Genetic disease keeps sufferers unhealthily thin

2 March 2011

It is well understood that having excess body fat can be detrimental to health. Having too little fat, however, can also be damaging. New research from the University of Cambridge Metabolic Research Laboratories has revealed a rare genetic condition that prevents people from being able to produce fat cells correctly.

The association between obesity and many medical problems, including diabetes and heart disease, is well established. Fat is not inherently bad for our health, though: fat cells are vital for storing and releasing surplus energy and for preventing an excess of fatty acids - the breakdown products of fats - in blood after eating fatty meals.

Most human cells store small amounts of fat, but the majority is found in specialised ‘white fat cells’ - each containing a lipid droplet that makes up 90 per cent of its volume. Several proteins are involved in the structural organisation of this droplet.

New research published in the 'New England Journal of Medicine' shows that mutations in the gene PLIN1, which encodes the protein perilipin 1, lead to incorrect storage of lipids within fat cells, a condition known as lipodystrophy. This inability to store fats correctly means patients with the disease deposit lipids abnormally in places such as skeletal muscle or the liver. Having very little body fat can lead to many of the metabolic diseases usually associated with obesity, such as insulin resistance or a fatty liver.

In healthy individuals, perilipin 1 surrounds the lipid droplet found within a fat cell, regulating the transport of fatty acids into and out of the droplet. The researchers identified two separate mutations of the perilipin 1 protein capable of causing incorrect lipid processing. Patients with these mutations showed reduced fat levels, something also seen in mice unable to produce perilipin 1. The reduction in fat appeared uniform throughout the body, unlike in other forms of lipodystrophy.

These findings show that defects in a protein that is present only in fat cells can lead to all the features of the metabolic syndrome and highlight the requirement for optimal fat tissue function.

Image caption: Fat cells. SEM of part of lobule of adipose tissue. Credit: Wellcome Images.

Reference

Gandotra S et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med (2011) 24;364(8):740-8