Fat is a physiologist issue

"You can boil our project down to two questions," says Professor Steve O’Rahilly from the University of Cambridge: "Why do people get fat, and when they get fat why do they get diabetes?"

Although genes are known to influence both obesity and diabetes, cheap and available food, coupled with less physical exercise and manual labour, takes much of the blame: "In a global sense, we don’t need much integrative physiology to understand why people get fat," says Professor O’Rahilly. "Obesity results when there is an imbalance between the amount of energy eaten and the amount expended: if energy in is more than energy out, energy is stored."

Yet research into obesity is becoming ever more essential. Despite the undoubted link between weight gain and ill-health, the prevalence of obesity has rocketed in the developed world over the last 50 years. Diabetes is already the fourth leading cause of death in these regions, and it is estimated that, by 2025, 300 million people worldwide will be affected by diabetes. "Although environmental factors are hugely important," notes Professor O’Rahilly, "there are enormous inter-individual differences in people’s susceptibility to develop obesity and its adverse consequences. If we can understand the biology underlying such differences we may be able to ameliorate the effects of the modern environment. This approach doesn’t diminish the importance of public health efforts but complements them."

Attempting to understand how the body handles fat, the impact of obesity on the body, and why some people are more prone to obesity and diabetes, is complicated by the number of bodily systems involved. "We’re interested in the brain, the pancreas beta cells, fat tissue, liver and muscle," says Professor O’Rahilly. "These are the players, but it is the interplay between them in the dynamic body that it so important." With £4.8 million funding from the Wellcome Trust’s Integrative Animal and Human Physiology Initiative, 14 research teams from the Universities of Cambridge and Oxford have now come together to tackle the problem.

"The Integrative Physiology Initiative came along at just the right time," says Professor O’Rahilly. "Obesity and diabetes are disorders of the body’s whole system, not just of cells, so there are many different areas that we need to examine. We’ve got together a full range of expertise in human studies and mouse studies, in genomics, biochemistry, physiology, endocrinology, and so on. Oxford and Cambridge are usually thought of as rivals, but we’ve allied the Oxford strengths in the study of human physiology with our expertise in genetics in Cambridge; they’re very complementary."

Risky business

At the University of Cambridge, Professor O’Rahilly’s research team is searching for the genetic factors that underlie obesity and diabetes. Many genes are likely to be involved, with subtle variations influencing how prone we are to putting on weight, or how likely we are to develop insulin resistance, which can lead to diabetes. "It’s a tough goal to find variations and polymorphisms that might be involved," says Professor O’Rahilly. "We’ve been working away steadily on polygenics, but our real success in identifying relevant genes has been through extreme phenotypes."

The study of such phenotypes - where a mutation in just one gene causes a dramatic effect on the body - took a leap forward when, in 1994, a hormone called leptin was found to be a key regulator of appetite and weight. In people, mutations are rare but all affected children were hugely obese, with ravenous appetites. In Cambridge and Canada, children are being treated with leptin, with equally dramatic effects as they have returned to a normal body weight. "It’s very pleasing that we can use a rational approach to treatment, and correct extreme obesity in a human," says Professor O’Rahilly.

Most cases will not be this straightforward, however. Another family being studied by Professor O’Rahilly’s team includes five women who are severely insulin resistant and diabetic. The disorder is caused by the combined action of mutations in two separate genes; other members of the family with one mutation alone are almost completely unaffected. "This is a good example of how an integrative approach can work," says Professor O’Rahilly. "We can study the people in this family who carry one or both mutations, take individual mutations and put them in cells, produce mouse models, and study the mouse and human situation in parallel. We can pull together expertise from all different angles."

The genes involved in extreme phenotypes may well influence a more general susceptibility to obesity and diabetes, and are prime candidates for studies in animal models. "We’ll be using the mouse to create models of the diseases that we find in the genetic programme, to explore aspects of physiology," says Professor O’Rahilly. "Or we will be using them to test hypotheses about specific molecules, often molecules that might be drug targets for obesity and diabetes."

Apples and pears

In a typical Western diet, we eat about 100g of fat every day. Yet at any one time, the bloodstream contains only about 1-3g of fat. "The human body has beautifully coordinated mechanisms that minimise the amount of fat in the blood and protect the tissues from excessive amounts of fat," says Professor Keith Frayn who, together with Dr Fredrik Karpe at the University of Oxford, specialises in studying these mechanisms in living humans. "Fat cells have a remarkable capacity for taking up fat, and if you continue to eat a lot of fat, they enlarge and new cells are generated."

