Adipose Tissue

G Frühbeck and J Gomez-Ambrosi, Universidad de

Navarra, Pamplona, Spain

© 2005 Elsevier Ltd. All rights reserved.

Introduction

The role of white adipose tissue (WAT) in storing and releasing lipids for oxidation by skeletal muscle and other tissues became so firmly established decades ago that a persistent lack of interest hindered the study of the extraordinarily dynamic behavior of adipocytes. However, disentangling the neuroendocrine systems that regulate energy homeostasis and adiposity has jumped to a first-priority challenge, with the recognition of obesity as one of the major public health problems. Strictly speaking, obesity is not defined as an excess of body weight but as an increased adipose tissue accretion, to the extent that health may be adversely affected. Therefore, in the last decades, adipose tissue has become the research focus of biomedical scientists for epide-miological, pathophysiological, and molecular reasons. Although the primary role of adipocytes is to store triglycerides during periods of caloric excess and to mobilize this reserve when expenditure exceeds intake, it is now widely recognized that adipose tissue lies at the heart of a complex network that participates in the regulation of a variety of quite diverse biological functions (Figure 1).

Development

Adipose tissue develops extensively in home-otherms with the proportion to body weight varying greatly among species. Adipocytes differentiate from stellate or fusiform precursor cells of mesenchymal origin. There are two processes of adipose tissue formation. In the primary fat formation, which takes place relatively early (in human fetuses the first traces of a fat organ are detectable between the 14th and 16th weeks of prenatal life), gland-like aggregations of epithe-loid precursor cells, called lipoblasts or preadipocytes, are laid down in specific locations and accumulate multiple lipid droplets becoming brown adipocytes. The secondary fat formation takes place later in fetal life (after the 23rd week of gestation) as well as in the early postnatal period, whereby the differentiation of other fusiform precursor cells that accumulate lipid to ultimately coalesce into a single large drop per cell leads to the dissemination of fat depots formed by unilocular white adipocytes in many areas of connective tissue. Adipose tissue may be partitioned by connective tissue septa into lobules. The number of fat lobules remains constant, while in the subsequent developmental phases the lobules continuously increase in size. At the sites of early fat development, a multilo-cular morphology of adipocytes predominates, reflecting the early developmental stage. Microscopic studies have shown that the second trimester may be a critical period for the development of obesity in later life. At the beginning of the third trimester, adipocytes are present in the main fat depots but are still relatively small. During embryonic development it is important to emphasize the temporospacial tight coordination of angiogenesis with the formation of fat cell clusters. At birth, body fat has been reported to

Appetite regulation

Appetite regulation

metabolism

Figure 1 Dynamic view of white adipose tissue based on the pleiotropic effects on quite diverse physiological functions.

metabolism

Figure 1 Dynamic view of white adipose tissue based on the pleiotropic effects on quite diverse physiological functions.

account for approximately 16% of total body weight (with brown fat constituting 2-5%) with an increase in body fat of around 0.7-2.8 kg during the first year of life.

Adipogenesis, i.e., the development of adipose tissue, varies according to sex and age. Furthermore, the existence of sensitive periods for changes in adipose tissue cellularity throughout life has been postulated. In this regard, two peaks of accelerated adipose mass enlargement have been established, namely after birth and between 9 and 13 years of age. The capacity for cell proliferation and differentiation is highest during the first year of life, while it is less pronounced in the years before puberty. Thereafter, the rate of cell proliferation slows down during adolescence and, in weight stable individuals, remains fairly constant throughout adulthood. In case of a maintained positive energy balance adipose mass expansion takes places initially by an enlargement of the existing fat cells. The perpetuation of this situation ends up in severe obesity where the total fat cell number can be easily trebled. Childhood-onset obesity is characterized by a combination of fat cell hyperplasia and hypertrophy, whereas in adult-onset obesity a hypertrophic growth predominates. However, it has been recently shown that adult humans are capable of new adipocyte formation, with fat tissue containing a significant proportion of cells with the ability to undergo differentiation. Interestingly, the hyper-plasic growth of fat cells in adults does not take place until the existing adipocytes reach a critical cell size.

Initially, excess energy storage starts as hyper-trophic obesity resulting from the accumulation of excess lipid in a normal number of unilocular adipose cells. In this case, adipocytes may be four times their normal size. If the positive energy balance is maintained, a hyperplasic or hypercellular obesity characterized by a greater than normal number of cells is developed. Recent observations regarding the occurrence of apoptosis in WAT have changed the traditional belief that acquisition of fat cells is irreversible. The adipose lineage originates from multipotent mesenchymal stem cells that develop into adipoblasts (Figure 2). Commitment of these adipoblasts gives rise to preadipose cells (preadipocytes), which are cells that have expressed early but not late markers and have yet to accumulate triacylglycerol stores (Figure 3). Multipotent stem cells and adipoblasts, which are found during embryonic development, are still present postnatally. The relationship between brown and white fat during development has not been completely solved. Brown adipocytes can be detected among all white fat depots in variable amounts depending on species, localization, and environmental temperature. The transformation of characteristic brown adipocytes into white fat cells can take place rapidly in numerous species and depots during postnatal development.

