Metabolic Syndrome & Therapy: Impacted by polymorphic genes, environment (Epigenetics) and Nutrigenomics


Kenneth Blum, PhD1,3,4,5, Marlene Oscar-Berman, PhD2, James Fratantonio, PharmD3, Gozde Agan, Bsc4.,B.W. Downs, Bsc5., Zsolt Demetrovics, PhD6, Mark S. Gold, MD7.

 

1Department of Psychiatry and McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, Florida, USA
2Departments of Psychiatry and Anatomy & Neurobiology, Boston University School of Medicine and Boston VA Healthcare System, Boston, Massachusetts , USA.
3Division of Applied Clinical Research, Dominion Diagnostics, LLC, North Kingstown, Rhode Island, USA
4Division of Addiction Services, Dominion Diagnostics, LLC, North Kingstown, Rhode Island, USA
5 Division of Applied Nutrition Research, Victory Nutrition International, LLC.,  Lederoch , Pennsylvania, USA.
6Department of Clinical Psychology and Addiction, Institute of Psychology, Eötvös Loránd University
7Retired, Department of Psychiatry and McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, Florida, USA

 

*Corresponding author: Kenneth Blum, Ph.D., Department of Psychiatry & McKnight Brain Institute, University of Florida, College of Medicine, Box 100183 Gainesville. FL., USA 32610-0183. Tel: 352-392-6680; Fax: 352-392-8217; E-mail: drd2gene@ufl.edu


ABSTRACT

Obesity is a global health problem affecting more than 300 million people. Popular weight loss tactics can reduce pounds, but maintaining weight loss remains the most difficult endeavor. Managing the obesity problem seems within reach because potential drug/nutrient responses, as a function of our genome, have become better understood. Nutriepigenomics and neurogenetics have a lifetime role in both the treatment and prevention of metabolic syndrome. A review of strategies involving inhibition of DNA methylation and histone deacetylation is presented here. The strategies involve moderation of miRNA expression, the epigenetic targeting of dysfunctional metabolic pathways, and the inhibition of DNA methyltransferase and histone deacetylase. Other discussed strategies include genetically based individualized functional amino acids, phytochemicals, and vitamin supplementation. In addition, the strategies will go over targeted epigenetically induced modification of chromatin structures and augmented imprinted genes,  which have key roles in controlling fetoplacental nutrient supply and demand. All these strategies affect dopamine signaling, molecular transport, and nervous system development. We encourage targeted strategies to improve dopamine (DA) function with the goal of the prevention of metabolic syndrome and treatment and prevention of obesity, a subtype of reward deficiency syndrome.


KEYWORDS: Nutriepigenomics, Neurogenetics, Metabolic Syndrome, Obesity, Dopamine, Reward Deficiency Syndrome (RDS).


CURRENT ISSUES

Obesity is a very common condition affecting over 2/3 of the American population. Exercise and diet are important factors related to regulating a healthy body composition, however, managing these alone has been unsuccessful in reversing the growing obesity epidemic. Although it is well understood that many of the factors involved in obesity and related symptoms are inheritable, the implications of the pivotal role played by genetics may have been overlooked.

According to the World Health Organization, obesity is a global health problem affecting more than 500 million people. Obesity has been defined as an excessive or abnormal fat accumulation that may impair health. Body mass index (BMI) is an index of height and weight (kg/m2). A BMI of greater than or equal to 25 is classified as overweight. A BMI greater than or equal to 30 is defined as Obesity.1

The Body Mass Index (BMI) was developed for Caucasian populations, but increasing evidence indicates healthy BMI is different for different ethnicities.1

Obesity is due to:

  • imbalance between energy intake and expenditure
  • nutritional deficiencies
  • multiple molecular and physiological mechanisms, influencing body fat regulation
  • genetic factors

Currently “state of the art” as it relates to popular treatments for obesity and overweight, may reduce copious pounds, however, the maintenance of the weight loss, remains elusive for the majority. In addition to calorie reduction and recommending healthy lifestyle activities, popular weight loss products most frequently target a single mechanistic path. Examples of single mechanism interventions are; fat blocking, central nervous system (CNS) stimulation to increase the rate of calorie burning, appetite suppression, and cortisol inhibition. In order to restore balance the body resorts to ‘protective’ energy conservation by a lowering the basal metabolic rate and increasing fat storage and cravings for carbohydrates. The “weight gain rebound effect” -gaining more weight gain than the originally lost, is usually caused by these automatic homeostatic protective responses. As advanced as these weight loss tactics appear to be, they are missing the mark and have failed.


