IV. Discussion
This is the first study to associate the prevalence of
the DRD2 A1 allele and percent body fat. Our findings of a 67% A1 allele
prevalence in obese subjects compared to 33% A1 allele prevalence in non-obese
controls appears to be in agreement with the work of Evans
et al, 2001.
While there is increasing evidence that genetic
factors can influence differences in vulnerability to obesity, there still is
controversy as to the exact genetic mechanism. Dopamine, acting through many
receptors, can modulate the activity of neuronal reward pathways and thus
affect a number of impulsive, addictive and compulsive behaviors, including
overeating and carbohydrate bingeing. While obesity is a heterogeneous and
prevalent disorder with both genetic and environmental components, the causes
of this disease are still unknown. Over the last decade, a number of genetic
variants have been associated with obesity and related substrates. Included in
this list is CNS regulatory genes such as the OB (LEP) gene and the dopamine D2
receptor gene. In this regard a number of studies (Comings
et al, 1993, 1996; Noble et al, 1994; Blum et al, 1996; Levitan et al, 2000; Wang et al, 2001) (Table 1) have reported a positive association of the Taq1
dopamine D2 receptor A1 allele and low density of D2
receptors in obesity, body mass index, carbohydrate binging, parental history
of obesity, co-morbid substance use disorder (SUD) and reduced energy
expenditure.
In this study we found a significant association of
the DRD2 A1 allele and percent body fat. In terms of the phenomena observed herein,
there are a number of plausible mechanisms that may contribute. They include:
(1) role of the DRD2 gene polymorphisms in obesity and related behaviors; (2)
role of the DRD2 mutations and energy expenditure; (3) the interaction of
glucose and dopamine release and hyperphagia; (4) role of dopamine and
hyperglycemia; and (5) the importance of using ÒsuperÓ normal controls in
association studies.
A. Role
of the DRD2 gene polymorphisms in obesity and related behaviors
Specifically, the reinforcing properties
of food have also led to an examination of the involvement of DRD2 polymorphisms in obesity. Haplotype 4 (GT) of intron
6 and exon 7 of the DRD2 gene were
found to be associated with increasing risk for obesity (Comings et al, 1993). In another study, the DRD2 A1 allele was present in 45.2% of obese subjects (Noble et al, 1994), a prevalence similar to that
found in alcoholics, nicotine and other drug dependent subjects. In addition,
the A1 allele was significantly associated with carbohydrate cravings. Variants
of the human leptin (LEPT, OB) and
the DRD2 genes have been examined
in relationship to obesity. Polymorphisms of the OB gene and the DRD2 A1 allele each associated significantly with obesity
(Comings et al, 1996). These two polymorphisms
together accounted for about 20% of the variance in BMI, particularly in
younger women. Another study has ascertained the relationship of the DRD2 A1
allele in obese subjects with and without co-morbid substance use disorders (Blum et al, 1996). In obese subjects, A1 allelic
prevalence was significantly higher than controls (P< 10-4).
Moreover, the progressive increase in co-morbid substance use disorders in
these obese subjects was positively related to increased A1 allelic prevalence
(P < 10-6). Furthermore, another case control study (Blum et al.
1996) compared variants of the DRD2
gene in obese (BMI > 30) and non-obese control subjects. The prevalence of
the DRD2 A1 allele was
significantly higher in obese subjects compared to controls (P = 2 x 10-3)
as was the DRD2 B1 allele (P = 3 x
10-3). The odds ratio for obesity associated with the DRD2 A1 genotype was 3.48 compared to 4.55 for the DRD2 B1 genotype. Moreover, Thomas et al, (2000) and
Rosmond et al, (2001), assessed Taq1
A DRD2 alleles in 484 obese and 506
non-obese Chinese subjects. Obese subjects, using either BMI or waist-to-hip
ratio criteria, had a significantly higher prevalence of the A1 allele (P=0.02)
and A1 allelic frequency (P= 0.03) than non-obese subjects.
