Rare syndrome provides clues on obesity, blood pressure

March 3, 2008

University of Iowa researchers have found a clue about how resistance to the hormone leptin might disrupt the brain signals that tell the body when to stop eating. The research, which focused on the rare genetic disorder Bardet-Biedl syndrome (BBS), also found an association between leptin resistance and high blood pressure.

The findings, which were based on mouse models developed at the UI, have implications for treating BBS as well as obesity and high blood pressure in people without BBS. The study appeared online March 3 in the Journal of Clinical Investigation.

"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," said Kamal Rahmouni, Ph.D., the study's principal investigator and assistant professor of internal medicine at the UI Roy J. and Lucille A. Carver College of Medicine. "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."

The research builds on previous BBS findings, including research led by current study team member Val Sheffield, M.D., Ph.D., the Martin and Ruth Carver Chair in Genetics and professor of pediatrics at the UI and a Howard Hughes Medical Institute investigator.

Fewer than one in 10,000 people have BBS. Sheffield, who has discovered or co-discovered the majority of the 12 known BBS genes, developed BBS mice that have the same features as the human condition. The study 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.

The team measured daily food intake and body weight of each mouse. Some mice also received daily leptin injections. Mice without BBS lost weight when injected with leptin. However, the mice with any of the three types of BBS gene defects did not respond to leptin and gained weight.

Rahmouni, who has expertise in metabolism and obesity, said the hormone leptin is an obvious candidate when looking at causes of weight gain.

"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," he said.

The team also found that even very young mice with BBS, whose body weights were the same as the non-BBS mice, had high levels of leptin in the plasma, indicating leptin resistance. The team then looked at a specific brain region of mice with BBS to understand why this occurred.

"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," Rahmouni said.

"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," he added.

Rahmouni and colleagues will next examine the specific deficit in the neurons in the brain that might cause the problem with the Pomc (pronounced "pom-c") gene.

In another aspect of the study, the team saw that two of the three mouse models with BBS protein problems (Bbs4 and Bbs6) had high blood pressure. Recent research published by another institution has pointed to the same problem in humans with the same gene defects.

The UI team found that using a chemical to block neurotransmission in mice with the Bbs4 and Bbs6 gene defects lowered blood pressure.

"Because there are so few people with BBS, mouse models are very helpful in trying to understand the blood pressure problem," Rahmouni said. "Currently, there is no specific recommendation on what drug or level of drug to use to treat hypertension in BBS patients. In addition, this work may lead to improved treatment of hypertensive patients without BBS. We hope to learn more about the mechanism in order to improve and even customize treatment."

Source: University of Iowa

Explore further: Is obesity a ciliopathy, triggered by malfunctioning primary cilia?

Related Stories

Is obesity a ciliopathy, triggered by malfunctioning primary cilia?

December 6, 2011
Is obesity a ciliopathy, a disorder such as polycystic kidney disease (PKD), which is triggered by a defect in the microscopic hair-like cilia that protrude from virtually every cell of humans and other vertebrates?

Recommended for you

Scientists find key to regenerating blood vessels

November 23, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies a signaling pathway that is essential for angiogenesis, the growth of new blood vessels from pre-existing vessels. The ...

Surprising roles for muscle in tissue regeneration, study finds

November 22, 2017
A team of researchers at Whitehead has illuminated an important role for different subtypes of muscle cells in orchestrating the process of tissue regeneration. In a paper published in the November 22 issue of Nature, they ...

Study reveals new mechanisms of cell death in neurodegenerative disorders

November 22, 2017
Researchers at King's College London have discovered new mechanisms of cell death, which may be involved in debilitating neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease.

Cinnamon turns up the heat on fat cells

November 21, 2017
New research from the University of Michigan Life Sciences Institute has determined how a common holiday spice—cinnamon—might be enlisted in the fight against obesity.

How rogue immune cells cross the blood-brain barrier to cause multiple sclerosis

November 21, 2017
Drug designers working on therapeutics against multiple sclerosis should focus on blocking two distinct ways rogue immune cells attack healthy neurons, according to a new study in the journal Cell Reports.

New simple test could help cystic fibrosis patients find best treatment

November 21, 2017
Several cutting-edge treatments have become available in recent years to correct the debilitating chronic lung congestion associated with cystic fibrosis. While the new drugs are life-changing for some patients, they do not ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.