Where the fat gets stored may have important consequences for health. In the upper part of the body - particularly around the abdomen - creates the ‘apple’ shape characteristic of overweight men, while that in the buttocks and thighs leads to the ‘pear’ shape typical of women. "Fat in the upper parts of the body seems to lead to increased risk of cardiovascular disease or diabetes," says Dr Karpe. "On the other hand, there is good evidence that exercise selectively mobilises abdominal fat."

Yet fat tissue is not the inert, silent store it is often perceived to be. "Fat tissue is highly regulated by the nervous system, by the rate of blood flow through the tissue, and by a complex mixture of hormones and fats that are delivered in the blood," says Professor Frayn. "It’s highly structured and efficient, and you can’t study it unless you study it in the living body."

Using tiny catheters, Professor Frayn and his team can take blood samples from the arteries leading into stomach fat and from the veins that drain the tissue. This technique has shown us that fat tissue is extremely dynamic, regulated on a minute-to-minute basis. Dr Karpe has extended this technique by tagging food with stable isotopes and then monitoring the incorporation of fat from the diet into the tissue. "The Cambridge group have identified patients with rare, genetic causes of fat malfunction, and we can use our techniques to study them in detail," says Dr Karpe.

Increased fat tissue leads to increased risk of developing diabetes. As the fat cells enlarge, they begin to lose their ability to buffer the body’s daily influx of fat in the diet. Fat begins to be deposited in the other tissues such as the skeletal muscle and the liver, and they become less sensitive to insulin. The fat cells also appear to produce hormones that directly affect other tissues’ sensitivity to insulin. "The concentration of glucose in the blood rises, and the pancreas responds by producing more insulin," says Professor Frayn. "At some point, probably in those with a genetic predisposition, the beta cells in the pancreas fail, can’t produce any more insulin, and diabetes results."

"I think that the programme is very well placed to understand insulin resistance from a whole-body perspective," says Dr Karpe. "In five years’ time we will know a lot more about the function and integration of the tissues, why people become fat and why they become ill, and this will change our thinking about how we treat patients."

See also

• transatlantic alliance to tackle diabetes

Further reading

Professor Keith Frayn recommends...
Frayn K N (1996). Metabolic Regulation: A Human Perspective. London: Portland Press.

Koutsari C, Karpe F, Humphreys S M, Frayn K N, Hardman A E (2001). Exercise prevents the accumulation of triglyceride-rich lipoproteins and their remnants seen when changing to a high-carbohydrate diet. Art Thromb. Vasc. Biol. 21:1520-1525

Cruz M L, Evans K, Frayn K N (2001). Postprandial lipid metabolism and insulin sensitivity in young Northern Europeans, South Asians and Latin Americans in the UK. Atherosclerosis 159:441-449

Summers L K M, Fielding B A, Bradshaw H A, Ilic V, Beysen C, Clark M L, Moore N R, Frayn K N (2002). Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity. Diabetologia 45:369-377

Karpe F, Fielding B A, Ardilouze J-A, Ilic V, Macdonald I A, Frayn K N (2002). Effects of insulin on adipose tissue blood flow in man. J. Physiol. 540:1087-1093

Frayn K N. Adipose tissue as a buffer for daily lipid flux. Diabetologia (in press).

Professor Stephen O’Rahilly recommends...
Savage D B, Agostini M, Barroso I, Gurnell M, Luan J A, Meirhaeghe A, Harding A-H, Ihrke G, Soos M A, Ratanayagam O, George S, Berger D, Thomas E L, Bell J D, McCarthy M, Hattersley A T, Hitman G A, Levy J, Walkers M, Meeran K, Ross R, Vidal-Puig A, Wareham N J, O’Rahilly S, Chatterjee V K K, Schafer A J (2002). Digenic inheritance of severe insulin resistance in a human pedigree. Nature Genetics (in press).

Farooqi I S, Keogh J, Kamath S, Jones S, Gibson W, Trussell R, Jebb S, Lip G, O’Rahilly S (2001). Partial leptin deficiency increases adiposity in humans. Nature, 414: 34-35.

Farooqi I S, Yeo G S H, Keogh J M, Aminian S, Jebb S A, Butler G, Cheetham T, O’Rahilly S (2000). Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest. 106 (2): 271-279