B. Role of the DRD2
mutations and energy expenditure
Two studies (Jenkinson et al, 2000; Tataranni et al, 2001),
assessed the role of other DRD2 mutations on weight and energy expenditure in Pima
Indians. Individuals with a Cys-encoding allele had a higher BMI than those
homozygous for the Ser-311 allele (Jenkinson et al,
2000). Further, total energy expenditure and 24 hour resting energy
expenditure were lower in homozygotes for the Cys311 allele when compared to
heterozygotes and homozygotes for the Ser-311-encoding allele (Tataranni et al, 2001).
C. The interaction of
glucose and dopamine release and hyperphagia
Moreover, it is well known that pharmacologic doses of
the glucose analogue, 2-deoxyglucose (2DG), cause acute glucoprivation and are
associated with enhanced dopamine turnover in pre-clinical studies. In fact,
lines of evidence indicate that a variety of metabolic stressors, including
acute glucose deprivation are associated with dopamine release. Using PET,
Adler and colleagues (2000) found that 2DG administration enhanced synaptic
dopamine concentrations. The administration of 2DG is associated with
significant striatal dopamine release even in healthy volunteers. These studies
are important because they further closely tie glucose levels to dopaminergic
activity and strengthen our understanding of the interactive symbiotic
relationship between insulin, serotonin and dopamine. As such, there is a
relationship between insulin levels and dopamine release in the
tuberonfundibular neurons. The insulin effect is dependent on CA++
ions, protein kinase C, and the Na+-H+
exchange system. Additionally, when there is lower glucose in the brain leading
to cerebral global transient ischemia, monoamine release, especially dopamine,
is inhibited. In this regard, Trugman and James
(1993) showed D1 antagonists lowered glucose utilization by 24 %-28 % in
the globus pallidus, entopeduncular nucleus, subthalmic nucleus, substantia
nigra, and even the motor cortex, suggesting that stimulation of the D1
receptor by endogenous dopamine contributes to basal metabolism in these
regions. In contrast both D1 and D2 agonists increase glucose utilization.
These results suggest that feeding behavior is tied into the stimulation of
both D1 and D2 receptors and provides metabolic evidence for the importance of
D1 and D2 functional linkage in the brain, which relates to hyperphagia or
overeating.
D. Role of
dopamine and hyperglycemia
The direct effect of dopamine on glucose release from
primary cultured rat hepatocytes was studied in Japan by Shiroyama and colleagues
in 1998. In this regard, dopamine is known to
induce hyperglycemia in both animals and man. Their study
investigated whether dopamine has any direct effect on glucose release from
hepatocytes through the glycogenolytic and/or gluconeogenic pathways, and at
the same time determined the main type of adrenergic receptor involved in
glucose release. Glycogen-rich and gluconeogenic-depleted hepatocytes were
prepared in order to study glycogenolytic and gluconeogenic-depleted glucose
release, respectively. Dopamine caused release of glucose which was inhibited
by the beta blocker propranolol. Their study
demonstrates that dopamine has a direct effect on hepatocytes,
increasing glucose release via both glycogenolytic and gluconeogenic pathways
and mediated by beta adrenergic receptors.
E. ÒSuperÓ
versus normal controls in association studies.
This
is the first report that provides direct genetic evidence that the dopamine D2
receptor A1 allele, which has been associated with lower D2
receptors in humans (Noble et al, 1991; Wang et al, 2001),
is positively associated with increased percent body fat. The process of fat
storage and the role of genes are poorly understood. However, with confirming
data, our findings point to a significant involvement of human percent body fat
and dopamine functionality. In regards to using highly screened, ÒsuperÓ
controls, using similarly well screened controls, Neiswanger and colleagues
found a strong association of the D2 A1 allele and
alcoholism (Neiswanger et al, 1995). Hill suggested
failures reported in the literature were due to poor assessment of controls.
