Fat of the land

As we become progressively more rotund, our body chemistry undergoes critical changes that have a major impact on our health. Dennis Rouvray sizes up this burgeoning problem

Recent decades have seen the statistics on obesity become inexorably worse. In each of the past 25 years, a new high has been reached in the number of individuals who are overweight, obese or suffering from chronic weight-related maladies. According to World Health Organisation (WHO) reports, the overall incidence of obesity in the UK has rocketed some 400 per cent over this period, with the result that nearly 55 per cent of the adult population is now overweight and of these almost 25 per cent are obese. Among children, the percentages are no less stark: some 30 per cent are overweight with 15 per cent being obese.  

Such figures are hardly surprising when current eating habits are taken into account. Last year alone Britons munched their way through more than two billion fast-food meals and made light work of half a million tonnes of chocolate. These figures are greatly exceeded in the US where the latest US National health and nutrition survey indicates that a third of the populace is now clinically obese - a level that on contemporary projections will be attained in Britain around 2010.  

The current obesity pandemic afflicts not only rich industrialised nations but is becoming a problem even in developing countries, especially among affluent urbanites. The net result of our seemingly insatiable appetite for food is that the worldwide total of overweight persons now stands at 1.2 billion.  

Our overeating has two major downsides: it is rapidly developing into a serious threat to public health and the associated costs are reaching dizzying heights.  

At present, some 400,000 Americans die prematurely every year from obesity-induced diseases and the corresponding figure for the UK is 30,000. These numbers are steadily increasing and the WHO has predicted that the rising generation will be the first since the mid-18th century for which life expectancy is lower than that of the preceding generation. Annual expenditure on obesity and obesity-linked disorders by the UK’s National Health Service has now surpassed the ?1 billion mark and in the US the tally amounts to around $50 billion (?26 billion). 

Bingeing on food is manifestly not an activity for which the human body is well adapted. In fact, this activity is so alien to our species that as soon as we begin to pile on the pounds we become susceptible to at least 45 different diseases. All of these are debilitating and most of them eventually prove to be fatal.  

An early warning sign that our health is suffering is the emergence of a rather ill-defined medical condition known as metabolic syndrome. This is characterised by the presence of one or more of the following five disorders: hyperinsulinaemia (elevated basal insulin level); hyperglycaemia (elevated fasting blood glucose level); hypertriglyceridaemia (elevated triglyceride level); dyslipidaemia (decreased high-density lipoprotein level); and hypertension (elevated blood pressure levels). 

If no corrective measures are taken, it is only a matter of time until the metabolic syndrome progresses to a variety of more serious diseases that include heart disease, stroke, diverse cancers and type 2 diabetes. 

Fatty deposits 

Because fats play an indispensable role in maintaining our health, the human body always endeavours to keep on tap a large stockpile of fatty acids that can be drawn upon as and when the need arises. Fatty acids provide us with our major source of stored chemical energy and are packaged in the form of triglycerides.  

A triglyceride is an esterified glycerol molecule whose three hydroxyl groups have been replaced by any permutation of the fatty acid residues derived from oleic, palmitic or stearic acids. When fat is oxidised it releases large amounts of energy: one gram of fat typically yields about nine calories compared with four calories for a carbohydrate. Thus, a 70 kilogram man with a store of around 15 kilograms of fat has at his disposal an energy resource of some 135 kilocalories - enough to see him through a starvation period of three months. A secondary reserve of energy that is stored in the liver and skeletal muscles is the polysaccharide glycogen. Our 70 kilogram man would store about 225 grams of glycogen, enough to yield some 900 calories of energy after it has been completely hydrolysed to D-(+) glucose. 

Our prevailing culture, which all too often promotes overindulgence in energy-rich foods, makes it a challenging task for many to keep body fat deposition under control, and to maintain a body mass index below 25 (see box).  

Saturated fats and refined sugars are prime examples of energy-rich foods that predispose to adiposity. The consumption of both of these has skyrocketed over the past 250 years. The rise in the amount of sugar we consume is particularly dramatic. Starting out as a rather exotic condiment used to spice foods, sugar began to increase in popularity in the 18th century when around 10g per day was consumed.  

