UCLA/VA scientists have identified a new gene that controls how the body produces and uses fat. Called lipin, the gene may provide a new target for therapies to control obesity, diabetes and other weight-related disorders. The first issue of the new journal Cell Metabolism publishes the findings in its January 2005 edition.
"Lipin regulates how the body stores and burns fat. Our findings suggest that differences in lipin levels may play a role in why some people are more prone to weight gain than others who consume the same calories," said principal investigator Karen Reue, Ph.D., a professor of medicine and human genetics at the David Geffen School of Medicine at UCLA and a researcher at the Veterans Affairs Greater Los Angeles Healthcare System.
In 2001, Reue's laboratory was the first to isolate the lipin gene and link it to lipodystrophy, a wasting disorder in which the body is unable to produce fat. She also found that too little lipin prevented both genetic and diet-related obesity.
For this study, Reue and coauthor Jack Phan, Ph.D., tested whether too much lipin would produce the opposite effect. Her team developed animal models using two sets of specially bred mice. Each group had a genetic mutation that boosted the level of lipin – one group in their fat tissue and the other group in their muscles.
When fed a high-fat diet for six weeks, the mice with elevated lipin in their fat or muscles showed accelerated weight gain – double the amount of weight gained by the normal mice.
"The mice with too much lipin in their fat tissue or muscles quickly grew obese – gaining more than twice the weight gained by the normal mice on the same diet," said Reue.
Although both sets of mice gained excessive weight, the researchers were surprised to see that the lipin affected fat tissue and muscles differently.
Lipin functions in diverse ways to affect body weight. While lipin in fat tissue influences the capacity of cells to store fat – lipin in muscle affects the rate at which the body expends energy and burns fat.
"When we increased lipin in the muscle, the cells burned carbohydrates before fat. When lipin is absent, however, the cells burn fat before carbohydrates," explained Reue.
"We saw a different effect when lipin acted on fat tissue," she noted. "High levels of lipin promoted fat storage. Lipin deficiency prevented the cells from forming and storing fat."
In other words, the mice with excess lipin in their fat gained weight because their cells stored more fat. The mice with more lipin in their muscle grew obese because the gene repressed their metabolism, causing them to burn fewer calories than normal mice.
In contrast, Reue's study showed that lipin-deficient mice expended more energy to perform their daily activities. Because lipin moderates calorie use in muscle, its absence caused the mice to burn more calories to fulfill the same tasks as normal mice.
"Our study suggests that variations in lipin levels could determine a person's tendency to gain weight by influencing how their body stores and burns fat," explained Reue.
"Prior to our research, scientists typically viewed obesity and emaciation as opposite ends of the spectrum caused by changes in different genes," Reue said. "Yet lipin is a single gene that can regulate body-fat content from one extreme to the other. As a result, it may present a target for the treatment of human diseases related to both excess and insufficient fat."
In an unexpected finding, the study also discovered that lipin levels helped the fat cells metabolize glucose more efficiently, leading to lower blood-sugar levels. The obese mice with excess lipin in their fat tissue demonstrated even lower blood-sugar levels than normal mice with regular levels of lipin.
"Because obesity and lipodystrophy are both associated with insulin resistance and high blood sugar, we hope that our results may point to new therapies for diabetes," said Reue.
The National Institute of Heart, Lung and Blood funded the research. Phan, a student in the medical scientist-training program at the David Geffen School of Medicine at UCLA, co-authored the study.
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