Their suggestion significantly bolsters the appropriate use of
"super" controls to more accurately assess a true phenotype. This is
especially important when studying complex behavioral diseases (Hill, 1998). The same researchers found evidence for
linkage between the dopamine D2 receptor gene and severe alcoholism,
early onset, physical dependence symptoms, and Antisocial Personality Disorder
(Hill et al, 1999). However, the use of
ÒsuperÓ controls may not be appropriate because these individuals do not mirror
the general population, and similar comorbid disorders were not eliminated from
the obese group. Thus these results should be regarded as preliminary.
Moreover, we also examined a non-super control group, screened only to exclude
obesity and DSM-IIIR axis I disorders. There the prevalence of the DRD2 A1 allele was still significantly lower than for the
obese group.
F.
The ANNKI gene: A potential candidate dopaminergic linkage site
It is noteworthy, that regarding the observed
polymorphic association in this paper, a major difficulty with an association
of the DRD2 Taq1 A1 allele
with other complex behaviors such as alcoholism, is that the Taq1 A
polymorphism is located more than 10kb downstream from the coding region of the
DRD2 gene (Johnson, 1996) and a mutation at
this site would not be expected to lead to any structural change in the
dopamine receptor. The most likely explanation for an association is that Taq1
A polymorphism is in linkage
disequilibrium with an upstream regulatory element, or a 3Õ flanking element,
or another gene which confers susceptibility to RDS behaviors. Several linkage
disequilibrium studies have found strong linkage disequilibrium between Taq1 A1 allele and the Taq1 B allele and the SSCP 1 allele
(Blum et al, 1991; Hauge
et al, 1991; Goldman et al, 1993; O'Hara et al, 1993; Johnson, 1996). As we have pointed out, the
dopamine D2 receptor has been implicated extensively in relation to alcoholism,
substance use disorder, nicotine dependence, anxiety, memory, glucose control,
pathological aggression, pathological gambling, and certain sexual behaviors;
all RDS behaviors. The most frequently examined polymorphism linked to this
gene is the Taq1 A restriction
fragment length polymorphism which has been associated with a reduction in D2
receptor density. In a recent study, within the 10kb downstream region of the Taq1
A1 RFLP, Neville and associates
identified a novel kinase gene, named ankyrin repeat and kinase domain
containing 1 (ANKK1), which
contains a single serine/threonine kinase domain and is expressed at low levels
in placenta and whole spinal cord RNA but its presence has not localized to
brain tissue as yet. This gene is a member of an extensive family of proteins
involved in signal transduction pathways. The DRD2 Taq1A allele is a single
nucleotide polymorphism (SNP) that causes an amino acid substitution within the
11th ankyrin repeat of ANKK1 (p. Glu713lYs), which, while unlikely
to affect structural integrity, may affect substrate-binding specificity. If
this is the case, then changes in ANKK1 activity may provide an alternative
explanation for previously described associations between the DRD2 gene and RDS
behaviors (Neville et al, 2004). Most recently
additional studies of this gene and nicotine dependence suggests that the
ANNK1 flanking gene is closely tied to the DRD2 gene and it is strongly
associated with smoking behavior (Gelenter et al, 2006).
G. Reexamining the consequences of calorie deprivation
on obesity and related RDS characteristics
Some of the earliest research providing
data still relevant today assessed the effects of starvation and subsequent
refeeding in healthy volunteers (Keys et al, 1950).
Keys and colleagues reported in 1950 that semi-starvation dieting resulted in a
down regulation of metabolic rate, reduced thermogenesis and subsequent phase 2
accelerated fat deposition. Thirty two men volunteered to participate in an
experiment in which their average daily food intake was cut in half. This was
to be carried out for six months so the researchers could study an extended
physiological and biochemical response to semi-starvation. The men were
provided with 1600 calories a day including the vitamins, minerals and protein
calculated to meet needs. Over the course of the six months all the subjects
lost on average a quarter of their initial body weight with over half of the
weight being from lean tissue. They also experienced a 40% decrease in basal
metabolic rate and a significant increase in food and weight obsession. All of
the men began to sneak food, binge eat, obsessively collect recipes and food
became the sole topic of conversation. They also experienced a loss of interest
in sex and daily activities. By the end of the study all of the men were
extremely apathetic. Interestingly, this ÒoldÓ research still provides insight
into the repercussions of low calorie dieting as a method of weight loss.
