Eat sugar and fat, get fat. Conventional wisdom tells us that's all there is to obesity. The bad news: there's much more to it. Even worse: there's too much we don't know. Jamie Morton explains.

There was a time, Professor Peter Shepherd says, when our best hope against cancer was the catch-all approach of chemotherapy.

Revolutionary advances in the field have since delivered us into a new age of individualised drugs and interventions.

Yet, the renowned University of Auckland scientist worries, our grasp of the tangle of complex drivers underlying obesity – an epidemic now overtaking even smoking as a health burden – lags where cancer research was mired all those decades ago.

"In many ways, we are in the dark ages of our understanding metabolic diseases," Shepherd says.

"Only now are we starting to learn that it really does involve a whole range of different causes, in a whole range of different individuals."

Shepherd says the simple problem is an environment problem – fatty, sugar-heavy diets creating an energy overload we can't burn off – and one that's worsened under today's onslaught of junk food exposure.

The tougher problem, however, is working out why some of us are more at risk than others.

That not only means understanding the tens of thousands of genes that make up our genetic jigsaw – but also how those genes interact and change with the environment we put them in.

"If we've all got combination locks that have 20 different numbers; it's quite complicated getting them all to line up to unlock the obesity puzzle," says Professor Wayne Cutfield, a paediatric endocrinologist at Auckland University's Liggins Institute.

"Things like diet, medication, activity can all change the way that genes behave, and it's becoming increasingly clear that epigenetics – or the way in which genes are turned on and off by environment – are coming into play."

THE GENETIC PUZZLE 

It's frontier science, but researchers have suspected for half a century that genes have a hidden role.

Back in 1962, geneticist James Neel proposed that humans once had "thrifty genes" that doled out energy intake to our prehistoric hunter-gatherer ancestors over times of famine and feast, and their unsuitability to today's world of plenty exacerbated obesity.

There is evidence to suggest this effect may play out in some populations today – among them Pima Indians and Pacific Islanders – but scientists today don't ever expect to find Neel's universal, enigmatic thrifty gene.

Criticism of that evolutionary argument actually led to a new path of thinking: we can't look at genes in isolation, and what's really evolving is our own organism, tightly in step with our environment.

Shepherd believes half of obesity might be explained by a wide range of genes contributing to the overall risk.

"For most people, it's those different genes regulating your propensity to eat, your ability to metabolise the food that you do take in, whether you absorb it from your gut in the first place, or whether you store it in your fatty cells or elsewhere."

This appreciation grew in the 1990s, with discoveries that pinpointed multiple genes directly affecting appetite and metabolism.

Then DNA technology let us sequence, or download, the human genome for the first time, allowing scientists to delve much deeper into our genetic make-up.

More than 50 different genes have since been reported as being related to obesity phenotypes, yet just 10 have so far been conclusively linked.

But answers could even lie outside those regions of DNA that have codes which create proteins in cells - in areas we call "junk DNA".

Just last year, Liggins researchers found genetic changes hidden in these supposedly useless areas, uncovering a possible missing link between type 2 diabetes and obesity.

The fact that obesity and diabetes so often affect the same people has led scientists to suspect similar genes are contributing to the development of the disorders.

"Every day, we are making new findings - and what's clear is each individual in our world has a different subset of genes and gene variants, which means we are all at different risks for all sorts of diseases," Shepherd says.

"But, in the case of obesity, if we are all put in the same environment, we will all respond differently."

Scientists imagine an age of individualised healthcare, much like cancer treatment, where obesity interventions won't just be based on nutrition, but genetic predisposition.

To get there, says Associate Professor Justin O'Sullivan, another leading Liggins researcher, we need to boil down the population-scale picture to the personal.

It's the big aim of the GENO Project, a new transtasman effort tapping into a longitudinal study of 10,000 Australian children, and nearly 2000 parent-child pairs, making it one of the richest such datasets in the world.

The effort will be helped by a seminal discovery O'Sullivan helped make in 2014.

It revealed how a microscopic, effortlessly-efficient organisational structure inside DNA was involved in turning genes on and off - something that could distinguish each of the 200 different cell types in our bodies and weed out new insights from the GENO data.

