Research Paper on Adipocytes

Introduction

Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions.

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Adipose tissue has been ignored by anatomists and physicians for centuries, considered to be an energy storage depot with few interesting attributes. The well-documented rise in obesity during the past 30 years1has contributed to the negative image of adipose tissue, particularly in the popular mind. The past two decades, however, have seen a wave of intense scientific interest in this cell type, fuelled in part by concerns about obesity and its attendant metabolic sequelae2, and also by the recognition that adipocytes integrate a wide array of homeostatic processes. In addition to regulating fat mass and nutrient homeostasis (discussed below), adipocytes are involved in the immune response, blood pressure control, haemostasis, bone mass, and thyroid and reproductive function3. These processes are coordinated mainly through the synthesis and release of peptide hormones by adipocytes.

Adipocytes also release fatty acids into the circulation, which are used by most organs for fuel when glucose is limiting. These fatty acids are generated by breaking down triacylglycerols, which contain more energy per unit mass than do carbohydrates and can essentially be stored anhydrously. By contrast, glycogen has only the half the energy content per unit of pure mass, and must be stored in association with water, further decreasing its efficiency.

Although most multicellular organisms have cells that store excess energy, adipocytes evolved to meet this need at the time of the vertebrate radiation. Mammals, birds, reptiles, amphibians and many (but not all) fish have cells that are readily identifiable as adipocytes, although the anatomical location of fat tissues varies considerably between species4. Most mammals have stereotypical adipose depots located throughout the body. Some of these depots are thought to be largely structural, providing mechanical support but contributing relatively little to energy homeostasis. Examples include the fat pads of the heels, fingers and toes, and the periorbital fat supporting the eyes. Other adipocytes exist in loose association with the skin, and have been termed subcutaneous fat. These cells are the cause of 'cellulite', and are the target of cosmetic procedures such as liposuction. Finally, there are several distinct depots within the body cavity, surrounding the heart and other organs, associated with the intestinal mesentery, and in the retroperitoneum. Some of these depots, known as visceral fat, drain directly into the portal circulation and have been linked to many of the morbidities associated with obesity, including type 2 diabetes and cardiovascular disease. Adipocytes and precursor cells from different depots have different replicative potential, different developmental attributes and different responses to hormonal signals, although the mechanistic basis for these distinctions is still unclear5.

In addition to depot-specific differences, a further distinction must be made between brown and white adipocytes. Brown adipocytes are found only in mammals, and differ from the more typical white adipocytes in that they express uncoupling protein-1 (UCP-1), which dissipates the proton gradient across the inner mitochondrial membrane that is produced by the action of the electron transport chain. This generates heat at the expense of ATP. Morphologically, brown adipocytes are multilocular and contain less overall lipid than their white counterparts, and are particularly rich in mitochondria. Rodents have a distinct brown fat pad, which lies in the interscapular region. In humans, brown adipose tissue surrounds the heart and great vessels in infancy but tends to disappear over time until only scattered cells can be found within white fat pads.

This review briefly examines the transcriptional basis of adipocyte development, and then discusses energy homeostasis in mammals and how adipocytes regulate components of that system. The second part of the review provides a similar look at the role of adipose tissue in glucose homeostasis. Adipocytes have a crucial role in regulating both of these physiological processes through a series of endocrine and non-endocrine mechanisms. These involve a widening array of adipose-derived secreted molecules (known as adipokines), neural connections and changes in whole-body physiology wrought by primary alterations in adipocyte cellular metabolism.

Transcriptional Regulation of Adipocyte Differentiation

Adipocytes have been a popular model for the study of cell differentiation since the development of the murine adipose 3T3 cell culture system by Green and colleagues. There have been several thorough reviews on this aspect of adipose biology recently7, 8, so we present only the core of this regulatory system. The central engine of adipose differentiation is peroxisome proliferator-activated receptor-gh (PPAR-gh)9-11. When this receptor is activated by an agonist ligand in fibroblastic cells, a full programme of differentiation is stimulated, including morphological changes, lipid accumulation and the expression of almost all genes characteristic of fat cells. Multiple CCAAT/enhancer-binding proteins (C/EBPs) also have a critical role in adipogenesis, with C/EBP-v and C/EBP-d driving PPAR-gh expression in the early stages of differentiation and C/EBPa maintaining PPAR-gh expression later on in the process7. C/EBPs and PPAR-gh also directly activate many of the genes of terminally differentiated adipocytes. More recently, other factors have been implicated in the differentiation process, including several Kruppel-like factors12-14, early growth response 2 (Krox20)15 and early B-cell factors16.