The morphological and functional changes that take place in the course of adipogenesis represent a shift in transcription factor expression and activity leading from a primitive, multipotent state to a final phenotype characterized by alterations in cell shape and lipid accumulation. Various redundant signaling pathways and transcription factors directly influence fat cell development by converging in the upregula-tion of PPAR7, which embodies a common and essential regulator of adipogenesis as well as of adi-pocyte hypertrophy. Among the broad panoply of transcription factors, C/EBPs and the basic helix-loop-helix family (ADD1/SREBP-1c) also stand out together with their link with the existing nutritional status. The transcriptional repression of adipogen-esis includes both active and passive mechanisms. The former directly interferes with the transcrip-tional machinery, while the latter is based on the binding of negative regulators to yield inactive forms of known activators.

Hormones, cytokines, growth factors, and nutrients influence the dynamic changes related to adipose tissue mass as well as its pattern of distribution (Figure 4). The responsiveness of fat cells to neurohumoral signals may vary according to peculiarities in the adipose lineage stage at the moment of exposure. Moreover, the simultaneous presence of some adipogenic factors at specific threshold concentrations may be a necessary requirement to trigger terminal differentiation.

Enhancer Tissue Specific
Figure 2 Schematic diagram of the histogenesis of white and brown adipocytes. C/EBPs, CCAAT/enhancer binding proteins; PGC-1a, peroxisome proliferator-activated receptor-7 coactivator-1; PPAR7, peroxisome proliferator-activated receptor-7.

Structure

Adipose tissue is a special loose connective tissue dominated by adipocytes. The name of these cells is based on the presence of a large lipid droplet with 'adipo' derived from the Latin adeps meaning 'pertaining to fat.' In adipose tissue, fat cells are individually held in place by delicate reticular fibers clustering in lobular masses bounded by fibrous septa surrounded by a rich capillary network. In adults, adipocytes may comprise around 90% of adipose mass accounting only for roughly 25% of the total cell population. Thus, adipose tissue itself is composed not only of adipocytes, but also other cell types called the stroma-vascular fraction, comprising blood cells, endothelial cells, pericytes, and adipose precursor cells among others (Figure 5);

these account for the remaining 75% of the total cell population, representing a wide range of targets for extensive autocrine-paracrine cross-talk.

Adipocytes, which are typically spherical and vary enormously in size (20-200 mm in diameter, with variable volumes ranging from a few picoliters to about 3 nanoliters), are embedded in a connective tissue matrix and are uniquely adapted to store and release energy. Surplus energy is assimilated by adipocytes and stored as lipid droplets. The stored fat is composed mainly of triacylglycerols (about 95% of the total lipid content comprised principally of oleic and palmitic acids) and to a smaller degree of diacylglycerols, phospholipids, unesteri-fied fatty acids, and cholesterol. To accommodate the lipids adipocytes are capable of changing their

Mesenchymal Immature Mature stem cell Adipoblast Preadipocyte adipocyte adipocyte

expansion k \ accumulation"- Ii |

st + expansion accumulation

Molecular/ Proliferation expansion physiological „

events , Growth arrest +

and early markers' appearance emerging regulatory genes

ECM alterations Cytoskeletal remodeling LPL CD36 SREBP-1 C/EBP/3 & S PPAR7 C/EBPa GLUT4

Lipogenic enzymes aP2

Leptin & other secreted factors

Figure 3 Multistep process of adipogenesis together with events and participating regulatory elements. aP2, adipocyte fatty acid binding protein; C/EBPa, CCAAT/enhancer binding protein a; C/EBPp & S, CCAAT/enhancer binding protein p & S; CD36, fatty acid translocase; ECM, extracellular matrix; GLUT4, glucose transporter type 4; LPL, lipoprotein lipase; PPAR7, peroxisome proliferator-activated receptor-7; Pref-1, preadipocyte factor-1; SREBP-1, sterol regulatory element binding protein-1.

diameter 20-fold and their volumes by several thousandfold. However, fat cells do not increase in size indefinitely. Once a maximum capacity is attained, which in humans averages 1000 picoliters, the formation of new adipocytes from the precursor pool takes place.

Histologically, the interior of adipocytes appears unstained since the techniques of standard tissue

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