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Newborn lambs' central heating system could aid fat busting in humans

April 14, 2004

The way newborn lambs regulate their temperature in the first few weeks of life using a special deposit of brown fat could give clues for tackling obesity in humans, according to Imperial College London scientists.

Unlike normal white fat that stores surplus energy, brown fat generates heat in response to cold or excess caloric intake. While some mammals such as rodents maintain this 'good' fat throughout life, humans are similar to lambs: brown fat is present in the newborn to act as an internal central heating system maintaining body temperature and preventing hypothermia, but rapidly disappears as brown fat is irreversibly replaced by normal white fat.

Now, researchers based at Imperial's Wye campus in Kent are determining the molecular switch in lambs that transforms brown fat into normal white fat, and investigations are underway to determine whether this conversion could be reversed and used as a new fat busting technique.

Professor Michael Lomax, head of Imperial's Animal Science Research section at Wye and leader of the project says:

"Obesity is fast becoming one of the biggest problems for the Western world. In the UK statistics suggest 20 per cent of us are overweight and in the USA the situation is even worse with more than 60 per cent of the population either overweight or clinically obese.

"While researchers continue to investigate how to increase the body's natural appetite suppressants most of us at some point will have resorted to some kind of diet to move those couple of extra stubborn pounds. But by reactivating natural brown fat we could lose weight without even trying.

"Each year between two to three million newborn lambs die of hypothermia at cost of up to £100 million to the industry. Farmers have even tried to put quilted jackets on vulnerable lambs to try and save them from hypothermia during cold, wet snaps but often it's difficult to reach lambs in time especially in remote areas. The ability to extend the period that lambs maintain their brown fat deposits would help to solve this problem. This project is a good example of why we need to understand the basic biology of animals so that we can come up with better ways of treating problems in animal and human medicine."

In most cells, mitochondria use the energy they liberate to make ATP, the fuel that drives chemical reactions in living organisms. But in brown fat cells, Uncoupling Protein 1 (UCP-1) interferes with this process, forcing the cells to release energy as heat. However, researchers are unsure how the molecular switch is flicked during development, turning UCP-1 expression off after birth in some mammals and not others.

During development so called master fat determination genes or PPARs govern whether an immature cell commits to becoming a fat cell, explains Dr Fouzia Sadiq of Imperial's Animal Science Research section.

"A further signal, PGC- 1 alpha is then needed to convert immature fat cells into brown fat that expresses UCP-1 rather than normal white fat," she says.

"But what we don't know is the underlying mechanism that regulates the loss of UCP-1 activity after birth. If we can establish this then we will be in a much better position to understand how to switch back on the signals that make immature fat cells develop into brown fat."

To establish whether PPARs and PGC-1 alpha play a role in switching UCP-1 off the researchers looked at expression levels during late pregnancy and over the first month after birth. The results indicate that levels of UCP-1 closely mirror levels of PPARs and PGC-1 alpha, suggesting that they are the key switches that control conversion of immature fat cells into brown rather than white fat.

"Having established the key role of PPARs and PGC-1 alpha we're now focusing on what drugs and natural compounds could reverse the process," says Dr Sadiq.

"Already the drug isoprenaline has been shown to increases levels of PGC-1 alpha and PPARs with a subsequent increase UCP-1 after birth. Now we're looking at whether synthetic and natural activators of the genes that express PPARs and PGC-1 alpha have the same effect."

The research is funded by the Biotechnology and Biological Sciences Research Council.

Imperial College, University of London