Researchers discover molecular 'switch' that tells body to store or burn fat

July 11, 2002

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, M.D., Ph.D., a Howard Hughes Medical Institute investigator at The Rockefeller University, and James M. Ntambi, Ph.D., at the University of Wisconsin at Madison, showed that obese (ob/ob) mice, which lack the hormone leptin, lost weight by burning calories, when genetically crossed with a strain of mice carrying a mutation in SCD-1.

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. 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, graduate student in the joint 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 University of Wisconsin 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. Co-author and Rockefeller scientist Nicholas Socci, Ph.D., developed a computer program to sift through some 6500 mouse genes contained in a single Affymetrix Inc. gene chip. The researchers looked for genes that are specifically suppressed by leptin, and SCD-1 topped a final list of 36 genes.

"Gene chips identify hundreds of genes that are potentially important, and we wanted to do something to prioritize that list for further follow up," says Cohen. "Nicholas wrote a software program to rank the genes based on the extent of their response to leptin with the idea that some or all of these genes might be required for development of obesity."

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. These 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, Ph.D., at Johns Hopkins University.

"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, professor of biochemistry and nutritional sciences at the University of Wisconsin at Madison.

The next question the researchers asked was: to what extent does repression of SCD-1 contribute to leptin's actions?

They hypothesized that if suppression of SCD-1 is required for leptin action, then a mouse lacking SCD-1 should mimic some of leptin's effects. The researchers crossed leptin-deficient (ob/ob) mice with a mouse strain called "asebia," which carries mutations in the SCD-1 gene. The fatty acids that SCD-1 synthesizes are also required for normal function of sebaceous glands, so its absence leads to the "absence of sebaceous glands," hence the name "asebia." Sebaceous glands are embedded in the skin over most of the body and are more concentrated in the scalp, face, forehead and eyes. In the absence of sebaceous glands, mice have patchy, abnormal skin and abnormal corneas.

The researchers found that, similar to leptin treatment, removing SCD-1 markedly reduces the weight of the obese mouse -- at 16 weeks of age, weight was reduced by 29 percent in females and 34 percent in males. The reduced weight of these animals could be accounted for by a dramatic increase in energy expenditure. Indeed, removing SCD-1 completely corrected the effects of leptin deficiency on energy expenditure.

"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 as evidenced by the abnormalities of asebia mice. Mice which completely lack the SCD-1 enzyme suffer from corneal dryness, which can lead to corneal opacities, as well as the condition known as scarring dermatitis. Inhibition of SCD-1 could also increase tissue-damaging free radicals, a potential sequelae of increased oxidative metabolism.

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, Ph.D., a biochemist at the University of Wisconsin at Madison, 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," cautions Friedman.

How Does SCD-1 work?

Fat in liver generally can be stored, exported in very low-density lipoprotein (VLDL) particles or burned for energy.

"Our experiments show that fat storage and export of fat via VLDL in the obese mice lacking SCD-1 were reduced," says Cohen. "We hypothesize that the only option left is to burn the fat, which explains the elevated energy expenditure."

The mechanism by which SCD1 deficiency leads to the burning of calories is unknown, but there are several possibilities. "One possibility is that SCD-1 deficiency leads to an alteration in the levels of lipid metabolites that regulate transcription factors that control metabolism," says Friedman.

"Transcription factors turn groups of genes on and off. A second possibility is that the properties of the cell membrane, which is composed largely of lipid, is altered," he adds. "A third possibility is that reduced levels of SCD-1 changes the levels of saturated fats, which indirectly stimulate the burning of calories by mitochondria."

In cells, a key metabolite called malonyl CoA controls whether fat is synthesized or burned. Malonyl CoA is required for the synthesis of fatty acids, and it also inhibits CPT-1, the key molecule that transports fatty acids from the cytoplasm in the cell to the mitochondria, where they are burned to produce energy.

"Malonyl CoA is known to inhibit the metabolism of fats, and one possibility is that somehow SCD-1 controls its levels," says Friedman.

If SCD-1 is blocked, cells may no longer generate normal levels of monounsaturated fats, which are required for normal synthesis of VLDL and triglycerides. If that happens, saturated fatty acids might build up. Scientists reported in the 1970s that fatty acids inhibit the enzymes, now called ACC1 and ACC2, which produce malonyl CoA. Such a buildup of saturated fatty acids might act to decrease malonyl CoA levels and stimulate fatty acid import into mitochondria, and in turn, the burning of fat.

"Reduced levels of malonyl CoA are known to increase fatty acid metabolism and decrease fat synthesis," says Friedman. "We hypothesize that leptin may act in part by suppressing SCD-1 activity, reducing malonyl CoA levels thus activating this metabolic pathway. Of course this and several alternative possibilities need to be further evaluated."

This possibility is supported by other results from researchers at Baylor College of Medicine and Johns Hopkins University, showing that the inhibition of other components of this metabolic pathway yield similar results. Salih Wakil, Ph.D., and colleagues at Baylor showed that mice lacking ACC2 have higher than normal metabolic levels and weigh 10 to 15 percent less than control mice. At Johns Hopkins, M. Daniel Lane, Francis P. Kuhajda, M.D., and co-workers designed a molecule called C75 that activates CPT-1 (by repressing the ability of malonyl CoA to inhibit it) and blocks fatty acid synthase, an enzyme important for converting carbohydrates into the building blocks of fat. This drug also reduces weight and increases energy expenditure.

"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," Friedman says.
In addition to Cohen, Friedman, Ntambi, Miyazaki and Socci, other authors on the Science paper are Aaron Hagge-Greenberg, Wolfgang Liedtke, M.D., Alexander Soukas, Ph.D., and Ratnendra Sharma at Rockefeller and Lisa C. Hudgins, M.D., at the Rogosin Institute.

This 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).

Additional Contact:
Terry Devitt at University of Wisconsin at Madison 608-262-8282

Rockefeller University

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