Science - November 10, 2005

Wageningen hormone protects the heart

Wageningen scientists have stumbled upon what could become a new medicine against heart and circulatory diseases. With a bit of luck future textbooks will describe the publication that appeared last weekend in the Journal of Biological Chemistry as a breakthrough.

The hormone that Fokko Zandbergen, first author of the article and PhD researcher in the sub-department of Human Nutrition, studied for four years was already known. His supervisor, Dr Sander Kersten, discovered it at the end of the 1990s when he was working at the University of Lausanne in Switzerland. ‘During that period I developed/bred the gene-mice that Fokko has worked with,’ said Kersten. ‘They are mice that manufacture extra quantities of the hormone FIAF. When I came to Wageningen, I brought FIAF-mice embryos along as well.’ Zandbergen’s discoveries concerning FIAF are largely due to these mice.

In the first experiments Kersten discovered that FIAF is made in fat cells. The concentration of the new hormone in the blood rose in mice that had not had food for a long time. Hence the name: FIAF stands for fasting-induced adipose factor. ‘What we didn’t know is the role that FIAF plays in the body,’ added team-leader Kersten. The experiments described in the just published article lift a corner of the veil/give us a glimpse of what’s to come. The indication is that the hormone, which is composed of more than four hundred amino acids, influences fat metabolism. In a favourable way, the Wageningen researchers hope.

‘The FIAF-mice have half the amount of fat that normal mice have,’ continues Zandbergen. ‘That is a direct consequence of the hormone: FIAF stimulates the breakdown of fats in the body’. But what is most important is that the hormone increases the concentration of the good cholesterol HDL. The higher the concentration of HDL, the lower the risk of heart attack.
How FIAF raises the level of HDL is not yet known. What scientists do know is that FIAF blocks an enzyme that removes fatty acids from fats. This effect makes FIAF-mice thinner than normal mice. The fats from our food are transported through the blood as triglycerides. A triglyceride consists of three fatty acids attached to glycerol. Cells cannot absorb triglycerides, but the enzyme lipoprotein lipase detaches the fatty acids from the glycerol, enabling the cells to absorb them.

‘This becomes clear when you give the mice a meal with a lot of fat,’ says Zandbergen. ‘In normal mice the triglyceride concentration rises a little in the hours afterwards. When you do the same thing to FIAF-mice, the level continues to increase for up to eight hours after the meal.’

That is not desirable. ‘A high level of triglycerides in the blood increases the risk of heart and circulatory diseases,’ says Kersten. ‘It is a sign that something is seriously wrong with the fat metabolism.’ It is not yet known exactly what happens to the unused triglycerides in the circulation. Some seem to reach the liver, which is also not good news.

However, Kersten does not exclude the possibility that the undesired effect in mice does not occur in humans. In humans a high concentration of FIAF is not always combined with a higher concentration of triglycerides. Zandbergen noticed this when he analysed human blood samples. But even if the situation is not as promising as it first seemed there are other likely benefits. The researchers in Wageningen discovered that the hormone breaks up into two pieces, one bigger and one smaller.

‘We think that FIAF itself does not do much,’ says Kersten. ‘We suspect that the effects we have found are the work of the fragments.

‘We see two effects in mice,’ continues Kersten. ‘A desirable effect, the increase of HDL, and an undesirable effect, the increase in the amount of triglycerides. We hope that it is one fragment that causes the desirable effect, and the other fragment that causes the undesirable effect.’

Willem Koert