A mismatch between nutrition before and after birth can lead to poor health

A child in the womb is not just some hapless creature waiting to be born into a world of experience. It is preparing. Through its mother, it senses the conditions of the world outside and its body plans its growth accordingly.

There is strong evidence that people who are under-nourished as embryos grow up to have higher risks of heart disease and other chronic illnesses. For example, people born to women during the Dutch Famine of 1945 had higher risks of coronary heart disease as adults.

We might nod our heads at this as if it were expected news, but it’s actually quite a strange result. After all, during the early stages of pregnancy, the embryo is actually relatively undemanding. Any embryos that get off to an early slow start can easily catch up during the foetal stage, and they can certainly do it after birth.

But Jane Cleal and colleagues from the University of Southampton have found, from studying sheep, that catching up may actually be the problem

Pre-adapting to life outside the womb

She divided several pregnant ewes into two groups and fed one on half the calorie intake of the other during the first quarter of their pregnancy. As expected, they put on less weight. Pregnant human teenagers often go through the same thing because they tend to be more active than older expectant mothers.

Lambs born to undernourished mothers weighed about the same as those whose mothers had it easy, but they packed on weight more quickly. And when the lambs were deprived of food between their third and sixth months of life, those that experienced poor nutrition in the womb bounced back faster than those that had it easier.

These results supports a theory that developing foetuses prepare for the world outside by using the health of their mother as a sort of nutritional barometer. If mum isn’t getting much nutrients, the foetus steels itself for a life of hardship.

In the case of the lambs, those that were under-nourished in the womb went through an initial growth spurt to give them a reserve to draw upon in times of anticipated hardship. And sure enough, they proved to be more resilient when such hardship did occur.

When the foetus gets it wrong, its health suffers

This is all perfectly sensible from an evolutionary point of view – after all, if mum can only afford to eat for one-and-a-half, life on the other side of the uterus is hardly going to be rosier.

But problems crop up when the foetus’s intel is wrong – when nutrition before and after birth don’t match up. Right from birth, it is poorly adapted to the world around it. The malnourished foetus that is born into a world of plenty is like a karaoke singer thrust into the spotlight at the Royal Opera House – unprepared and likely to do badly.

Cleal found that lambs that had poor nutrition before birth but plenty of food after it might grow faster, but not always in the right way. By their third year of life, they showed signs of poor blood pressure control and cardiac hypertrophy, a thickening of the heart’s walls linked to a higher risk of heart disease and hypertension. Even their kidneys showed signs of weakness.

From lambs to humans

The potential harm of mismatched pre- and post-birth nutrition is particularly relevant for countries going through large spurts of economic development, or people emigrating to more affluent parts of the world. These mismatches could be made even worse by feeding newborn babies on calorific, high-fat diets, or weaning them onto unhealthy foods.

Other studies support Cleal’s concerns. For example, Indian children who are small at birth and heavy at 8 years of age have higher levels of cholesterol later on in life, and higher risks of heart disease and diabetes. And children who are small at birth and put on lots of weight during development have higher risks of chronic diseases that those who are born heavy but grow more steadily.

Pre-adapting to the outside world has served us well in our evolutionary history. But in today’s rapidly changing world, it might be contributing to the rising levels of heart disease, diabetes and other metabolic diseases in the Western world. The important next step is to find out exactly how this process works.

Reference: Cleal, Poore, Boullin, Khan, Chau, Hambridge, Torrens, Newman, Poston, Noakes, Hanson & Green. 2007. Mismatches pre- and postnatal nutrition leads to cardiovascular dysfunction and altered renal function in adulthood. PNAS doi:0610373104.

Technorati Tags: predictive+adaptive+responses, nutrition, pre-natal, science

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Discovery of ‘fat gene’ highlights stigma against obese people

On Friday, the media was abuzz with the discovery of a ‘gene for obesity’. Researchers funded by the Wellcome Trust found that people who carry a single copy of a variant of the FTO gene are 30% more likely to be obese than people with no copies.

But one in six Europeans carry two copies of this variant, and they are 70% more likely to be obese. On average, these dual carriers weighed three kilograms heavier than their peers.

The FTO gene itself is a mystery. Noone knows what it does or even which other genes it interacts with, and the Wellcome Trust team are now probably itching to find out.

But in this case, the reaction to the discovery was almost more interesting than the science itself. If internet talkbacks are any indication, people roughly fall into two groups.

To the first camp, the findings echo their own experiences of finding it difficult to maintain a healthy body weight. It points to something deeper and innate at work.

But the reactions from the other, slightly louder camp have been acrimonious to say the least. To them, the discovery of the FTO variant is yet another way for obese people to brush off the burden of responsibility from their shoulders.

After all, they say, obesity is just a matter of eating healthily and exercising regularly. To go beyond this is to over-complicate a simple lack of willpower. And where exactly was this gene in post-war Britain when obesity levels were much lower?

This attitude couldn’t be more wrong or more unhelpful, and many of these complaints misunderstand the nature of obesity-related genes.

It is clear that obesity has some genetic basis, but no researcher worth their salt would imagine that a single gene dictates whether a person becomes obese or not.

Obesity-related genes are likely to work through much more delicate ways. Some may affect how we metabolise food or lay down fat. But subtlest of all are genes that affect our very behaviour.

These inherited influences could make individuals more responsive to the smells or sights of food. They could make the brain less responsive to signals from the gut that say, “I’m full.” They could give people a strong innate preference for the chemicals that give fatty foods their taste, or equally put them off the chemicals (often bitter ones) within healthier choices.

