Drugs that block some activities of the enzyme, known as xanthine oxidoreductase (XOR), might therefore offer a novel antiobesity therapy designed to fight fat before it even forms, the researchers said.
Known for its role in producing the metabolic byproduct uric acid, XOR had earlier been implicated in gout, said Jeffrey Friedman of The Rockefeller University, senior author of the study. Gout is a painful type of arthritis that results when uric acid crystals build up in the joints.
"These findings are novel in many aspects," said Iphigenia Tzameli of Harvard Medical School, one of the study's first authors. "This enzyme was originally known in association with the catabolism of purines into uric acid, the production of reactive oxygen species, and its involvement in gout. It has never been looked at in the context of fat development before."
The findings further suggest that adipose-tissue XOR may be a contributing factor to other symptoms commonly seen in obese individuals, including high blood levels of uric acid (hyperuricemia), the presence of plaque-forming lipids, and oxidative stress, the researchers added.
The research team, which also included Kevin Cheung of The Rockefeller University, screened fat precursor cells for genes that switch on early in the path to fat formation. Using a novel method to rank genes, they found that XOR was at the top of the list of genes that fit the profile of a fat generator.
Indeed, they found evidence that XOR controls PPAR-gamma a transcription factor considered to be the master regulator of fat production since it is both necessary and sufficient for adipose differentiation both in vitro and in vivo, the researchers said.
Treatments that inhibited XOR activity in cells blocked fat formation and PPAR-gamma activity, the researchers reported. Likewise, increased XOR levels hiked activity of the PPAR-gamma receptor in both fat cells and fat cell precursors. Mice lacking XOR showed a 50% reduction in fat tissue mass compared to their normal littermates. Genetically obese mice exhibited increased XOR activity and urate in the adipose tissue. Urate is a salt derived from uric acid.
"Our results identify XOR as a potential therapeutic target for metabolic abnormalities beyond hyperuricemia," the researchers said.
"To our knowledge, there have not been studies designed to explore the effects of XOR inhibitors on body weight, and in light of our findings, such studies may be warranted," they added.
Erin Doonan | EurekAlert!
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