Orphan Nuclear Receptor Shows Fat-Fighting Potential

Science's STKE  11 May 2004:
Vol. 2004, Issue 232, pp. tw163-TW163
DOI: 10.1126/stke.2322004TW163

Fighting obesity would seem a relatively straightforward problem that could be solved by reduced intake of food. However, as many dieters can tell you, the body can work against you in this endeavor because of homeostatic mechanisms that act to reduce weight loss in periods of fasting or low caloric intake. What happens is that endocrine mechanisms compensate by reducing the basal metabolic rate, so that less energy is consumed (and less fat goes away). A new study from Maglich et al. presents a possible mechanism that could allow this compensatory mechanism to be disabled and thus enhance weight loss during fasting. The authors show that the orphan nuclear receptor CAR (also called NR1I3), previously shown to function in sensing xenobiotics and regulation of expression of detoxifying enzymes and transporters, also has a key role in regulating thyroid hormone metabolism. That is important because it is a decrease in circulating concentrations of thyroid hormones that leads to the reduced metabolic rate observed during fasting. 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. As expected, mice fasted for 24 hours showed reduced amounts of circulating thyroid hormones, but Car–/– mice had a significantly smaller reduction in the amount of circulating hormone. Mice were also subjected to a weight-loss regimen in which caloric intake was reduced 40% for 12 weeks (don't try this at home!). In this case, Car–/– animals lost 2.5 times as much weight as did the wild-type animals. The authors propose that CAR is a critical component of the mechanisms that prevent weight loss. 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.

J. M. Maglich, J. Watson, P. J. McMillen, B. Goodwin, T. M. Willson, J. T. Moore, The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J. Biol. Chem. 279, 19832-19838 (2004). [Abstract] [Full Text]