More recently, Dulloo and Jacquet reexamined
in 1998 data from this study and confirmed that semi-starvation lowers BMR and
thermogenesis. However, they noted that upon refeeding it was observed that fat
deposition was accelerated in a preferential fashion over lean tissue
synthesis. They further noted that the rate and amount of fat deposition,
termed catch-up fat gain, was proportional to the degree of initial fat
storage. In other words, the greater the pre-starvation BMI, the greater the
suppression of thermogenesis, and the greater the rate and quantity of fat
deposition upon refeeding. In addition, they found that the lower protein ratio
during refeeding was not due to a shift in the individualÕs energy partitioning
characteristic, but was attributed to other mechanisms operating via the
suppression of thermogenesis in response to severe fat depletion, with the
energy thus conserved being directed specifically towards accelerating fat (and
not protein) recovery. Under conditions whereby the refed animals were pair fed
with weight-matched controls, the rate of protein deposition was the same as in
the controls but that of fat deposition was increased by 3-fold as a result of
energy spared from a 10–15% lower energy expenditure during the early
phase of weight recovery (Dulloo and Girardier, 1990; Dulloo and Jacquet, 1998). A number of animal studies and
human research by some of our own authors (already cited elsewhere)
demonstrates that calorie reductions result in an attempt to increase dopamine,
and/or dopamine stimuli, i.e. hyperphagia, sugar, alcohol, nicotine, gambling,
etc (Hao et al, 2000; Johansen et al, 2001). We have already shown that calorie deprivation or
restriction promotes abnormal dopamine activity that, especially in individuals
carrying the DRD2 Taq 1 A1 allele, leads to a number of excessive RDS behaviors
like hyperphagia, sugar cravings, binge eating, etc.
H. Metabolic
and neurogenomic integration: future application and perspective
The body's number one "Prime Directive" is
survival. There are many aspects of gene induced behavior, from normal metabolism
to emergency failsafe protective metabolism that can be and are induced to
ensure survival. As
previously shown, there is a clear connection between dopamine D2 Receptor gene
polymorphisms and excessive craving-induced aberrant behaviors. In addition, as
stated earlier, chronic stress causes a phase 2 reduction in dopamine
concentration and the number of active dopamine cells (Gambarana, 2001; Moore
et al, 2001; Miyasaka et al, 2005). As such,
in a population carrying a particular polymorphism (i.e. DRD2 Taq1 A1 allele), our notion is that chronic stress (or stressors) causes reduced
dopamine secretion/receptivity, thereby increasing the craving or need for
reward compensation.
Evidence has been demonstrated that
persistent stress can lead to a self-sustaining pattern of abnormal craving
behavior in both animals and humans, such as carbohydrate bingeing or long-term
abuse of sugar. Animal model support for this premise can be derived from a
series of experiments carried out by Li and associates (Mcbride et al 1990,
1997; Hwang et al, 1990; Volkow and Li 2005, 1990, Russell et al, 2004) upon
substance-preferring (P) [seek carbohydrates, alcohol, opiates, etc.] and nonpreferring (NP) rat lines. Among
a number of other factors, they found that P rats had a reduced dopamine supply
at the nucleus accumbens and reduced densities of dopamine D2 receptors in the meso-limbic areas, accompanied by lower serotonin
neurons in the hypothalamus, higher levels of enkephalin in the hypothalamus (due to a lower
release) and more GABA neurons in the nucleus accumbens.
Crossing a certain stress threshold not
only affects dopamine, but can induce survival gene expressions that affect
neurogenobolic signaling, which can retard phase 2 energy, fat and endocrine
metabolism (the aftermath of initial stress response).
