BioWorld International Correspondent

LONDON - Scientists have identified a crucial metabolic complex: If you put all the pieces together, you get fat; if you pull them apart, you get thin.

In cystic fibrosis, some of the pieces have fallen apart - people with the disease are thin - but it seems that each piece of the complex acting alone can cause increased rates of diabetes and cancer.

The lynchpin of the complex has been called the "fat controller" by the researchers who discovered it. It lies, they say, at the confluence of central metabolism.

Anil Mehta, who works at the Department of Maternal and Child Health Sciences at the University of Dundee in Scotland, who led the research, told BioWorld International: "This finding opens up new avenues, new treatments, new ways of thinking about all these conditions. I can see in my mind's eye how to make people who are overweight lose weight, and I can see how you might be able to make the protein complex come back together in cystic fibrosis - though I don't how to do it yet."

His team is looking for collaborative partnerships with industry to help them develop drugs that target the molecules they have identified. The University of Dundee holds patents on the molecular mechanisms involved. An international conference on the implications of the discovery will be held in Dundee in September 2007.

A report of the team's most recent publication appears in the August 2006 edition of Molecular and Cellular Biology, titled "Understanding the Molecular Basis of the Interaction between NDPK-A and AMPK α1." An earlier paper appeared in Cellular Signalling online on Feb. 8. Its title was "NDPK-A (but not NDPK-B) and AMPK α1 (but not AMPK α2) bind the cystic fibrosis transmembrane conductance regulator in epithelial cell membranes."

Mehta said the work reported in the papers by his team could have a major impact on research into cystic fibrosis, cancer, diabetes and obesity. "We have opened up a whole new area of research, which links these conditions and from here on in, researchers looking at cancer, diabetes, obesity and cystic fibrosis should all be working with each other and looking at what the other is doing, because it is all linked together."

Mehta, who has worked in cystic fibrosis research for 15 years, had never been able to reconcile the fact that the CFTR protein (the gene that is mutated in cystic fibrosis) is only a chloride channel, with his observations about his patients with cystic fibrosis.

His observations were that those patients were too thin and lose weight very easily, and that about half of them, as adults, have an odd form of diabetes with insulin resistance. "I could not understand how mutations in a chloride channel could bring about these effects," he said.

Mehta went to Dundee University to work with Professor Grahame Hardie, an expert on fat regulation and metabolism. Hardie discovered the enzyme acetyl coenzyme A carboxylase 1 (ACC1) - a regulator of fat metabolism - and its regulator AMP-activated protein kinase (AMPK) during the 1980s. Once there, Mehta embarked on a long series of experiments - many of them funded by the Cystic Fibrosis Trust and the Wellcome Trust - to try to explain the conundrum he had observed.

Some of his most recent experiments are reported in Molecular and Cellular Biology and in Cellular Signalling. They demonstrate a link between CFTR and another enzyme, called nucleoside diphosphate kinase (NDPK). NDPK is known to convert the cell's energy currencies into different forms, but also acts as a suppressor of cancer metastasis and G-protein function.

Mehta found that if CFTR was mutated, NDPK in the vicinity stopped working. Different mutations in CFTR affected the function of NDPK in different ways.

"To cut a long story short, we then found that NDPK controlled ACC1, via the enzyme earlier discovered by Hardie, called AMPK. This gave us the direct link between CFTR and fat metabolism, which we had been looking for," Mehta said.

Further studies presented at recent conferences in the U.S. confirmed that, in people with cystic fibrosis, neither NDPK, AMPK, nor ACC1 interacted normally with each other.

Other groups have found that diabetes develops in rats lacking a functional copy of NDPK. Knocking out NDPK in mice stops them producing breast milk - an important function of ACC1 is milk fat production.

Future work will involve, as Mehta put it, "unravelling the complex, taking it apart into little pieces and understanding what sticks to what, with a view to understanding how best to make it fall apart or come back together again." His team, which includes Russell Crawford and Kate Treharne, are busy doing just that, having been awarded new grants from the Wellcome Trust and Cystic Fibrosis Trust.