Friday October 3 2008
More research will need to be carried out before tests in humans
“‘Switch’ in brain linked to weight gain” is the headline in The Daily Telegraph. If this switch is faulty, the newspaper says, then the body will not recognise that it is full, and “the brain sends out signals to eat more and to store more sugars as fat”. The newspaper suggests “drugs could be used to suppress this switch and help people get back to a healthy weight”.
The news report is based on a complex study in mice. The findings suggest that there is a chemical in the brains of the mice that may be key in regulating the response to overnutrition, which ultimately leads to obesity and associated problems. However, mice and humans have very different metabolisms, so the results will need to be confirmed in humans, and research will need to go into developing safe drugs for humans and safe methods of delivering drugs to a very specific site in the brain. These developments are undoubtedly a long way off.
Where did the story come from?
Dr Xiaoqing Zhang and colleagues from the University of Wisconsin and the University of California carried out this study. The research was funded by grants from the National Institutes of Health, American Diabetes Association and by UW-Madison start-up funds. It was published in the peer-reviewed medical journal, Cell.
What kind of scientific study was this?
The study behind this news report is an animal study. The researchers were interested in looking at the link between overnutrition and the activation of inflammation pathways in a part of the brain called the hypothalamus. This region controls temperature, hunger and thirst, and it regulates hormone releases in the body. One disease characterised by chronic metabolic inflammation is type 2 diabetes, the result of which is insulin resistance. The effects of inflammation on organs such as the liver and adipose tissue have been studied extensively, but the effects of inflammation on the central nervous system, including the brain, are less well-known.
There are a variety of chemicals involved in the inflammatory response to overnutrition. In this study, the researchers explored the role of a particular chemical (IKKβ/NF-κB) which they suspected was responsible for the hypothalamus not functioning correctly, leading to obesity and related problems. Researchers removed the hypothalamus and other organs from mice to find out where the chemical IKKβ/NF-κB was concentrated. They also looked at the levels of NF-κB in the hypothalamus to study the effects of overfeeding mice a high-fat diet, and whether obese mice had higher levels of NF-κB than normal mice.
In further experiments, researchers delivered genes for IKKβ by injection to the brains of mice to see whether this could induce the activation or inactivation of NF-κB. In another part of the study, the researchers investigated what role IKKβ/NF-κB plays in insulin and leptin resistance in the hypothalamus. The activity of insulin and leptin are both critical for regulating fuel availability in the body (and therefore preventing excess energy stores).
What were the results of the study?
The researchers confirmed that in normal physiology, chemical IKKβ/NF-κB exists in an inactive form, and in this form it inhibits the activity of the inflammatory protein NF-κB. In mice fed normal food, the levels of NF-κB were low. In obese mice, they found that activity of NF-κB in the hypothalamus was five to six times higher. IKKβ/NF-κB was also involved in insulin and leptin resistance in the hypothalamus.
What interpretations did the researchers draw from these results?
Researchers conclude that their study suggests that the chemical IKKβ/NF-κB, which is normally not activated in the hypothalamus, may be activated – leading to inflammation – in response to chronic over-nutrition. They say that ‘hypothalmic IKKβ/NF-κB’ could underlie the entire family of modern diseases induced by over-nutrition and obesity.
What does the NHS Knowledge Service make of this study?
This complex animal study has profiled the activity of a chemical called IKKβ/NF-κB, which in normal physiology is inactive, but overnutrition causes it to be activated, and this leads to an inflammatory response. This finding will be of interest to the scientific community, which will seek to replicate the findings.
While the researchers are optimistic that their “results suggest a novel therapeutic strategy for combating the ever-increasing spread of obesity and associated diseases”, it will be some time before we see the application of these findings in humans. It will be difficult, for example, to develop anti-inflammatory drugs that specifically target the brain. The study was also conducted in mice in a disease model that was similar to obesity. But there are likely to be huge metabolic differences between mice and humans, so it is not clear whether the exact same reactions happen in response to over-nutrition in the human brain. Human research, which is the only way to establish this, is still a long way off.
This is exciting research, and IKKβ/NF-κB may be the obesity ‘master switch’, but this needs to be confirmed in humans and then used to develop drugs that target the part of the brain where it acts.