Work by Kogan et al. confirms that the
drug DR4004, a putative 5-HT7 receptor antagonist, also has
functional activity at the dopamine D2 receptor (Kogan, et al, 2002). It is of
interest that neuroanatomical data suggest a potentially interactive role
between accumbens acetylcholine (ACh) and dopamine. There is evidence that Nacc
ACh is apparently related to neural processes underlying not only
psychostimulant reward but also natural consumption behavior (i.e. feeding). In
this regard, Hajnal and colleagues found in 2000 that accumbens cholinergic
interneurons play a role in the regulation of body weight and metabolism. In
this context both stress and the role of dopamine play an important part in the
Ach response (Hajnal et al, 2000).
It has also been known for some time that
stress induces the preferential release of the circulatory hormone cortisol in
humans (Reddy, 2006). Additionally, lipolysis is the major activity involved in
the burning of fat in adipose tissue. Ottosson and colleagues clearly showed in
2000 that
cortisol significantly reduced the basal rate of lipolysis (p<0.01) and the
catecholamine lipolysis stimulators isoprenaline and noradrenalin in vitro (Ottosson et al, 2000). Furthermore, stress induction studies in animals showed a
significantly higher food intake than controls within a few days following the
stress-induced events (Miyasaka et al, 2005).
These findings are consistent with those in humans demonstrating that stress
alters dopamine metabolism, contributing to overeating and increases in other
aberrant craving behaviors. In contrast, a reduction in stress, via massage
therapy, was shown to reduce cortisol and increase levels of serotonin and
dopamine (Field et al, 2005). In addition, dopamine has been associated with
pleasure, and has been called the Òanti-stress moleculeÓ and/or the Òpleasure
moleculeÓ (Blum et al, 2000). When dopamine is
released into the synapse, it stimulates a number of receptors (D1-D5)
which results in increased feelings of well-being and stress reduction.
Sufficient stress also increases cell
turnover, induces apoptosis and causes a cascade of survival events.
Gene-mediated apoptosis (programmed cell suicide) is an attempt to "get
rid of the bad" so as not to encumber or interfere with and/or essentially
"make room" for the good. Recent research in mice corroborates that
stress-induced mutations in mitochondrial DNA (mtDNA) accumulate in tissues of
mammalian species and are believed to be a significant contributor to aging.
Accumulation of mtDNA mutations was not associated with increased markers of
oxidative stress defects in cellular proliferation, but was correlated with the
induction of apoptosis, particularly in tissues characterized by rapid cellular
turnover. The levels of apoptotic markers were also found to increase during
aging in normal mice (Dulloo and Jacquet 1998). The more severe and stressful
the adverse environment in the body/tissues, the more aggressive is apoptosis,
as has been shown by research in which apoptosis is curtailed (with appropriate
genes being "silenced") as a result of exposure to certain
nutraceutical substances (i.e. botanicals/nutrients) (Chanvitayapongs et al, 1997; Jang et al, 1997;
Joshi et al, 1999; Ray et al, 1999; Criswell
et al, 2005; Kujoth et al, 2005).
While in the past it was thought that DNA
was a static non-changeable constituent of the organism, today it well
established that environmental, pharmaceutical and nutraceutical elements can
indeed have profound effects on altering polymorphic gene expressions. One
example of these interesting phenomena is the influence of folic acid upon the
methylation of certain DNA. Other examples include predisposition to aberrant
sugar craving behavior, such as with excessive carbohydrate/alcohol binging and
development of the polymorphism for the Dopamine Receptor D2 A1 Taq1 allele,
which increases pleasure cravings in the reward circuitry of the brain (the
dopamine system). The actual gene expression depends on an individualÕs life
style and nutritional status rather than the DNA per se. As way of an example, this known and established
polymorphism requires an almost excessive need for certain precursor amino
acids to assist in the synthesis of certain brain neurotransmitters and
minerals to "over nourish" and answer the excessive needs of this
pathway and reduce, eliminate and/or normalize the excessive behavior that
results from those demands (Blum et al, 2000).
We propose that a complete understanding of
neurometabolic systems, as related to obesity and all of its behavioral subsets
when coupled with genomic principles will provide novel targets to combat
genetic, physiological, neurological, nutritional and peripheral metabolic
dependent deficiencies.
