estrogen has been shown to have an inconsistent effect on lipolysis. For instance, it was shown to decrease LPL activity in the lower body of pre-menopausal women and yet have the opposite effect in postmenopausal women, again accounting for greater rates of central obesity seen after menopause. Gluteal fat cells are larger in size and richer in α ₂ -AR in pre-menopausal and post-menopausal women undergoing hormone replacement therapy.

White and brown adipocytes

Adipocytes are organized in a ‘multidepot organ’ with only one-third of adipose tissue containing mature adipocytes. The remaining two-thirds consist of a combination of nerves, fibroblasts, and adipocyte precursor cells, or pre-adipocytes ( Fig. 5.2 ). Mature adipocytes exist as two cell types, white adipose tissue (WAT) and brown adipose tissue (BAT), that are distinguished by their color and function. WAT is yellow or ivory and contains predominantly white adipocytes. BAT, which appears brown, contains multilocular brown adipocytes. Compared with WAT, BAT contains a richer vascular tree and denser capillaries in combination with mitochondria, which accounts for its ‘brown’ color. Both types of adipose tissue are innervated by the noradrenergic sympathetic nervous system.

BAT and WAT are histologically distinct yet interchangeable. Lipids in WAT are organized within one large, ‘unilocular’ droplet, the size of which exceeds 50 µm. White adipocytes are spherical, allowing for maximum volume expansion within minimal space. The nucleus is compressed to one side because of the high lipid content. Lipids within brown adipocytes are organized into multiple smaller, multilocular droplets. They have higher mitochondrial content packed with cristae within the cytoplasm. Cells are polygonal, have centrally placed nuclei, and are relatively smaller than WAT, ranging from 20 µm to 40 µm.

WAT is distributed in several anatomically distinct and separate collections or ‘depots’, namely the subcutaneous and intra-abdominal, each with its own characteristic metabolic, endocrine, paracrine, and autocrine function ( Table 5.1 ). In humans, BAT is most abundant in newborns and neonates. However in adults, it is also found around many major vessels, in perinephric fat pads and near adrenal glands. In small mammals, such as rodents, BAT persists throughout life. In larger mammals and humans, BAT depots undergo a morphologic transformation in which they rapidly accumulate fat, become unilocular, and lose the ultrastructural and molecular properties that define them, including mitochondria. Because of this, there are very few, if any, collections of BAT in adult humans.

Although WAT and BAT distribution patterns have been well documented, their morphology has been defined on the basis of histologic features alone, which are not sufficient to differentiate between the two. Brown adipocytes may appear white when not stimulated. Likewise, the morphology of white adipocytes changes progressively during fasting. They can become elongated and multilocular, or so-called ‘slim’. Because of difficulty differentiating adipocytes based on morphology alone, more advanced techniques are designed to detect the presence of uncoupling protein-1 (UCP-1), a protein that is unique to brown adipocytes. UCP-1 mRNA in adipose tissues is now considered a more accurate method for identifying activated brown adipocytes. Recent polymerase chain reaction (PCR) studies to detect UCP-1 mRNA in adipose tissue from rodents and humans have revealed the existence of scattered BAT within the WAT depots. Furthermore, trans-differentiation of white adipocytes into brown can be induced under certain conditions, thereby refuting the notion that stem cell commitment to, and differentiation into, the white or brown cell lineage is permanent.

WAT and BAT both express many of the same adipocyte-specific genes needed for lipid synthesis and hydrolysis in addition to secreting hormones that regulate energy homeostasis, such as leptin. However, BAT has emerged as an independent organ with specific expression of proteins and unique functions. Mitochondrial protein UCP-1 or thermogenin, which is expressed exclusively in BAT, is responsible for mediating the basic function of brown fat cells – namely, the transfer of energy from nutrition to heat. Being a means of energy expenditure rather than storage, BAT, in theory, may serve a protective function against obesity.

It has been long known that men and women differ in terms of distribution of body fat. Adipose accumulation favors the upper body, trunk and abdomen in men; while women accumulate fat tissue in the lower body, including hips and thighs. This is known as android (male) and gynoid (female) fat distribution patterns. With age, visceral fat accumulation has been shown to increase primarily in men and in menopausal and post-menopausal women. In contrast, pre-menopausal women may accumulate substantial amounts of body fat before starting to accumulate visceral fat. The differences in ways men and women accumulate fat suggest that body fat patterns are strongly influenced by sex hormone homeostasis. The relationship between estrogens, androgens and abdominal obesity is complex but broadly speaking treatment with testosterone generally leads to a shift to an android pattern of fat distribution. Conversely, estrogen treatment tends to increase fat deposition in all subcutaneous fat depots without increasing visceral fat. While a growing body of data has led to a better understanding of the role of sex hormone homeostasis on adipose tissue distribution and function, more research will be needed to fully understand their physiologic interactions and specific effects on individual adipose compartments.