Although no clear-cut clinical evidence links either fat or sugar directly to any medical condition - with the exception of tooth decay in the case of sugar - both are implicated indirectly because of their contribution to obesity. Overconsuming sugars, for instance, rapidly leads to weight gain because the sugars are enzymatically converted to glucose, thence to glycerol and finally stored as triglycerides.  

At the cellular level, obesity can be defined as an abnormal increase in the preponderance of fat cells, known technically as adipocytes, in the human body. Obesity thus comes in two basic varieties: hyperplastic obesity in which the number of adipocytes increases, and hypertrophic obesity in which the existing adipocytes grow larger.  

Adipocytes consist largely of globules of triglycerides, the amount present at any given time depending on their influx and how quickly they are used up. There are marked differences in where fatty tissue is accumulated in men and women. In men, excess fat is located mainly in the abdominal cavity whereas in women the fat is distributed peripherally in the thighs and buttocks. It is also of note that men have a mere 26 billion adipocytes compared with 35 billion in women.  

The deposition of adipose tissue is a complex phenomenon only partly under genetic control, with fat distribution around the body being subject to a greater degree of genetic control than the total fat mass that is stored. The gene ADRB2, situated on the long arm of chromosome five, is thought to be one of the potential regulators.  

Chemistry in the round  

It is now well established that the severity of any metabolic disruption, such as that encountered in metabolic syndrome, is in general proportional to the amount of excess adipose tissue accumulated and that in the absence of obesity no disorder is manifested. The cellular mechanisms that ultimately determine whether the effect of a specific fat mass will be benign or pathogenetic are currently under intense scrutiny.  

It is already known that visceral fat deposition - the pattern characteristic of men - is far more dangerous than the subcutaneous fat distribution typical of women. This is because abdominal fat is stored in close proximity to the viscera, the vital organs that include the heart, kidneys, liver and pancreas. We now recognise that abdominal adiposity plays a far more active role than previously suspected and it can no longer be dismissed simply as an inert superstore of energy passively waiting to be mobilised. In fact, visceral fatty tissue functions as a new bodily organ with significant endrocrinal activity, generating a host of molecules with high physiological activity. Because hormones are prominently featured among their number, these molecules interact with all of the surrounding cells and organs in ways that disrupt normal modes of operation and alter major regulatory pathways. 

Because the pathophysiology of obesity arises from interactions of bioactive protein molecules with a plethora of different chemical species operating within highly complex reaction networks, the opportunities for compromising normal body chemistry are legion and the effects induced are often far reaching. Although the overall picture now emerging is reasonably clear, it will likely take decades until all of the molecular mechanisms involved have been fully elucidated. Broadly speaking, the cytokines (secreted proteins) elicit cellular stress that is associated with stress signalling and setting up inflammation pathways within the targeted tissues. The stress response appears to originate in the endoplasmic reticulum, a membranous network in the cytoplasm of cells that is responsible for synthesing proteins. The inflammation is triggered by the increased levels of free fatty acids released by adipocytes, low levels of insulin-sensitising cytokines such as adiponectin, and relatively high levels of insulin-inhibiting cytokines such as resistin.  

One of the major consequences of disrupted intracellular communication and chronic inflammation is a systemic condition known as insulin resistance, in which the effectiveness of the hormone insulin is diminished. The condition may also be described as impaired glucose tolerance because any reduction in insulin’s efficacy inevitably leads to a build up of blood glucose levels. Diabetes can be diagnosed when the glucose present exceeds certain pre-defined threshold levels. 

Pharmaceutical intervention 

In recent years several new therapeutic approaches for treating obesity have emerged and the field is abuzz with innovative ideas, some of them quite futuristic. Getting the human body to react against its own fatty tissue is one of them. Japanese workers, for instance, have suggested attacking adipose tissue with antibodies that could be produced by novel genes inserted into the genome via infectious organisms such as the adenovirus.  

A team led by Kim Janda of the Scripps Research Institute in La Jolla, California, US, has developed an anti-ghrelin vaccine that contains three ghrelin antigens. Ghrelin is a hormone present in the stomach that regulates appetite, metabolism and thus weight. The vaccine, given to rats in an attempt to ’train the immune system to recognise ghrelin,’ showed considerable promise according to Janda. ’The rats were eating the same [as other rats] but still losing weight - which is pretty cool,’ he says.  

