Professor P Trayhurn, Obesity Biology Unit, School of Clinical Sciences, University of Liverpool, 3rd Floor UCD Building, Liverpool L69 3GA, UK. E-mail: email@example.com
Obesity is fundamentally a problem of energy balance – irrespective of the underlying social, cultural, behavioural and genetic determinants. As such, it can only develop when energy (food) intake is in excess of total energy expenditure (Basal Metabolic Rate, ‘thermogenesis’, physical activity, ‘non-exercise activity thermogenesis’). Differences between intake and expenditure are primarily buffered by changes in the amount of lipid (triacylglycerols) deposited in the specialized fuel storage organ, white adipose tissue (or white fat). Until recently, research on energy balance and obesity focused particularly on the central neuroendocrine pathways involved in the hypothalamic control of food intake and on the peripheral mechanisms of adaptive energy expenditure. White adipose tissue, however, attracted little research interest.
Adipose tissue has now moved centre stage in obesity research, there having been a revolution in our understanding of the biological role of the tissue over the past decade. Indeed, adipose tissue biology is currently one of the ‘hot’ areas of biomedical science – principally because it is now recognized as a major endocrine and signalling organ.
Characteristics of white adipose tissue
White adipose tissue is part of what Cinti has termed ‘the adipose organ’, which consists of two functionally distinct tissues – brown and white adipose tissue. Brown adipose tissue is specialized for heat production by non-shivering thermogenesis, and in this tissue the stored lipid droplets serve primarily as a fuel for the production of heat. In white adipose tissue, on the other hand, the stored triacylglycerols provide a long-term fuel reserve for the animal. Indeed, white fat is the main energy reservoir in mammals, triacylglycerols providing fuel storage at a high energy density, both because of the considerable caloric value of lipid (39.1 kJ g−1 vs. 15.4–17.5 kJ g−1 for carbohydrate) and because, in contrast to carbohydrates, triacylglycerols can be stored with little associated water. The result is that up to 85% of the weight of adipocytes consists of lipid.
In addition to fuel storage, white adipose tissue can act as a thermal insulator and protect other organs from mechanical damage. Two further features of the tissue should be highlighted. First, unlike most other organs, white fat is distributed in multiple depots in the body, both subcutaneously and internally, and clusters of adipocytes may also be located adjacent to, or embedded in, other organs such as the lymph nodes and skeletal muscle. A second important feature is that adipose tissue is not made up simply of mature adipocytes, which store the lipid, but contains a variety of other cells (e.g. fibroblasts, endothelial cells, macrophages) which constitute around 50% of the total cellular content. From the functional viewpoint, it is, of course, the mature adipocytes that are the pivotal cells within adipose tissue.
The focus on white adipose tissue
There are several reasons why the role of white adipose tissue in energy balance and obesity research has become a current focus of research. An obvious point that has been ignored until recently is that obesity is defined by the expansion of adipose tissue mass and it must therefore be central to our understanding of obesity. More specifically, adipose tissue is now recognized as the source of key hormones which play an important role in the regulation of energy balance – particularly leptin – and adipocytes are today recognized as secreting a diverse range of protein factors and signals termed ‘adipokines’, which are involved in overall metabolic regulation and increasingly considered to be directly linked to the pathologies associated with obesity.
White adipocytes are major secretory cells, making adipose tissue a key endocrine organ. Indeed, adipose tissue is the largest endocrine organ in most humans – and certainly so in the overweight and obese. For example, in a lean individual [body mass index (BMI) 22–23], approximately 20% of total body weight is adipose tissue, while in an obese subject (BMI 30) almost half of body weight is due to the tissue. There is a clear implication that even minor metabolic changes in such a large secretory organ have the potential to impact broadly on the body as a whole.
Quantitatively, the most important secretion from adipocytes is fatty acids, of which there is net release at periods of negative energy balance (particularly fasting). In addition to fatty acids, several other lipid moieties are released by fat cells; these include prostanoids, which are synthesized by the tissue, and cholesterol and retinol, which are not synthesized but rather are stored and subsequently released. In addition, certain steroid hormone conversions can take place within white adipocytes.
The ‘new’ component of the ‘secretome’ of adipocytes is the wide range of protein factors and signals that are released. These ‘adipokines’ (or ‘adipocytokines’) now number in excess of 50 different molecular entities.
The adipokines are highly diverse in terms of protein structure and physiological function. They include classical cytokines, growth factors and proteins of the alternative complement system; they also include proteins involved in the regulation of blood pressure, vascular haemostasis, lipid metabolism, glucose homeostasis and angiogenesis.
Leptin is the adipokine which has received most attention. Its discovery in 1994, as the product of the Ob gene in the genetically obese (ob/ob) mouse, was the pivotal discovery which led to the realization that adipose tissue is a critical endocrine organ. Leptin is an essential signal from adipocytes to the hypothalamus in the control of appetite and energy balance. Indeed, without functional leptin, severe obesity ensues as in the ob/ob mouse and the human homologues that have been described. Leptin is in practice a pleiotropic hormone, its functions extending far wider than appetite and energy balance to encompass a multiplicity of actions, including acting as a signal in reproduction and immunity.
Much attention has also been focused on adiponectin, which is a hormone produced exclusively by adipocytes. In contrast to most adipokines, and leptin in particular, the expression and circulating levels of adiponectin fall in obesity. A number of roles are attributed to adiponectin, including the modulation of insulin sensitivity and vascular function, as well as an anti-inflammatory action. Adiponectin, like leptin, is a powerful example of an adipocyte-derived hormone which interacts with other organs and a wide range of physiological systems and metabolic processes.
