Research provides better understanding of lipodystrophies disorders

Mar 22 2004

More than a decade of work conducted by UT Southwestern Medical Center at Dallas researchers has led to a better understanding of the underlying causes of lipodystrophies - disorders characterized by the selective loss of fat tissues, resulting in metabolic complications, such as severe diabetes and high blood cholesterol levels.
 
By gaining a better understanding of the molecular mechanisms that lead to both inherited and acquired lipodystrophies, researchers hope to discover new therapeutic approaches to prevent the loss of fat tissues and prevent or possibly delay the onset of metabolic complications associated with these disorders.

Dr. Abhimanyu Garg, chief of nutrition and metabolic diseases has been studying patients with lipodystrophies for the past 16 years.

A review article summarizing research spearheaded by scientists at UT Southwestern is published in today's issue of The New England Journal of Medicine.

"We hear about the metabolic complications of obesity all the time, but these complications also occur in disorders of fat cells that cause partial or total loss of fat from the human body - the exact opposite of what occurs in obese individuals," said Dr. Abhimanyu Garg, chief of nutrition and metabolic diseases who has been studying patients with lipodystrophies for the past 16 years. "These disorders have not been widely recognized."

Recently, many HIV-infected patients being treated with a class of drugs known as protease inhibitors have developed lipodystrophies, which has raised awareness of these rare disorders.

Improved knowledge of these disorders will have implications to understanding more prevalent disorders that occur as a result of obesity, like diabetes, which affects more than 16 million Americans, Dr. Garg said.

"What we're learning from treating patients with lipodystrophies may also be applicable to obese patients with abnormal fat distribution, who are more prone to complications," Dr. Garg said. "All of these patients are predisposed to diabetes. Some of these patients even develop diabetes in their 20s. Compared to the normal population, there is a much higher prevalence of metabolic complications, including low levels of high-density lipoproteins, the good cholesterol, and high triglycerides, two risk factors for heart disease."

UT Southwestern researchers have led the way in identifying gene mutations responsible for several forms of lipodystrophies and in identifying novel therapeutic approaches for these patients.

UT Southwestern findings about these disorders include:

• In 1998 researchers localized a human gene that caused familial partial lipodystrophy, called Dunnigan type (FPLD).
• In 2002 a mutation - PPARã - was linked to another type of familial partial lipodystrophy.
• In 2002 the mutated gene, AGPAT2, linked to congenital generalized lipodystrophy, was identified.
• In 2002 researchers, in collaboration with researchers with the National Institutes of Health, reported that replacing the protein leptin drastically reduced triglyceride levels and controlled diabetes in patients with generalized lipodystrophies.
• In 2003 a novel gene, ZMPSTE24, linked to generalized loss of body fat and skeletal disorders, was identified.

There are two categories of lipodystrophies: acquired and inherited. Acquired lipodystrophy in HIV-infected patients is, by far, the most prevalent type, affecting more than 100,000 Americans, said Dr. Garg.

Dr. Garg and his collaborators are currently evaluating three low-risk therapeutic measures in HIV-infected patients with lipodystrophies to lower cholesterol levels and improve insulin resistance.

Dr. Garg has also studied more than 200 families with various types of inherited lipodystrophies and hundreds of patients with HIV who have developed this condition. 

"Our hope is to learn more about the metabolic processes of the fat cell," Dr. Garg said. "As new pathways are discovered, we will likely be able to find the connection between fat cell abnormalities and the metabolic complications associated with these disorders."