French pharmaceutical company Sanofi-Aventis recently launched its new drug Acomplia, the first of its kind, as a selective antagonist for receptors in the brain and on human adipocytes. The relevant receptors are part of the endocannabinoid system which regulates lipid metabolism as well as insulin resistance. In clinical trials, the drug has performed well, yielding notable weight loss with minimal side effects. 

Also in the human context, a team headed by Steve Bloom at Imperial College, London, UK, has made the highly encouraging discovery that injecting the hormone oxyntomodulin both reduces food intake and increases activity levels. Bloom enthuses that this discovery ’could be of huge importance [because] oxyntomodulin decreases calorific intake and actually increases energy expenditure, making it an ideal intervention for the obese.’  

Another approach being increasingly adopted is to seek ways to boost those cytokines that are potentially protective while at the same time suppressing those that are harmful. Rexford Ahima from the University of Pennsylvania School of Medicine, US, has proposed using the 22kDa protein ciliary neurotrophic factor (CNTF) to overcome resistance to both insulin and leptin.  

CNTF, unlike leptin, is not inhibited by the high lipid levels present in the obese although, like leptin, it is able to control appetite. Similarly, Sarah Griffiths and David Granger of Cambridge University’s department of medicine, UK, have suggested that the cytokine PAI-1, one of a small number of specific molecular markers for metabolic syndrome, inhibits the activity of the proprotein convertase class of serine proteases. This interaction is claimed to be responsible for many of the characteristic features of metabolic syndrome and if its effects could be blocked a return to normal insulin sensitivity might be re-established. 

The conventional treatments for metabolic syndrome and obesity have hitherto been rather more prosaic than these possible new therapies. Metabolic syndrome has typically been dealt with by administering sulfonyl urea drugs to stimulate the production of insulin or biguanides to prevent the liver from releasing excess glucose into the blood.  

Two types of drugs are used to treat obesity itself, namely anorexiants, which suppress appetite, and lipase inhibitors, which reduce fat uptake. In the former category is sibutramine from Abbott Laboratories in Chicago, US, and approved by the US Food and Drug Administration (FDA) in 1997.  

According to William McCloskey of the Massachusetts College of Pharmacy in Boston, US, sibutramine and its metabolites ’inhibit the reuptake of norepinephrine, serotonin and, to a lesser extent, dopamine in the central nervous system, resulting in reduced hunger and increased satiety’. 

Because of its efficacy and good safety record, sibutramine has not had to be withdrawn from the market, unlike several other anorexiants, and is currently one of only two medications in use for the long-term treatment of obesity.  

The other long-term drug is GlaxoSmithKline/Roche’s orlistat or Xenical which received FDA approval in 1999. This drug effectively inhibits the hydrolysis of dietary fat or triglycerides in the gastrointestinal tract and thereby prevents the formation of smaller free fatty acids that would be readily absorbable. Its minimal side effects have made this the drug of choice for lipase inhibition.  

Looking to the future 

An ever burgeoning reliance on the public purse for the treatment of obesity and its concomitant diseases constitutes an imposition on our resources that is probably not sustainable in the long run. We will need to find ways to reduce dramatically the incidence of obesity. Some actions that have already been taken include the regular weighing of school children, repeated exhortations by those in power for us to adopt a healthier lifestyle, and the existence of support groups such as Overeaters Anonymous. Moreover, chemists and other researchers will continue to try to save us from ourselves. But, in the long run it might be better to reduce our food intake and to wean ourselves 
from chemical intervention altogether.  

Ultimately we may be obliged to heed the sage words of French playwright Moli?re who insisted that one should eat to live, not live to eat.  

Dennis Rouvray recently retired from the University of Georgia, US, and is now a freelance technical author based in Camberley, UK

Further Reading

D Crawford and R W Jeffery (eds), Obesity prevention and public health. Oxford: Oxford University Press, 2005 
D J P Barker (ed), Type 2 diabetes: the thrifty phenotype. Oxford: Oxford University Press, 2001 
J C K Wells, Biol. Rev., 2006, 81, 183  
P A Kiberstis, Science, 2005, 307, 369 
B Topp et al, J. Theor. Biol.,  2000, 206, 605