In a society where food supplies are modest, say post-war Britain, variations in such genes across a population wouldn’t have much effect. But in the 21^st century, things are very different.

With more junk food widely available at cheaper cost, and active lives replaced by office jobs, cars and the telly, it is notoriously easy to eat lots and do little. In this environment, small genetic differences that affect how people react to food or activity can have massive effects.

So where was the FTO variant in post-war Britain? Well, in all likelihood, it was around, but its effects have been masked until now. Genes and environment interact with each other to affect our lives – nature and nurture usually walk hand in hand.

Obese people are likely to carry around a host of genetic variants that alter their behaviour in ways that leave them very vulnerable in a world where obesity is just around the corner. Obesity then, is a complex disease with many underlying causes.

And because of this, throwing words like ‘self-discipline’ and ‘laziness’ about with cavalier abandon does nothing for the obesity debate or for obese people themselves.

After all, where are personality traits like ‘discipline’ housed, if not the brain? And what controls behaviour and the development of the brain if not genetic information?

Is the combination of genes and environment an excuse for obesity? Hardly. But it does go some way toward explaining it, which is more than an accusation of faulty willpower will do.

Scientists hope that the discovery of genetic variants that influence the risk of obesity may one day herald new treatments for obesity. But this is a distant dream. For the present, very little actually changes for obese and overweight people.

To overcome the effects of genes and environment, they must still make lifestyle choices. The old maxim of “eat well, be active” still applies. The real benefit to FTO’s discovery would be a change in the attitudes of everyone else, from damning to supportive and from accusatory to understanding.

More on obesity:
A mismatch between nutrition before and after birth can lead to poor health
Human gut bacteria linked to obesity

Reference: Frayling, Timpson, Weedon, Zeggini et al. 2007. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 10.1126/science.1141634.

Image: Photographs by Boochan and Clarita

Technorati Tags: obesity, fat, genes, obesity+gene, fat+gene, science, FTO

Human gut bacteria linked to obesity

The obesity epidemic is a massive concern for the 21st century. New research shows that the bacteria that live inside our digestive systems could have a large impact on our risk of being obese.

There is a widespread belief, that being overweight or obese is a question of failing willpower, fuelled in no small part by food, fitness and beauty industries. But if we look at the issue of obesity through a scientific spyglass, a very different picture emerges.

Research is increasingly showing that a large part of the tendency to become obese is genetically controlled, often in very subtle ways. Genetic variation could mean that some people are more sensitive to the smell or sight of food, or are less able to sense when they are full. These small variations can play havoc in our modern environment, where calories are readily available and inactive lifestyles are common.

But it’s not just our own genes that we should be worried about. In terms of processing food, humans are hardly self-sufficient. Our guts are the home of trillions of bacteria that help to break down foodstuffs that our own cells cannot cope with. Together the genes expressed by these intestinal comrades outnumber our own by thousands of times, and yet we are still largely in the dark what they do.

Over 90% of these bacteria, collectively known as the microbiota, come from just two groups – the Bacteroidetes and the Firmicutes. Now, new research suggests that the proportion of these groups is an important factor in the obesity epidemic.

Ruth Ley, Peter Turnbaugh, Jeffrey Gordon and colleagues at Washington University first noticed the link between the microbiota and obesity by studying a special strain of fat mice.

These mice lack the hormone leptin, which controls the body’s ‘fat thermostat’. Without it, the mice cannot monitor the amount of fat in their body and quickly become obese through overeating. The team noticed that these mice had 50% fewer Bacteroidetes and 50% more Firmicutes in their bowels than their lean counterparts.

They saw the same thing in humans. The relative proportion of Bacteroidetes increased in obese people as they lost weight through low-fat or low-carbohydrate diets, while the Firmicutes became less abundant.

The link between the microbiota and obesity became even clearer when Gordon looked at a special strain of mice with no microbiota of their own. These intestinal tabula rasas proved to be strongly resistant to the fattening effects of unhealthy diets. After eight weeks on a 40% fat diet, these animals put on less than half as much weight as their normal peers, despite eating the same amount of food.

When the team transplanted the microbiota from fat and lean mice into the germ-free strains, those colonised by microbiota from fat donors packed on far more weight than those paired with lean donors.

To find out why the shifting bacterial balances were affecting body weight, Gordon and co. compared the microbiota of fat and lean mice at a genetic level. Samples from fat mice showed much stronger activation of genes that coded for carbohydrate-destroying enzymes, which break down otherwise indigestible starches and sugars. As a result, these mice were extracting more energy from their food than their lean cousins.

The bacteria were also manipulating the animals’ own genes, triggering biochemical pathways that store fats in the liver and muscles, rather than metabolising them. While these effects are relatively small, Gordon believes that they can lead to very large fluctuations in weight, over the course of months or years.

Obviously, the microbiota are not the whole story behind the obesity epidemic. We now need to understand how they interact with other things that affect our risk of becoming obese, not least of all, our own genes.

And there is much we still don’t know about our life-long passenger, such as how they sense and respond to their host’s condition, how they are passed on, or how they are affected by our diet. By answering these questions, scientists could then assess whether actively shifting our bacterial balances could help to stem the worldwide increase in obesity levels.

Backhed, Manchester, Semenkovich & Gordon. 2006. PNAS 104: 979-984.
Ley, Turnbaugh, Klein & Gordon. 2006. Nature 444: 1022-1023. Turnbaugh, Ley, Mahowald, Magrini, Mardis & Gordon. 2006. Nature 444: 1027-1031.
Technorati Tags: obesity, bacteria, gut bacteria, intestinal flora, Bacteroidetes, Firmicutes, microbiota, causes of obesity, science

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