Researchers focussing on the rare genetic disorder Bardet-Biedl syndrome (BBS), have identified a clue to show how resistance to the hormone leptin might disrupt the brain signals that tell the body when to stop eating.
Researchers at the University of Iowa, led by Kamal Rahmouni, Ph.D., assistant professor of internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine, also found a link between leptin resistance and high blood pressure.
Their findings, based on mouse models, may have implications for the treatment of BBS, as well as obesity and high blood pressure in people without BBS.
"Bardet-Biedl syndrome is rare but its symptoms, including obesity and increased risk of heart disease, are similar to problems faced by many people without the syndrome. Leptin normally suppresses appetite and increases caloric use. The more we know about how leptin and gene defects affect people with BBS, the more likely it is that we can improve treatment for them and people with similar symptoms," said Rahmouni.
This study comes in line with previous BBS findings and indicates that less than one in 10,000 people have BBS.
For the study, the researchers developed BBS mice that have the same features as the human condition. The researchers used a mouse model without BBS and three mouse models that each lacks a protein (Bbs2, Bbs4 or Bbs6) due to a BBS gene deletion.
Daily food intake and body weight of each mouse was measured. Some mice were also given daily leptin injections.
It was found that mice without BBS lost weight when injected with leptin but on the other hand, the mice with any of the three types of BBS gene defects did not respond to leptin and gained weight.
Rahmouni indicated that leptin might be responsible for weight gain, saying: "Leptin is made in adipose (fat) tissue and is supposed to decrease fat stores. However, if we find high levels of it in the plasma, and people still are obese, we know it's not acting correctly and that there is leptin resistance."
It was also found that even very young mice with BBS, having same body weights as the non-BBS mice, had high levels of leptin in the plasma, indicating leptin resistance. In order to understand the reason behind this occurrence, the researchers then looked at a specific brain region of mice with BBS.
"We know that leptin regulates body weight and food intake through the hypothalamus in the brain. In the mice with BBS, we saw that Pomc, one of the three main genes normally regulated by leptin, was not properly regulated. This finding allowed us to pinpoint a very specific defect that explains why these mice are obese. The brain normally uses the Pomc gene to tell the body to stop eating, but in the animals with BBS, it doesn't work and so the mice won't feel full. We know that people without this gene have the same symptoms as the mice in our study, so the finding is meaningful," said Rahmouni.
In the other phase of the study, the researchers found that two of the three mouse models with BBS protein problems (Bbs4 and Bbs6) had high blood pressure. Recent research by another institution has also indicated to the same problem in humans with the same gene defects.
The UI researchers found that blood pressure was lowered by using a chemical to block neurotransmission in mice with the Bbs4 and Bbs6 gene defects.
The study appeared online in the Journal of Clinical Investigation.