NUTRIGENOMICS AND PERSONALIZED MEDICINE

As scientists, we are engaged in understanding the effects of our genome on the potential of drug/nutrient responses. With this understanding, that has both academic and commercial aspects, our ability to manage the obesity problem successfullyseems attainable. However, these gene-nutrition-genome responses will be the basis of solid scientific approaches able to assist individuals in choosing functional foods (beneficial to health in more then just nutritional aspects), dietary supplements, and nutritional beverages on a personalized basis. Environmentally modified nutrigenomics and nutrigenetics are key to what has been termed “nutritional gene therapy.” Understanding these principles will at least open the gate for the intelligent insertion of what heretofore has been the missing link to the war against obesity.3


GENETICS VS GENOMICS

The difference between genetics and even more mysterious genomics is that Genetics is the study of the effects of single genes, while Genomics is the study of the interactions and functions of all the genes in the genome. In fact, genomics, a term coined only 17 years ago, has a broader and more ambitious reach than genetics. With the advent of the mapping of the entire genome, the discipline of genomics has emerged. Genomics is a way to develop DNA targeted solutions based on candidate gene polymorphisms. Solutions to various inheritable disorders such as obesity can primarily involve nutrient, over surgical, or pharmacological modalities.

One socially and medically relevant characteristic of the human genome is that on average two unrelated people share over 99.9% of their DNA sequences. It is noteworthy, however, that the human genome contains more than 3 billion base pairs so that two unrelated humans vary at millions of bases in their DNA sequences. Additionally, since a person’s genotype represents the blending of parental genotypes each person is also heterozygous at about 3 million base pairs. Both academic and commercial sectors are currently involved in efforts to catalog these variants, commonly referred to as “single-nucleotide polymorphisms’ (SNPs). They are working to correlate measures of health, including weight issues and nutritional status, with specific genotypic variations. In the case of a complex disorder such as obesity there are potentially hundreds of SNPs from multiple genes (both peripheral and neurological) involved.

The term Nutrigenetics refers to the testing of certain known polymorphisms (SNPs) and other types of genetic variations in candidate genes that have been shown to be associated with a defined phenotype. These genetic variations confer either a positive or negative biological effect or response. The importance of these phenomena relates to significant clinical outcomes, and, therefore, potential health nutrient recommendations to the public. The term nutrigenomics refers to the actual nutrient targeted solution, called “nutritional gene therapy,” utilized to restore the normal homeostasis of any known gene polymorphism involved in a specific phenotype.3 Nutriepigenomics is the study of the effects of food nutrients mediated through epigenetic modifications on human health. Metabolic disturbances during critical developmental time windows may result in epigenetic alterations, which can lead to long-term tissue changes and altered organ structure or function and predispose individuals to disease such as metabolic syndrome.3

There are epigenetic changes in gene function, independent of alterations in primary DNA sequence, that can be inheritable. Histone modification and DNA methylation are the epigenetic mechanisms primarily implicated in nutriepigenomics. DNA methylation in the gene promoter region results in gene silencing and influence gene expression. Methyl groups, often derived from dietary sources, such as folate and choline are used in DNA methylation. Thus, diet can have a significant impact on methylation patterns and gene expression.4 The recruitment of histone deacetylases to decrease transcriptional activation can reinforce gene silencing. In some cases, however, the converse is true whereby gene expression is increased by histone acetylation induced transcriptional activation. Appetite control, metabolic balance, and energy utilization are functions that can be influenced by epigenetic events initiated by dietary components that alter gene expression.5,6

Importantly, a transcriptome -wide analysis in mice found that gene expression, in approximately 1% of the fetal genes analyzed, is changed by a protein-restricted (PR) diet during gestation. Expression of genes involved in the p53 pathway and cell death negative regulators of cell metabolism and genes related to epigenetic control were increased.7 Moreover, the effect of PR-diet in rats investigated in other studies found changes in in promoter regions methylation of both the glucocorticoid receptor and peroxisome proliferator-activated receptor (PPAR). They also found individual polymorphic targets for the treatment of obesity.8-10 Lipid and carbohydrate metabolism and elevated blood glucose levels can result from altered by expression of both the glucocorticoid receptor and peroxisome proliferator-activated receptor (PPAR).11 Other genes and hormones which can be regulated by epigenetic mechanisms include SOCS3, leptin, glucose transporter, POMC, and corticotropin-releasing hormone. It is noteworthy that long-term changes in metabolism and fuel homeostasis may result from epigenetic modification of these genes and“metabolic programming” of the fetus.12

Determination of which disease-related genes will be influenced may be related to the developmental period in which the nutritional imbalance occurred. Epigenetic modifications made during development may not be expressed until later in life due to the function of the gene.13 While the majority of studies suggest that both prenatal and perinatal developmental stages are critical time windows, research has shown that nutritional intake during adulthood can also impact the epigenome.