Understanding the way DNA "folded" to reveal tissues affected by genetic variation, he says, might ultimately mean scientists can predict risk of developing certain non-communicable diseases later on in life.

But already, a third of Kiwi kids are considered either obese or overweight – disproportionately among Maori and Pacific Island children - and rates are rising fast.

A HEADSTART

More troubling is the building evidence that children could be at risk of obesity before they're even conceived.

"We now know that a mother's weight prior to conception is almost as important as how much weight she gains during pregnancy," Cutfield says.

"So the mother's diet and activity just prior to conception is crucial."

As is the health of the father.

Obesity can regulate the way in which genes in sperm behave, raising risk in the child – a theory that wasn't demonstrated until 2015.

"We are beginning to appreciate that the father is increasingly important, and we are still trying to understand exactly what it is in the pre-conceptual phase that is important for the mother," Cutfield says.

Pregnancy itself is where much of the Liggins Institute's focus lies and a big reason it's regarded as a world leader.

Thanks to its research, we know premature birth can raise the risk of obesity, and that first-borns have greater difficulty absorbing sugars into the body, among other landmark findings.

Fascinating current studies include an investigation into whether artificial sweeteners are just as bad for pregnant women as regular sugary drinks, and whether fish oil supplementstaken in pregnancy can help combat weight problems in children down the track.

Again, there's a long way to go.

"A healthy diet is promoted in pregnancy, but what an optimal diet actually is, we still haven't got that totally sorted," Cutfield says.

OUR ARMY OF BUGS

Another focus is the microbiome - essentially an army of microbes that keeps us alive by breaking down food to release energy, protecting us from germs and producing vitamins.

"You can think about our whole human genome as two parts: we have the fixed part, which is basically ours," says O'Sullivan, "and then you've got the plastic part, which is modified by the environment and everything else – that's the microbiome."

When we eat, rapidly digested food is absorbed in our small intestine and distributed straight into system as energy.

But if the food gets all the way to our large intestine, our microbes can play a much bigger role.

Some of those bacterial processes have good effects on our body – and some don't.

Studies have turned up correlations between obesity and the microbiome but O'Sullivan adds that's not the same as cause-and-effect.

"The short answer: it seems to contribute and associate with obesity, but how that works we are not sure."

Some promising research has suggested it's possible to target the microbiome with specific drugs – or even import an entire healthy microbiome through what have humorously been dubbed poo transplants.

Liggins researchers are trying to do just that with their intriguing Gut Bugs Trial.

"You can also re-programme your microbiome – you can eat very high fibre diets and it will change the structure," O'Sullivan says.

On the flipside, an unhealthy microbiome can linger long after radical lifestyle changes have been made, quietly dogging steps toward long-term weight loss.

So can factors such as stress, lack of sleep and foods we might not even suspect are bad for us, or know much about.

One major study Shepherd is overseeing, involving thousands of children, examines fructose – a little-understood, naturally-occurring substance that makes up half of the white stuff we know as sugar.

There is a wide variation in the amount of fructose individuals can absorb from the gut into the bloodstream and scientists are increasingly suspecting it's a big driver in obesity.

Those who are good at absorbing it are likely to retain more calories from sugar in diets than those who don't absorb it well, which may explain why some children are more at risk than others.

"But the bigger point about fructose," Shepherd says, "is that it's just another example of why we can't have a one-size-fits-all approach to confronting metabolic disabilities."

Cutfield sees another obvious problem: recognising obesity.

"In this country, regardless of ethnicity, 80 per cent of parents of an obese child don't recognise them as such," he says.

"There is a possibility that also extends, but not as dramatically, into childhood and adulthood, where we don't recognise an obese relative or friend.

"The significance of this is that if you don't see there might be a problem, then it's difficult to believe anything needs to be done."

At the same time, Shepherd adds, simply blaming those with obesity will get us no further.

"It just reduces self-esteem and makes it even harder to solve the problem," Shepherd says.

"Ultimately, we need a much more grown-up, linked-up approach – the bottom line is we can't go on treating metabolic diseases the way we always have."