Genes


Several months ago, I commented on a study that showed that there was an increased incidence of depression in patients taking a drug used to treat nicotine addition.  The study concluded that because nicotine and the endogenous neurotransmitter, acetylcholine, act to stimulate the brain’s own reward circuitry drugs which block this pathway would reduce the level of reward experienced by the subject during their normal life experiences.  Dopamine is an important neurotransmitter in the reward pathway and many activities that we enjoy activate this dopamine pathway.  One of these pleasurable and rewarding activities is eating. 

           

A recent study (http://www.sciencemag.org/cgi/content/full/322/5900/449) has further substantiated the role of dopamine in endogenous reward pathways and the results of this study suggest that deficiencies in the reward pathway might contribute to obesity.   The investigators used functional magnetic resonance imaging (fMRI) to measure blood flow in specific brain regions of human subjects.  Increases in blood flow indicate an increase in nerve activity in that area of the brain.  This study focused on the dorsal striatum which is a component of the endogenous reward pathway.  Dopamine is an important neurotransmitter in the dorsal striatum and dopamine stimulates D2 type dopamine receptors in this brain area.  The authors studied two groups of female subjects.  The first was a group of female college students while the second group was composed of adolescent females; the authors obtained genetic information about most of the women in the second group.  Body mass index (BMI) was calculated for all subjects in both groups. 

 

Subjects were shown pictures of a chocolate milkshake and then they were given a chocolate milkshake to drink.   During exposure to these stimuli fMRI scans of the ventral striatum were obtained.  The authors found that there was a negative correlation between BMI and activity in the ventral striatum when the subjects consumed the chocolate milkshake.  The authors interpreted these data to mean that the heavier subjects experienced less reward from consuming the chocolate milkshake compared to leaner subjects.  What was very interesting was that the subjects that experienced the least activation of the ventral striatum had a genetic polymorphism associated with low D2 receptor expression. 

 

Previous twin studies have shown that there is a genetic link for obesity.  This study suggests that at least in some subjects, reduced D2 dopamine receptor activity in the reward pathway may be associated with reduced levels of eating induced reward.  This would lead these individuals to consume more food in order to achieve some level of reward and this would predispose these subject to overeating.  Perhaps drugs which can activate the endogenous reward pathway, particularly the ventral striatum, might be useful in enhancing the reward associated with food intake and this might limit the size of meal needed to experience reward and therefore discourage overeating.    

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A healthy lifestyle that includes regular exercise and sensible eating can help to prolong life span and also improve the quality of life as people age. The underlying mechanisms responsible for the positive impact of a sensible diet on longevity and quality of life have been studied in a number of different organisms including bacteria, yeast, worms, fish, mice and rats. Dietary restriction in these organisms increases life span and this is associated with an increase in expression of genes that are involved in sugar and fat metabolism. So, it seems that dieting can have beneficial effects not only for humans but species throughout the phylogenetic tree. While dietary restriction has clear health benefits, it can also pose risks and not everyone is willing or able to maintain limited intake of food throughout the life span. The search is on for a drug that would produce the benefits of dietary restriction without the pain.

A recent paper published online in Cell Metabolism (Pearson et al., “Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span” doi:10.1016/j.cmet.2008.06.011) has shown that resveratrol may be the magic bullet. Resveratrol is a contained in red wine and is one of the components believed to be responsible for some of the health benefits of modest red wine consumption. In the study done be Pearson and colleagues, gene expression profiles in mice treated daily with resveratrol were compared with profiles obtained from mice placed on a restricted caloric intake diet beginning at 1 year of age. It was found that expression of genes involved in metabolism was very similar between the two groups. Moreover, “quality of life” measures, that included assessments of motor performance, cardiovascular health, osteoporosis and cataract development all revealed that mice on the restricted diet or resveratrol had significantly better scores than those mice on a standard diet. Interestingly, dietary restriction, but not resveratrol treatment, increased life span.

Vitamins and other supplements have been used for many years with the hope that these treatments would improve the quality of life and longevity. Limited data are available to verify the effectiveness of these treatments in achieving their goals. However the study by Pearson et al., suggest that supplements containing resveratrol may just do the trick. Sensible eating along with the occasional glass of red wine does not sound like such a horrible life style adjustment for those seeking longer and healthier lives!

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