Body temperature, energy expenditure and weight gain in mice can be influenced by the metabolite succinate through a previously unidentified temperature-regulation pathway, reports a paper published online this week in Nature.
Obesity develops when energy intake exceeds energy expenditure. There are two ways to lose weight: to eat less, thereby reducing the calories available for metabolism; or to burn more calories, such as by exercising. Calories can also be used as fuel by beige and brown fat. Unlike the energy-storing white fat that amasses with obesity, beige and brown fat cells are rich in mitochondria that generate heat through a variation of the process that normally creates energy-carrying molecules. In mammals, these fats are essential for temperature regulation against the cold. This heat generation burns calories, but activating beige and brown fats on demand has proven difficult.
Edward Chouchani and colleagues screened for metabolites that are abundant only in brown fats and whose concentration increases in cold temperatures. This probe highlighted succinate - an intermediate product of a process that unlocks stored energy. Succinate is released into the bloodstream by muscle activities like shivering, from where it is absorbed into fuel beige and brown fat cells. The authors found that, in mice, succinate can increase the local temperature of these fats - and that drinking succinate-laced water staved off obesity in mice that were fed a high-fat diet.
In an accompanying News & Views article, Sheng Hui and Joshua Rabinowitz note that it will be interesting to see whether succinate also induces calorie burning in humans. Emphasizing relevant differences between mice and humans - our relatively lower proportions of brown and beige fats, which also diminish with age - they caution that “this could limit the extent to which activation of metabolic processes in brown fat can alter calorie expenditure.”
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