I. Reward
deficiency syndrome (RDS): A paradigm shift
Taken together, results of research
indicate a profoundly integrated, interdependent and compensatory relationship
between the brainÕs reward/pleasure circuitry, stress management and the
neuroendocrine system (i.e Cortisol), and the energy management system, all of
which are affected by lifestyle factors and regulated by genetic ÒoversightÓ
influenced by particular gene polymorphisms. The dopamine system appears to be
a pivotal factor in the sequela of response initiators that, based on specific
polymorphisms, results in particular types of behavior described above. We
further propose that Reward deficiency Syndrome (RDS) (Blum et al, 1996) is a
subset of disorders contributing to a condition we propose be termed Neurobesigenics. The condition RDS accounts for the deficiencies in
metabolic competence brought on by 1) the Òexcessive compensatoryÓ expression
of genetic survival mechanisms provoked by chronic and significant dietary
stasis and concomitant nutrient deficiencies, 2) exacerbated by yo-yo BMI
induced unhealthy deprivation/stimulation tactics, 3) processed through genetic
predispositions involving the brainÕs reward management system, energy
management system, stress and inflammation management system, immune system,
and 4) the interplay of each system as theyÕre manifested through the endocrine
and metabolomic system. While the net release of dopamine is important for
normal neurological and metabolic functioning, other neurotransmitters are
involved in dopaminergic activation through a brain reward cascade. One of the
most important is serotonin, especially as it relates to sugar cravings and the
so called sweet tooth phenomena. The interplay of serotonergic and dopaminergic
systems are well known and established throughout the neuropharmacological
literature. While this strongly suggests that dopamine metabolism should be a
primary target for therapeutic intervention, and
potentially the ANNKI protein, it is also evident that therapeutic
address needs to include pathways like serotonin, leptin, Neuropeptide Y, and
potentially other systems that exert an influence on and/or are influenced by
dopamine.
In this regard, obesity is a result of a constellation
of metabolic dysfunctions influenced by variation of and/or amplified genetic
expressions (polymorphisms), as well as poor lifestyle decisions. Thus,
successful body recomposition requires the simultaneous address of multiple
systems. A novel Ca2+/K+ salt of (–)-hydroxycitric
acid (HCA-SX) from Garcinia cambogia, has shown to be effective in obesity
management. Appetite suppression of HCA is thought to result from increased
glycogen production and concomitant stimulation of glucoreceptors in the liver,
which sends signals of satiety to the brain. However, recent clinical and
pre-clinical studies show that HCA-SX increases levels of serotonin (5-HT), a
vital neurotransmitter involved in a wide range of behavioral functions in the
body, including mood, sleep and appetite control. Studies show that serotonin
affects eating behavior and body weight. Increased plasma levels of serotonin
are associated with decreased food intake, reduced weight gain and increased
energy expenditure. HCA-SX significantly inhibits serotonin re-uptake and
increases serum serotonin levels in the body. Another benefit of increasing
serotonin levels may be in addressing many of the emotional issues overweight
people face, including binge-eating and depression. HCA-SX has also been shown
to reduce levels of neuropeptide Y (NPY) in the hypothalamic tissue of animals.
Earlier research has shown that NPY significantly increases appetite in animals
that were pre-satiated with a meal. These new studies provide powerful new
evidence on HCA-SXÕs ability to influence brain chemicals and neuropeptides
involved in appetite control and eating behavior. Another recent finding is
HCA-SXÕs ability to increase fat oxidation and modulate blood lipid levels.
Human clinical trials have shown that HCA-SX significantly increases output of
urinary fat metabolites. Following exercise or other fat oxidation (burning)
processes, fat tissue breaks down into small molecular components, including
malondialdehyde, formaldehyde, acetaldehyde and acetone. Increased urinary
levels of these fat metabolites indicate increased fat degradation. Thus, HCA-SX
is a potent modulator of various metabolomic and genomic systems involved in
behavior, healthy body composition and obesity management (Chanvitayapongs et al, 1997; Jang et al, 1997; Joshi et al, 1999; Ray et al, 1999; Preuss et al, 2004a,b, 2005;
Criswell et al, 2005; Downs et al, 2005;
Kujoth et al, 2005).
