Gene deficiency is a protective barrier to obesity

A search for the molecular clues of longevity has taken Mayo Clinic researchers down another path that could explain why some people who consume excessive calories don’t gain weight. The study, which was done in laboratory mouse models, points to the absence of a gene called CD38. When absent, the gene prevented mice on high-fat diets from gaining weight, but when present, the mice became obese.

The findings were published this month in the online issue of The FASEB Journal, the journal of the Federation of American Societies for Experimental Biology. The study will appear in the November 2007 print issue of the journal.

“Obesity is a complex problem compounded by multiple factors, one of which is our genes. Genes play a role in about 50 percent of cases, and in this study, we demonstrate that CD38 regulates body weight,” states Eduardo Chini, M.D., Ph.D., an anesthesiologist at Mayo Clinic and corresponding author of the study.

Identifying the signaling mechanisms that lead to obesity caused by a high-fat, high-calorie diet is a critical part of understanding and developing new treatments for obesity, Dr. Chini says.

THE ROLE OF CD38

Research in animal models has shown that caloric restriction can lower cholesterol and blood pressure - often considered the biomarkers of aging. In addition, published research in animal models shows that caloric restriction, defined as consuming 30 percent to 40 percent less than your average daily intake, can turn on the SIRT1 gene, one of a family of seven genes linked to longevity.

In addition, recent studies have shown that the chemical receptor PGC1 (peroxisome proliferator-activated receptor coactivator) plays a key role in the development of obesity and control of metabolism. The SIRT genes activate PGC1 and in doing so, can offset the negative effects of obesity - at least in mice. But how the SIRT-PGC1 reaction works, hasn’t quite been explained until now.

In previous laboratory studies by the Mayo Clinic research team, CD38 was shown to be involved in regulating a wide variety of signaling pathways, such as those that regulate energy metabolism. In addition, recent studies in humans also show a possible connection between CD38 and metabolism, specifically metabolic syndrome. Metabolic syndrome includes metabolic-related health issues that usually afflict people who are obese. These health issues include high blood pressure, elevated insulin levels and high cholesterol levels.

In this study, researchers investigated and confirmed that CD38 inhibits SIRT and the expression of PGC1 in mouse models and, as a result, regulates body weight. In the absence of CD38, the SIRT-PGC1 pathway was activated and protected mice models from developing obesity.

THE STUDY

Researchers studied two groups of mice: one with the gene CD38 and the other without. Each group was fed a high-calorie diet with 60 percent of calories from fat. In a second test, each group was fed a standard diet in which 4 percent of calories came from fat.