Inflammation and obesity
A number of inflammation-related proteins are released by white adipocytes, as well as adiponectin, and these include cytokines, chemokines and acute phase proteins. In addition to these factors, several other inflammation-related adipokines are recognized, including leptin and the angiogenic protein, vascular endothelial growth factor. In obesity, the production of many of these adipokines increases markedly and the tissue is in effect ‘inflamed’.
One of the most important recent developments in obesity research is the emergence of the concept that obesity is characterized by chronic mild inflammation – paralleling the situation with other diseases. The basis for this view is that the circulating level of several cytokines and acute phase proteins associated with inflammation is increased in the obese. As adipocytes secrete a number of cytokines and acute phase proteins, it is considered that the expanded adipose tissue mass contributes, either directly or indirectly, to the increased production and circulating levels of inflammation-related factors in obesity. In other words, the state of inflammation in adipose tissue in obesity leads to an increased production and release of inflammation-related factors.
Close links, and even similarities, between adipocytes and immune cells are increasingly evident. The inflammatory state of adipose tissue in obesity has been highlighted by recent reports demonstrating that there is extensive infiltration of the tissue by macrophages in the obese. The arrival of macrophages is thought to lead to a considerable amplification of the inflammatory state in white fat, through the cytokines and chemokines that they secrete.
Adipose tissue and the diseases of obesity
The central change to the body in obesity is clearly the increase in the amount of adipose tissue – which may constitute more than half of total body mass in those with a BMI that is in excess of the threshold of obesity. It is not, however, only the total amount of fat that is important, but also its distribution. Thus, a more central fat deposition (‘android’ or ‘apples’, as opposed to ‘gynoid’ or ‘pears’) is associated with a greater risk of the metabolic syndrome and several of the other diseases linked to obesity. A key question is why visceral fat is particularly significant in terms of obesity-associated disorders, and a long-standing position is that it is the proximity to the liver and the portal circulation that is important.
The current view is that the inflammatory state of obesity plays a key causal role in the development of type 2 diabetes and the metabolic syndrome (which includes atherosclerosis, hypertension and hyperlipidaemia) associated with obesity. A central hypothesis is that it is the increases in inflammation-related adipokine production that occur in obesity that lead to the associated diseases. In this context, the reduction in adiponectin in the obese is thought to be of particular significance in view of the anti-inflammatory effect of this adipokine. Alterations in fatty acid flux have also been implicated.
Current research foci
As emphasized above, adipocyte biology is now a ‘hot’ area of biomedical research. Much of the work centres on the secreted protein signals and the secretory role of the tissue, and it also includes the potential links between fatty acids and the metabolic syndrome.
The key current areas of research are:
- • the identification of the full range of proteins secreted from fat cells – the ‘adipokinome’;
- • describing the physiological processes with which the adipokines are involved, and the extent to which adipocytes are in ‘conversation’ with other cells, organs and metabolic systems;
- • identification of the changes in the secretion of specific proteins when adipose tissue mass expands – and determining the potential pathological consequences of such changes;
- • the specific role of inflammation-related adipokines in the development of type 2 diabetes and the metabolic syndrome;
- • the importance of macrophages in modulating adipose tissue function in obesity;
- • understanding the mechanistic basis for inflammation of adipose tissue in obesity.
Additional areas of particular interest include an emphasis on the importance of blood flow to adipose tissue function and dysfunction, and the concept that, as with tumours, manipulation of angiogenesis could lead to a loss of body fat.
A key area for the next few years will undoubtedly be unravelling the role of inflammation in the development of obesity-related diseases – not only type 2 diabetes and the metabolic syndrome, but also cancer. Indeed, major insight into the causes of cancer may come from investigating the mechanistic link between adiposity and the development of tumours – and would be expected to lead to new opportunities for therapeutic intervention.
Predicting beyond the next decade is inevitably both difficult and hazardous, a situation amply illustrated by the fact that 20 years ago it was never envisaged that adipose tissue might be an important endocrine organ. Nevertheless, realistic scenarios within the existing paradigms can be entertained.
For example, treatment of obesity-related diseases might be possible if the production and/or action of specific adipokines, particularly those linked to inflammation, were to be targeted. There are already potential routes through which this might be achieved. Pharmacologically based approaches include harnessing the anti-inflammatory action of the new generation of anti-diabetic drugs – the thiazolidinediones – which operate through the PPARγ nuclear receptor. Nutritional intervention could also be envisaged through anti-inflammatory n-3 polyunsaturated fatty acids.
Nutritional genomics is likely to lead to the possibility of individualized dietary advice based on genetic profiling (specific polymorphisms); this could potentially be harnessed in terms of the modulation of adipokine production to minimize disease risk. New appetite and energy balance signals emanating from adipose tissue may be discovered, which could be targeted to inhibit appetite. A better understanding of the basis for functional differences between adipocytes in different depots (whether intrinsic or a reflection of local conditions) may lead to the possibility of manipulating cells in detrimental depots – primarily visceral – towards those in more benign depots.
The concepts established through work on obesity will flow to other areas – such as ‘healthy ageing’. Some of the diseases of ageing, such as the metabolic syndrome and the dementias, are linked to inflammation and it is speculated that adipose tissue, through various adipokines, may play an important and unexpected role in the aetiology of these diseases. This will be of special significance to an ageing population and provides a potent example of how growing knowledge of adipocyte biology is likely to impact in quite unexpected ways on other areas and issues beyond obesity.
Conflict of Interest Statement
No conflict of interest was declared.