This transcriptional cascade seems to function in both white and brown adipogenesis. However, ectopic expression of PPAR-gh or C/EBP proteins in fibroblasts results in the formation of adipocytes with the characteristics of white fat cells, with little or no expression of UCP-1 even when stimulated with v-adrenergic agents. Relatively little is known about brown fat differentiation, except for the important role of transcriptional cofactors, including pRb (ref. 17), p107 (ref. 18), SRC-1 and TIF2 (ref. 19), and PPAR-gh-coactivator-1a (PGC-1a)20. PGC-1a coactivates PPAR-gh and other transcription factors, is expressed at much higher levels in brown adipocytes than in white adipocytes, and is induced in brown cells upon cold exposure in vivo, or by v-adrenergic stimulation in isolated cells20,21. When introduced into white fat cells in culture or in vivo, PGC-1a 'switches on' many of the key features of brown cells, including mitochondrial biogenesis and UCP-1 activity20. Cells ectopically expressing PGC-1a also have an increased fraction of uncoupled respiration, a key characteristic of brown fat. Although PGC-1a is clearly a key effector of the thermogenic programme of brown fat, cells lacking PGC-1a still show a morphology that is brown-fat-like, and still express certain molecular markers of brown fat22. Thus, it seems likely that other factors function upstream of PGC-1a to control the determination of brown fat cells.

Principles of Energy Balance

Energy balance in animals is governed by the First Law of Thermo dynamics, and is often expressed as a simple equation:

Energy intake = energy burned + energy stored

Lipid storage in adipose tissue thus represents excess energy consumption relative to energy expenditure (Fig. 1). Although fundamentally true, this simple representation overlooks a few key features of energy homeostasis in vivo. First, although food intake is relatively easy to measure, it is not the precise parameter that determines the amount of energy brought into the system. The efficiency of calorie absorption in the gut, which is much more difficult to measure and is usually ignored in practice, must also be accounted for. A second consideration is that the body's response to alterations in energy input or expenditure is not static. In general, energy homeostasis is regulated to defend the highest weight achieved23. Thus voluntary reductions in food intake are countered by involuntary reductions in energy expenditure, making weight loss more difficult than a simple interpretation of equation (1) would indicate. Overall, energy balance is responsive to various factors, including hormones and neural inputs, in addition to psychological and cultural factors24.

Energy Homeostasis Depends Upon the Balance Between Caloric Intake and Energy Expenditure

Although caloric intake is almost entirely due to the consumption of food (minus whatever fails to be absorbed), energy expenditure has more components, including basal metabolism, physical activity (voluntary and involuntary) and adaptive thermogenesis. The last category includes the small amount of energy spent in absorbing and processing the diet (known as diet-induced thermogenesis) as well as energy spent to maintain body temperature in the face of cold.

Adipocytes and Energy Balance

Adipose tissue contains most of the energy stores in normal healthy humans. An important but underappreciated fact is that having more fat cells does not make an animal fatter. In the absence of altered energy balance, an increase in adipogenesis will result in smaller fat cells with no change in total adiposity. Conversely, a reduction in adipocyte number without a change in energy balance would result in larger fat cells, but not less total adipose mass. For example, surgical removal of fat can have cosmetic effects but does not change the energy balance equation. Careful studies in animals have shown that total body fat usually recovers after surgical removal of fat pads25. If certain depots are removed entirely, the fat usually increases at other anatomical locations, though careful clinical studies have not yet been reported in humans. The fact that adipocyte differentiation does not in itself cause obesity does not mean that adipocytes have no role in energy balance. In fact, adipose tissues are critical integrators of organismal energy balance, through the regulation of both food intake and energy expenditure. These effects are mediated by both endocrine and non-endocrine means.

Leptin

Leptin was the first adipokine discovered to have a role in modulating adiposity, and it remains the best studied26-29. Leptin is secreted almost exclusively by fat, and serves as a major 'adipostat' by repressing food intake and promoting energy expenditure. Predictably, animals and humans with mutations in either leptin or the leptin recept...