Science + Technology

UCLA/VA Researchers Discover Fat Gene; Finding May Offer New Target for Controlling Obesity, Diabetes

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UCLA/VA scientists have identified a new gene that controls howthe body produces and uses fat. Called lipin, thegene may provide a new target for therapies to control obesity, diabetes andother weight-related disorders. The first issue of the new journal CellMetabolism publishes the findings in its January edition.

 

"Lipinregulates how the body stores and burns fat. Our findings suggest thatdifferences in lipin levels may play a role in whysome people are more prone to weight gain than others who consume the samecalories," said principal investigator Karen Reue, a professor of medicine and human genetics at theDavid Geffen School of Medicine at UCLA and a researcher at the VeteransAffairs Greater Los Angeles Healthcare System.

In 2001 Reue's laboratory was the firstto isolate the lipin gene and link it to lipodystrophy, a wasting disorder in which the body isunable to produce fat. She also found that too little lipin prevented bothgenetic and diet-related obesity.

 

For this study, Reue and coauthor Jack Phan tested whether too much lipinwould produce the opposite effect. Her team developed animal models using twosets of specially bred mice. Each group had a genetic mutation that boosted thelevel of lipin — one group in their fat tissue and the other group in theirmuscles.

Whenfed a high-fat diet for six weeks, the mice with elevated lipinin their fat or muscles showed accelerated weight gain — double the amount ofweight gained by the normal mice.

 

"The mice with too much lipin in theirfat tissue or muscles quickly grew obese, gaining more than twice the weightgained by the normal mice on the same diet," Reuesaid.

 

Although both sets of mice gained excessive weight, theresearchers were surprised to see that the lipinaffected fat tissue and muscles differently.

 

Lipin functions in diverseways to affect body weight. While lipin in fat tissueinfluences the capacity of cells to store fat, lipinin muscle affects the rate at which the body expends energy and burns fat.

"Whenwe increased lipin in the muscle, the cells burnedcarbohydrates before fat. When lipin is absent,however, the cells burn fat before carbohydrates," Reuesaid.

"Wesaw a different effect when lipin acted on fat tissue," she said. "High levelsof lipin promoted fat storage. Lipin deficiencyprevented the cells from forming and storing fat."

Inother words, the mice with excess lipin in their fatgained weight because their cells stored more fat. The mice with more lipin in their muscle grew obese because the gene repressedtheir metabolism, causing them to burn fewer calories than normal mice.

Incontrast, Reue's study showed that lipin-deficient mice expended more energy to perform theirdaily activities. Because lipin moderates calorie usein muscle, its absence caused the mice to burn more calories to fulfill thesame tasks as normal mice.

"Ourstudy suggests that variations in lipin levels coulddetermine a person's tendency to gain weight by influencing how their bodystores and burns fat," Reue said.

"Priorto our research, scientists typically viewed obesity and emaciation as oppositeends of the spectrum caused by changes in different genes," Reuesaid. "Yet lipin is a single gene that can regulatebody-fat content from one extreme to the other. As a result, it may present atarget for the treatment of human diseases related to both excess andinsufficient fat."

 

Inan unexpected finding, the study also discovered that lipinlevels helped the fat cells metabolize glucose more efficiently, leading tolower blood-sugar levels. The obese mice with excess lipinin their fat tissue demonstrated even lower blood-sugar levels than normal micewith regular levels of lipin.

 

"Becauseobesity and lipodystrophy are both associated withinsulin resistance and high blood sugar, we hope that our results may point tonew therapies for diabetes," Reue said.

TheNational Institute of Heart, Lung and Blood funded the research. Phan, a student in the medical scientist-training programat the David Geffen School of Medicine at UCLA, co‑authored the study.

-UCLA-

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