Moreover, obesity is the result of a breakdown in the
harmonious (interdependent) symbiosis of multiple systems of genetically
regulated neurometabolic signaling due for the most part to deficiencies in
nourishment, excesses in burdensome environmental factors and/or inadequate
system responsiveness necessary for that symbiotic competence between the
energy management system (with regard to energy intake, expenditure and
storage), the stress and inflammation management system, the pleasure
management system, the immune management system, and the neuro-endocrine
system. As such, tactics that address less than all of these multiple systems
simultaneously can achieve only limited or no success in sustainable healthy
body recomposition. The phenomenon known as ÒYo-yo rebound weight gainÓ causes
increases in fat storage that occur as a result of ÒsuccessfulÓ early onset
Phase 1 weight loss efforts (from a variety of conventional
Òdeprivation/stimulationÓ tactics) followed by cessation of the tactic(s)
and/or the bodyÕs genetic survival response to such tactics by lowering the
neurometabolic rate, increasing fat storage and increasing appetite (Keys et al, 1950; Dulloo and
Jacquet, 1998; Dulloo and Girardier, 1990).
Over the last few decades this phenomenon has resulted in an obesity epidemic
that is spreading worldwide. Even with the overwhelming arsenal of modalities
and their endless combinations, obesity is the second leading cause of
preventable death in the United States after tobacco with nearly 200 million
Americans (roughly 60%) categorized as overweight or obese, according to the
Centers for Disease Control and Prevention.
V. Conclusion
The old adage Òas the head goes, so goes the body, is
a simple but appropriate characterization of the symbiosis that exists between
the brain, the genome and the resulting metabolomic symphony. We propose that
while obesity is a polygenic disorder, our findings indicate a putative
important role of the dopamine D2 receptor gene in morbid obesity,
especially in high risk populations (Jenkinson et al,
2000; Noble, 2003), and that high to low quality lifestyle factors can
exert a positive to negative influence respectively on gene expressions
accordingly. Most recently it has been determined by Malis and colleagues (2005) that total and regional fat distribution is
strongly influenced by genetic factors in young and elderly twins.
Specifically, the hereditability factor h2=0.83 (young) and 0.86
(elderly). In this regard, our results further suggest that certain
polymorphisms of the DRD2 gene observed to associate with percent body fat in
this study and possibly fat distribution, may provide the first evidence for
involvement of this gene in neurobeisigenics (a proposed new name for Obesity
and related disorders) and warrants further independent systematic
investigation.
Acknowledgements
The concept and design of the study was developed by
Kenneth Blum. THJ Chen, K Blum, G Kaats, D Pullin, ER Braverman, DE Comings,
contributed to the execution of the study. K Blum, DE Comings, G Kaats, D Pullin
and ER Braverman were involved in patient recruitment. The concept of ÒNeurobesigenicsÓ was initiated by K Blum, BW Downs and B Meshkin.
Editorial input was contributed by Debasis Bagchi,
Manashi Bagchi, Ariel Robarge, J. Mengucci, BW Downs, B Meshkin, and DE
Comings. Reference styling to conform with journal guidelines was
contributed by SH Blum, Vanessa Arcuri, Michael Varshavskiy. The manuscript was
drafted by K Blum, TJH Chen, DE Comings, ER Braverman, BW Downs, B Meshkin. All
authors commented on the text and the team revised accordingly. K Blum had full
access to all the data in the study and had final responsibility for the
decision to submit for publication.
The authors would like thank Salugen,
Inc., San Diego, California, Path Medical Research Foundation, New York,
NY, for their financial support and acknowledge the editorial assistance of
Gina S. Bender, Edward N. Bender, Randy Smart and Kristi Brandon. The authors
want to thank Dr. Mathew Mcgue for allowing us to utilize the lean controls.
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