While there are only three papers on Nutriepigenomics cited in PUBMED as of October 30, 2014,  there are many others involving both epigenetics and neurogenetics of metabolic syndrome. One paper by Paparoet et al.14 suggested the importance of an  epigenetic effect of dietary factors on the immune system in humans. Remely et al.15 suggested that dietary compounds affect epigenetic mechanisms through the regulation of gene expression. Gene expression impacts expression of enzymes, molecules responsible for drug absorption, distribution, metabolism and excretion, as well as, in cancer, metabolic syndrome, neurodegenerative disorders, and hormonal dysfunctions. In addition, Gerhauser et al.16 proposed certain chemo-preventive agents (examples listed in Table 3) that target the epigenome will provide a future framework to develop new therapeutics based on Nutriepigenomics.


EPIGENETICS OF METABOLIC SYNDROME

Numerous epigenetic studies of metabolic syndrome could have real clinical utility. For example, Janesick et al.17 proposed an environmental construct called obesogen that considers that chemical exposure during critical stages during development can affect subsequent adipogenesis, lipid balance, and obesity. They found that fetal exposure to xenobiotic compounds acting through the peroxisome-proliferator-activated receptor may have prolonged transgenerational effects. Other work by Nakagami et al.18 showed that the dipeptidyl peptidase-4 inhibitor teneligliptin improved endothelial function and decreased insulin resistance in the SHR/NDmcr-cp rat model of metabolic syndrome. Their work demonstrated that the long-term treatment with teneligliptin significantly reduced endothelial dysfunction through the up-regulation of endothelium-derived nitric oxide synthase mRNA. Guénard et al.19 investigated the role of methylated genes in men with metabolic syndrome compared to men without metabolic syndrome and found an overrepresentation of differentially methylated genes. They identified 41 overrepresented (P ≤ 0.05) pathways in men with metabolic syndrome compared to controls. These included pathways related to structural components of the cell membrane, cell cycle regulation, inflammation, and immunity.

Patients with metabolic syndrome exhibit hyperaldosteronism and are susceptible to salt-sensitive hypertension. Along these lines, Kawarazki and Fujita20 showed that a high-salt diet through epigenetics induces aberrant Rac1-mineralocorticoid receptor pathways in salt-sensitive hypertension. Recent work from Drummond and Gibney21  shows that the hypomethylation of the MC4 gene induces its overexpression. Risk of obesity is effected by this epigenetic effect which has a direct impact on appetite and intake. DelCurto et al.22 revealed that maternal nutritional imbalance predisposes the offspring to metabolic disease. Specifically, maternal nutritional imbalance increases the likelihood of metabolic disease in offspring through epigenetic mechanisms. Moreover, they pointed out that dietary intervention with select nutrients has been shown to attenuate postnatal disease phenotypes in offspring.

It is well-known that Obesity is a precursor to many chronic diseases such as hyperlipidemia, type 2 diabetes, and hypertension, which are the main causes of mortality and morbidity worldwide. In the human there are two types of adipose tissue; white and brown. Interestingly, efficient storage of energy occurs in white adipose tissue in the form of triglycerides, while brown adipose tissue involves energy consumption in the form of thermogenesis. The peroxisome proliferators-activated receptor-γ participates in regulating carbohydrate and lipid metabolism, it differentially regulates both white and brown adipogenesis, and can be effected by dietary induced epigenetic mechanisms.23 Moreover, research has shown that early postnatal over-nutrition contributes to excess adiposity and related symptoms of metabolic syndrome that persist into adulthood. Epigenetic mechanisms are responsible for genetic regulation of genes that are differentially expressed in visceral adipose tissue (VAT) in obese patients without metabolic syndrome compared to with metabolic syndrome. Moreover, Portella et al. discovered that postnatal overfeeding was associated with altered functions of the mesolimbic dopamine pathway, suggesting increased sensitivity, and expression of important proteins of the dopaminergic system.24 The difference could have important clinical applications that lead to more rational treatment options. Turcot et al25 evaluated long interspersed nuclear element 1 (LINE-1) elements DNA methylation levels (%meth) in blood, known to be associated with blood lipid levels, fasting glucose and even cardiovascular disease. They found lower global DNA methylation levels, as measured by LINE-1 repetitive elements methylation analysis, were associated with a greater risk for metabolic syndrome in the presence of obesity.

