Subcutaneous fat Adipose tissue anatomy

Subcutaneous fat

Brown and white adipocytes are histologically distinct. Lipids within white adipocytes are organized within one large, ‘‘unilocular’’ droplet, the size of which can exceed 50 mm. White adipocytes are spherical, thereby allowing for maximal volume within minimal space. Its diameter is variable, ranging between 30 and 70 mm according to depot site. The lipid droplet occupies the majority of intracellular space, compressing the cytoplasm and nucleus into a thin visible rim. Lipids within brown adipocytes are organized into multiple smaller ‘‘multilocular’’ droplets. Brown adipocytes are additionally characterized by their high content of large mitochondria packed with cristae within the cytoplasm. The cells are polygonal, have centrally placed nuclei, and are relatively smaller than white adipocytes, ranging from 20 to 40 mm (Alison et al., 2005).

WAT and BAT are both innervated by the noradrenergic fibers from the sympathetic nervous system. Noradrenergic fibers in WAT are mostly confined to the capillary wall, whereas in BAT they directly interface the plasma membrane of brown adipocytes via ‘‘incidental’’ synapses (Bartness and Bamshad ,1998).

Types of adipose tissue. Depots of white adipose tissue are found in areas all over the body, with subcutaneous and intra-abdominal depots representing the main compartments for fat storage. Brown adipose tissue is abundant at birth and still present in adulthood but to a lesser extent (Modified from Gesta et al., 2007).

Subcutaneous fat is organized into lobules of fat cells (lipocytes or adipocytes), and the lobules are separated by thin septa of connective tissue. The thickness of the subcutaneous fat varies from one part of the body to another, with a thinner sub cutis in areas of lax skin, such as the eyelids and scrotum, and thicker in the hips and buttocks. There are also gender differences in the deposition of fat, and an increased thickness of the sub cutis results in the rounded contours of the female body (Querleux et al., 2002).

Each individual lobule is supplied by an arteriole branching from the septa to form capillaries into the lobule, and a capillary network surrounds each individual adipocyte. Postcapillary venules meet in veins that also run along the septa. In each microlobule, the arteriole occupies a central position, whereas the venule runs along the periphery. In contrast with the dermal vascularization, the blood supply of each subcutaneous microlobule is terminal, meaning there are no capillary connections between adjacent microlobules or between dermis and subcutaneous fat. This peculiar structure of the blood supply in subcutaneous fat explains why large vessel vasculitis involving the septal vessels usually is accompanied by little inflammation of the fat lobules, whereas when the vasculitis involves small blood vessels, there is extensive necrosis of the adipocytes with centrilobular infarct and dense inflammatory infiltrate within the lobule. The septa of the subcutaneous fat also contain a rich lymphatic plexus, which come from the dermis and transverse the subcutis, first, parallel to the surface of the skin and then vertically penetrating the deep fascia and draining into the regional lymph nodes (Karpe et al., 2002).

In classic histopathology, changes in nuclei, namely, pyknosis, karyorrhesis, and karyolysis, are signs of cellular necrosis. In contrast, necrotic adipocytes, regardless of cause, may appear as either anucleated cells or with complete disintegration of the cellular structure. Sometimes the absence of nuclei is the only sign of necrosis of the adipocytes, and the fat cells appear as round empty bugs with no inflammatory infiltrate among them (White et al., 1996).

Adipocytes utilize glucose for TG synthesis via Glut4, a transmembrane transport protein produced by fat cells. Endocrine functions include production and secretion of peptides, including leptin, AGT, PAI-1, TNF-a, adiponectin, and adipsin. AGT, angiotensinogen; ATP, adenosine triphosphate; FFA, free fatty acid; Glut4, insulindependent glucose transporter; IL-6, interleukin 6; PAI-1, plasminogen activator inhibitor type 1; TG, triacylglycerol; TNF-a, tumor necrosis factor-a; VLDL, very-low-density lipoprotein (Modified from Morrison RF, Farmer SR. J Nutr 2000:130; 3116-21).

AC, Adenylate cyclase; ACS. acyl-coenzyme A synthetase; 59-AMP, 59-adenosine monophosphate; aP2, adipocyte fatty acid binding protein; α2-AR, α 2-adrenoreceptor; ATP, adenosine triphosphate; b-AR, b-adrenoreceptor; CO2, carbon dioxide; FATP, fatty acid transporter protein; FFA, free fatty acid; GI, inhibitory G protein; GS, stimulatory G protein; Glut4, insulin-sensitive glucose transporter; glycerol 3-P, glycerol 3-phosphate; IR, insulin receptor; HSL, hormone sensitive lipase; LPL, lipoprotein lipase; p, phosphorylation; PDE3B, cAMP phosphodiesterase 3B; PKA, protein kinase C (Modified from; Morrison RF, Farmer SR. J Nutr 2000:130;3116-21 ).

