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Fighting Fat

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Science  21 May 2004:
Vol. 304, Issue 5674, pp. 1081
DOI: 10.1126/science.304.5674.1081b

Obesity might seem a relatively tractable problem that could be solved by reduced intake of food. However, endocrine homeostatic mechanisms act to reduce weight loss during periods of fasting or low caloric intake by reducing the basal metabolic rate, so that less energy is consumed and less fat goes away. Maglich et al. propose that this compensatory pathway might be disabled. The orphan nuclear receptor CAR, previously shown to function in sensing xenobiotics and in regulating expression of detoxifying enzymes and transporters, also has a role in regulating thyroid hormone metabolism, which is important because a decrease in circulating concentrations of thyroid hormones leads to a reduced metabolic rate. Wild-type mice treated with pharmacological activators of CAR showed reduced concentrations of thyroid hormones in serum, but no such change was seen in Car−/− knockout mice, and mice fasted for 24 hours showed reduced amounts of circulating thyroid hormones, but Car−/− mice exhibited a significantly smaller reduction. When subjected to a weight-loss regimen in which caloric intake was reduced by 40% for 12 weeks, Car−/− animals lost 2.5 times as much weight as did the wild-type animals. This raises the possibility that inhibitors of CAR action could uncouple metabolic rate from food intake, thus promoting weight loss when caloric intake is restricted. — LBR

J. Biol. Chem. 279, 19832 (2004).

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