How Regulators of Fat Metabolism Work

The hormone leptin has been found to specifically repress RNA levels and enzymatic activity of a gene that catalyzes the biosynthesis of monounsaturated fatty acids, causing fat to be metabolized for energy rather than being stored. This finding and others were contained in an article published in the July 12, 2002, issue of Science.

Researchers at Rockefeller University (New York, NY, USA) found that when they crossed obese (ob/ob) mice that lack leptin with a strain called "asebia,” which carries mutations in the SCD-1 gene, the obese mice lost weight despite continuing to overeat. Leptin caused weight loss by reducing food intake and by increasing energy expenditure, while a deficiency of SCD-1 reduced obesity by increasing energy expenditure without affecting food intake at all.

Similar to leptin treatment, removal of SCD-1 markedly reduced the weight of the obese mice. At 16 weeks of age, weight was reduced by 29% in females and 34% in males. The reduced weight of these animals could be accounted for by a dramatic increase in energy expenditure. 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, explained Dr. Jeffrey Friedman of the laboratory of molecular genetics. "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.”

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,” said Dr. Friedman. "Still, many more studies will be necessary to confirm that molecules that inhibit SCD-1 have an acceptable therapeutic index.”

In the current study investigators used DNA microarrays. These were evaluated with the help of a computer program that was able to sift through some 6,500 mouse genes contained in a single gene chip. The researchers sought genes that were specifically suppressed by leptin, and SCD-1 topped a final list of 36 genes.



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