Fat ‘switch’ regulates weight

New findings by university biochemists add important information about how the hormone leptin regulates body weight and metabolism

An enzyme called SCD-1 plays a crucial role – through the hormone leptin – in signaling the body to either store fat or burn it, report a team of scientists in the July 12 issue of the journal Science.

The researchers, led by Jeffrey M. Friedman, a Howard Hughes Medical Institute investigator at The Rockefeller University, and James M. Ntambi at UW–Madison, showed that obese mice, which lack the hormone leptin, lost weight by burning calories, when genetically crossed with a strain of mice carrying a mutation in the SCD-1 enzyme.

The missing SCD-1 enzyme also corrects a major clinical problem called fatty liver, which is found in leptin-deficient mice and several clinical settings in humans. SCD-1 is an enzyme that is required for the synthesis of palmitoleate and oleate, the major monounsaturated fatty acids found in triglycerides in fat cells.

“SCD-1 has since been found to be very important for the synthesis of oleate despite the fact that mammalian diets supply abundant dietary oleate,” says Ntambi, UW–Madison professor of biochemistry and nutritional science.

The monounsaturated fatty acids are generated from saturated fatty acids. Co-author Ntambi and colleagues originally cloned the SCD-1 gene in 1988 together with M. Daniel Lane at Johns Hopkins University.

These new findings point to a potentially novel strategy for treating obesity and fatty liver and add important new information concerning the mechanism by which leptin regulates body weight and metabolism.

Obese, leptin-deficient mice with mutations in SCD-1 lost weight despite continuing to overeat.

“Leptin causes weight loss by reducing food intake and by increasing energy expenditure. It is both surprising and important that a deficiency of SCD-1 reduced obesity by increasing energy expenditure without affecting food intake at all,” says first author Paul Cohen, a graduate student in the tri-institutional M.D.-Ph.D. program of Rockefeller, Weill Medical College of Cornell University and Sloan-Kettering Institute.

“SCD-1 appears to be an important control point and may function as a switch determining whether fat is stored or burned,” adds Friedman, professor and head of laboratory at Rockefeller.

Leptin and SCD-1 are members of a complex metabolic pathway that governs the body’s propensity to burn fat. The ob gene, which codes for leptin, was isolated in 1994 by Friedman’s HHMI laboratory at Rockefeller. Leptin, named after the Greek root “leptos,” meaning thin, was subsequently identified by Friedman’s group in 1995. Friedman and his colleagues showed that leptin is a fat cell hormone that functions as a nutritional signal to regulate body weight, metabolism and other physiologic processes.

Since the discovery of leptin, Friedman and other scientists have been searching for other components of the biological system that control body weight. The Rockefeller and UW–Madison researchers now hypothesize that leptin acts in part by suppressing SCD-1’s activity, which in turn activates a metabolic pathway that promotes the burning of fat. Previous research by Friedman’s Rockefeller group and other scientists showed that lipids, or fats, in specific body tissues, including the liver, were elevated in leptin-deficient mice and humans and decreased when they received leptin treatment.

The scientists who conducted the Science study, including researchers from the Rogosin Institute in New York City, used “gene chip” technology, which enables researchers to study thousands of genes at one time, to identify genes that leptin regulates in the liver.

“The repression of SCD-1 accounts for a significant proportion, perhaps even all, of the effects of leptin on energy expenditure,” says Friedman. “SCD-1 may act like a switch to control fat storage. When SCD-1 is ‘up,’ the switch is flipped in the direction of storing fat, and when it’s ‘down,’ the switch is flipped in the direction of burning fat.”

“These data establish that SCD-1 is an important biological modulator of lipid metabolism,” adds Ntambi.

Obese (leptin-deficient) mice also have massively fatty livers, which is corrected when the mice are given leptin. The lack of SCD-1 in the mutant mice also caused their livers to be normal and not fatty.

“Inhibiting SCD-1 could be of potential use for reducing weight and for reducing fat content in liver, which is also an important clinical problem,” says Friedman. Fatty liver, clinically known as steatosis, often develops in people who are obese, who abuse alcohol or other drugs, or who are diabetic.

The researchers caution however that completely eliminating SCD-1 could cause other medical and health problems. A key question is whether a partial reduction in SCD-1 activity – rather than a complete loss of the enzyme’s activity as in asebia mice – could alter metabolism without incurring unwanted side effects.

The answer appears to be yes, according to Ntambi and co-author Makoto Miyazaki, a UW–Madison biochemist who have shown in separate studies that mutant mice with half the level of the enzyme appear normal.

“Still, many more studies will be necessary to confirm that molecules that inhibit SCD-1 have an acceptable therapeutic index,” Friedman says. “In aggregate, these findings suggest that modulating the activity of key metabolic pathways could provide a new therapeutic approach to increase energy expenditure and promote the burning of fat.”

The research was supported in part by the National Institute of General Medical Sciences, including a Medical Scientist Training Program grant, and National Institute of Diabetes and Digestive and Kidney Diseases, all of which are parts of the federal government’s National Institutes of Health; American Heart Association and Xenon Genetics Inc. (Vancouver, Canada).