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Food Restriction Increases Pleasure — In Rats

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A brain-imaging study of genetically obese rats conducted at the U.S. Department of Energy’s Brookhaven National Laboratory provides more evidence that dopamine – a brain chemical associated with reward, pleasure, movement, and motivation – plays a role in obesity. The scientists found that genetically obese rats had lower levels of dopamine D2 receptors than lean rats. They also demonstrated that restricting food intake can increase the number of D2 receptors, partially attenuating a normal decline associated with aging.

Autoradiograms showing dopamine D2 receptor levels in the brains of obese and lean rats at four months of age. Half of the rats, top row of images, had been given unrestricted access to food during the previous three months while the other half, bottom row of images, were kept on a restricted diet. Compared with images taken at one month of age, these images show that the number of dopamine receptors declined with age in both obese and lean rats, but significantly less so for animals on a restricted diet than for those given unrestricted access to food. This effect of food restriction was most apparent in the obese rats.

“This research corroborates brain-imaging studies conducted at Brookhaven that found decreased levels of dopamine D2 receptors in obese people compared with normal-weight people,” said Brookhaven neuroscientist Panayotis (Peter) Thanos, lead author of the current study, which will be published in the journal Synapse.

It’s not clear whether reduced receptor levels are a cause or consequence of obesity: Overeating may chronically reduce receptor levels, which, over the long term, could eventually contribute to obesity. But having genetically low receptor levels may also lead to obesity by predisposing the individual to overeating in an attempt to stimulate a “blunted” reward system. Either way, revving up receptor levels by restricting food intake could enhance the impact of this common strategy for combating obesity.

“Consuming fewer calories is obviously important for people trying to lose weight, plus improving the brain’s ability to respond to rewards other than food may help prevent overeating,” Thanos said. Because food intake can have such a dramatic effect on dopamine receptor levels, “this study also provides further evidence for the interplay of genetic factors with the environment in the development of obesity in our society,” he said.

The finding that food restriction can attenuate the effects of aging on the brain’s ability to respond to dopamine may also help explain why food restriction slows down other changes associated with aging, such as declines in locomotor activity and sensitivity to reward.

Methods and findings

The researchers measured dopamine D2 receptor levels in adolescent and young adult genetically obese Zucker rats and lean rats. Between measures, half of the rats in each group were given free access to food while the other half were given 70 percent of the daily average amount of food eaten by the unrestricted group.

The scientists measured D2 receptor levels using two different techniques: micro-positron emission tomography (microPET) in living animals, which uses a radioactively tagged molecule that competes with the brain’s natural dopamine for D2 receptor binding sites, and autoradiography, which uses a tracer that binds more strongly than natural dopamine but can only be used in tissue samples rather than in living animals. Together these two methods indicate the absolute number of D2 receptors found in the brain and how many are available or free during day-to-day function, which might be relevant to further elucidating the role of dopamine in obesity.

One main finding was that the overall number of D2 receptors was lower in obese than in lean rats. Also D2 receptor levels decreased with age, but this decline was significantly blunted in food-restricted rats compared with those given free access to food. This attenuation was most apparent in the obese rats.

Another main finding was that D2 receptor availability – that is, the number of receptors available for binding dopamine – was greater at adulthood in the obese rats compared to the lean rats. This suggests that perhaps the release of dopamine had significantly decreased with age in the obese unrestricted animals more than in the restricted ones or the lean rats. The possibility of lower release of dopamine in obese subjects is presently being examined, the researchers say.

Synapse. 2007 Oct 25;62(1):50-61 [Epub ahead of print]

Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in-vivo muPET imaging ([(11)C] raclopride) and in-vitro ([(3)H] spiperone) autoradiography.

Thanos PK, Michaelides M, Piyis YK, Wang GJ, Volkow ND.

Behavioral Neuropharmacology Laboratory, Medical Department, Brookhaven National Laboratory, Upton, New York 11973‐5000.

Introduction: Dopamine (DA) regulates food intake by modulating food reward and motivation but its involvement in obesity is much less understood. Recent evidence points to the involvement of leptin in the DA-related modulation of food intake. Here we assess DA D2 receptors (D2R) in a genetic rodent obesity model characterized by leptin-receptor deficiency and assess the influence of food restriction on these receptors. Methods: We compared D2R levels between Zucker Obese (fa/fa) and Lean (Fa/Fa) rats at 1 and 4 months of age and in two different feeding conditions (restricted and unrestricted food access) using in-vivo muPET imaging ([(11)C] raclopride, which is a method sensitive to competition with endogenous DA) and in-vitro ([(3)H] spiperone washed to ensure no competition with endogenous DA) autoradiography (ARG). Results: Both ARG and muPET showed that D2R were higher at 1 month than at 4 months of age and that food restricted animals had higher D2R than unrestricted animals. However there were significant differences in the results obtained at 4 months between ARG and muPET. ARG showed that at 1 month and at 4 months unrestricted lean rats (Le U) had significantly higher D2R binding than obese unrestricted rats (Ob U) but showed no differences between restricted obese (Ob R) and restricted lean rats (Le R). It also showed that D2R decline between 1 and 4 months of age was significantly attenuated in food restricted rats [both obese and lean]. In contrast, muPET showed that at 4 months of age, Ob U showed greater D2R availability than Le U rats but like ARG showed no differences between Ob R and Le R rats. Conclusion: The lower D2R binding in Ob U than Le U rats observed with ARG most likely reflects decreases in striatal D2 receptors levels whereas the increased availability observed with muPET is likely to reflect reduced DA release (resulting in decreased competition with endogenous DA). Lack of a significant difference between Ob R and Le R suggests that the differences in dopamine activity and D2R levels between Ob and Le Zucker rats are modulated by access to food. The ARG finding of an attenuation of the age-related loss of D2R binding corroborates previous studies of the salutary effects of food restriction in the aging process. Because [(11)C] raclopride is sensitive to competition with endogenous DA, the higher D2R binding in obese rats with raclopride despite the lower D2R levels shown with spiperone could reflect lower extracellular DA in the Ob rats and merits further investigation. Synapse 62:50-61, 2008. Published 2007 Wiley-Liss, Inc.

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