Stressed-Out Fat: The Force Driving the Obesity Epidemic?

We have all heard the ominous references to the ¡®epidemic of obesity¡¯. Globally, by 2015, 2.3 billion people will be overweight and 700 million obese. Alarmingly, children and developing nations show the biggest surge in numbers. As a result, society faces a massive future healthcare burden, including increased risks of cardiovascular disease, diabetes and certain cancers associated with obesity.

There are many theories about why the obesity epidemic arose. Research during the molecular genetics boom years suggested a plausible explanation: genes that once protected us from starvation during our hunter-gatherer evolutionary history¡ªenabling us to store energy as fat when food was limited¡ªmight conspire to create obesity against the modern backdrop of readily available processed foods and sedentary lifestyles. Yet, if this is the case then why do so many maintain a normal healthy weight in the face of this ¡®onslaught of plenty¡¯?

It seems more likely that variations around the upper set point of bodyweight occur naturally¡ªjust as Darwin predicted. Indeed, Professor John Speakman of Aberdeen University has proposed that in the absence of selective pressure against obesity (significant human predation from a few million years ago), a high prevalence of obesity can occur in the population if food is abundant. Indeed, large genetic screening studies in humans have recently identified brain-regulated ¡®appetite genes¡¯ as one key source of the natural diversity in our fatness. Extreme leanness, by comparison, is quite sensibly proscribed by nature. The constant threat of starvation (food shortage or disease) has effectively forced the evolution of a safe minimum weight range.

As well as identifying factors that may predispose people to obesity, we need to better understand why it has such negative consequences in order to help prevent and treat the conditions it causes.

My own research investigated a protein found within fat cells that triggers an important stress hormone, cortisol. We know that high circulating blood levels of cortisol in patients with a rare condition known as Cushing¡¯s syndrome often have ¡®apple-shape¡¯ obesity, diabetes and high blood pressure. Intriguingly, people with regular obesity have similar symptoms to those with Cushing¡¯s syndrome. However, in common obesity, rather than higher blood cortisol, we find higher levels of the cortisol activating protein in the fat cells. Further, when the protein was artificially raised in mouse fat or liver, obesity, diabetes and high blood pressure rates increased. This provides evidence that excessive ¡®local¡¯ cortisol production causes detrimental metabolic consequences. Mice that lack the gene for this cortisol-amplifying protein are resistant to obesity and diabetes, suggesting that medicines targeting the protein could be an effective therapy.

The obesity ¡®epidemic¡¯ has driven people to criticize fatness, but we must not forget that fat is an important part of the body. Fat actively secretes and responds to hundreds of hormones that regulate other organs. It controls the parts of the brain that hardwire our appetite; without it, our muscles, livers and hearts would not be able to store and use nutrients properly. It is also important for reproduction, since without sufficient fat stores a female is unable to begin the process of puberty.

So when fat does its job properly¡ªefficiently storing lipids and dynamically communicating the health status of the body¡ªit actually protects important metabolic organs from inappropriately accumulating fat. These facts are highlighted in people with defects in fat tissue development; for example, people with lipodystrophy have a high risk of diabetes and cardiovascular disease associated with inappropriate accumulation of fat in their other organs. More recent work from my group indicates that healthy lean animals have a robust anti-stress defence system that operates in the fat cells and activates when there is an exposure to excessive calories.

What of obesity in the 21^st century? The outlook for obesity research in coming years may depend on the development of alternate, patient-targeted anti-obesity therapies, some of which may be based on the enzyme systems alluded to above.

With the dominance of Big Pharma and the spiralling costs of basic and clinical research, it seems likely that future therapeutic strategies will be pursued through major university-industry partnerships.

Along with the billions of patients expected to suffer the consequences of excess weight, the benefit to society in terms of health and healthcare will presumably exceed the inevitable profit to be made from exploiting scientific discoveries on the mechanisms underlying obesity and leanness.

Alternatively, for many, a feasible change in eating and lifestyle habits would go a long way to easing many of these ills at minimum expense. Despite talk of ¡®fat genes¡¯ or obesity-targeted medicines, there also remains a responsibility of the individual for his or her health.