Once FAs released into the circulation, serve as fuel for metabolically active tissues via FA oxidation and the release of adenosine triphosphate (ATP), the body’s main energy source. Rates of FA oxidation are determined by the need for energy in the form of ATP. Glycerol generated from FA hydrolysis is converted via glycerol kinase in the liver to the glycerol moiety needed for TG synthesis. TGs are then packaged within very-low-density lipoproteins and released into circulation (Van Dijk, 2001).

The adipocyte, an important source for many physiologically active peptides, influences a multitude of organ systems, including adipose tissue, via endocrine, paracrine, and autocrine signals. Although most of the factors secreted from adipose tissue act in an autocrine/paracrine manner to regulate adipocyte metabolism, several are released into the bloodstream where they are carried to multiple distant sites for endocrine action. Some of these secreted factors share structural properties with cytokines and are, therefore, referred to collectively as ‘‘adipocytokines’’ (Trayhurn and Beattie, 2001).

AGT, Angiotensinogen; ALBP/aP2, adipocyte lipid-binding protein; α2-AR, α 2-adrenoreceptor; β-AR, β-adrenoreceptor; ASP, acylationstimulated protein; FA, fatty acid; FFA, free fatty acid; Glut4, insulin-dependent glucose transporter; IL-6, interleukin 6; LPL, lipoprotein lipase; PAI-1, plasminogen activator inhibitor type 1; PGE2, prostaglandin E2; PGI2, prostacyclin; TG, triacylglycerol; TNF-a, tumor necrosis factor-a; VLDL, very-low-density lipoprotein (Modified from Wajchenberg BL. Endocrine Rev 2000;21:697-738).

White adipocytes, which are the primary site of triglyceride/energy storage, but also brown adipocytes, which are important in both basal and inducible energy expenditure in the form of thermogenesis . This occurs through expression of uncoupling protein-1 (UCP-1), a 32 kDa protein found in the inner mitochondrial membrane, that allows dissipation of the proton electrochemical gradient generated by respiration in the form of heat (Cannon and Nedergaard, 2004).

In small mammals, such as rodents, BAT persists throughout its lifespan. In large mammals and humans, however, brown adipocytes from BAT depots undergo a morphologic transformation in which they rapidly accumulate lipids, become unilocular, and lose the ultrastructural and molecular properties that define them, including mitochondria. As a consequence, there are no discrete collections of BAT that can be found in the adult (Himms-Hagen, 2001).
BAT and WAT both express many of the same adipocyte-specific genes needed for lipid synthesis and hydrolysis.BAT has emerged as an independent organ with specific protein expression patterns and unique purpose .The 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 food into heat. UCP-1 activity, triggered in response to adrenergic signaling via the sympathetic nervous system, is up-regulated human neonates whenever extra heat is needed, such as during episodes of cold exposure, during the postnatal period, entry into a febrile state (Commins et al.,1999).
Physiologically, the heat produced by BAT and the resulting decrease in metabolic efficiency has significant impact. BAT not only provides an important adaptive mechanism for acute body temperature regulation, but also functions as protection against obesity (Sell et al., 2004).

Although it is unclear to what extent BAT might play a role in energy balance in adult humans, it was estimated that as little as 50 g of BAT could account for 20% of daily energy expenditure, if maximally stimulated. Furthermore, up to 24% of the increase in metabolism in lean men produced by ephedrine has been attributed to BAT. It has been suggested that the age-related decline in thermogenesis and regulatory energy expenditure in humans and rodents is associated with a reduction in the amount of functional BAT (Almind et al., 2007).

In human fetuses and newborns, BAT is found in axillary, cervical, perirenal, and periadrenal regions but decreases shortly after birth and has traditionally been considered insignificant in adults, except perhaps in patients with pheochromocytoma, where adrenergic activity is extremely high , or in outdoor workers in northern climes subject to prolonged cold exposure . However, morphological and scanning studies have shown that brown fat in humans may not be as rare as once believed. Areas of metabolically active brown fat can be detected in the cervical, supraclavicular, axillary, and paravertebral regions of normal individuals. UCP-1 mRNA can be detected in human WAT and is further induced by the antidiabetic drugs thiazolidinediones , suggesting some admixture of BAT in WAT depots (Nedergaard et al.,2007).

The 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 (Hansen et al.,2004).