In 2012, Ruemmele and Garnier–Lengline26 outlined the importance of the role of non-coding microRNAs (miRNA) in metabolic syndrome and obesity. This proposal was supported by Hulsmans and Holvoet27 who identified miRNA as early biomarkers for obesity and related metabolic and cardiovascular diseases. Through the use of literature, they identified that obesity-related risk factors are clustered in the metabolic syndrome. Several miRNAs known to be biomarkers of cardiovascular diseases can be associated with metabolic disorders prior to any manifestation of cardiovascular symptoms. These biomarkers can be used to identify those with metabolic syndrome who are also at high risk for associated cardiovascular disease. Recently, Ramírez et al.28 found miRNA-33, intronic-miRNA within the sterol regulatory element-binding protein (SREBP) genes, to be associated with high-density lipoprotein (HDL) formation, cholesterol efflux, fatty acid oxidation and insulin signaling.

Understanding epigenetics as it relates to metabolic syndrome may be linked to personalized medicine. As observed by Jufvas et al.29 histone variants in female fat cells resulted in surprisingly specific subject post-translational modifications. In six subjects, novel histone modification by acetylation/trimethylation, methylation, demethylation, phosphorylation, and ubiquitination, were found in 68 out of 78 histone modifications. More importantly, only 23 of these modifications were observed in two or more subjects while all the others were specific for the individual, suggesting personalized epigenetic analysis.29

From childhood, nutriepigenomics and neurogenetics have a role in both the treatment and prevention of metabolic syndrome. Strategies that involve inhibition of DNA methylation and histone deacetylation include:

  • moderation of miRNA expression
  • target disturbed metabolic pathways epigenetically
  • DNA methyltransferase inhibitors and histone deacetylase inhibitors
  • genetically based individualized dietary supplementation with functional amino acids, vitamins, and phytochemicals
  • targeted epigenetic induced chromatin structural modification
  • augmented expression of parental imprinted genes with key roles in controlling fetoplacental nutrient supply and demand

These goals have been espoused by many in the field.30-35


NEUROGENETIC LINKS: CONNECTING THE DOTS

The importance of the relationship of brain function and metabolic syndrome has sparked a plethora of global research that targets the role of obesity and diet especially as it relates to fetal nutrition and neurological regulation. Animal studies have shown that maternal over-nutrition may negatively impact hypothalamic development, which may cause metabolic syndrome. Tamashiro and Moran36 observed that offspring exposed to a high-fat, high-caloric maternal diet had higher levels of leptin, insulin, and glucose. They further hypothesized that disturbances in the neuronal network that involving the neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) pathways cause these increases. Altered neuronal signaling can impact food intake (salt) and drug seeking37 behavior and consequently lead to diet-induced obesity in adulthood. According to Campion et al.,38 genes involved in adipogenesis possess multiple CpG islands in their promoter sites and may act as epigenetic targets. The genes involved in adipogenesis include fibroblast growth-factor-2, phosphatase, tensin homologue, cyclin-dependent kinase inhibitor 1A, and estrogen receptor-alpha. In fact, prenatal exposure to hypomethylating agents, such as bisphenol A (BPA), is associated with increased body weight. Champion et al. correctly inferred that BPA modified DNA methylation could be a mechanism for increasing susceptibility to obesity.38

Obesity during pregnancy and high-fat maternal diets both show strong associations with offspring obesity. The accumulation of fat in fetal adipose tissue (adiposity) that predisposes infants to obesity in childhood and adulthood is caused by maternal obesity.39 Simmons has estimated that the number of overweight children and infants will increase as the number of overweight reproductive-age women increases.40

Importantly, large data sets suggest that the prevalence of metabolic syndrome is significantly higher (doubled) in patients with schizophrenia in comparison with the general population, which may be due to methylation patterns or variations in one carbon carbohydrate metabolism.41 Melka et al.42 suggest that the drug olanzapine used to treat schizophrenia induces change in methylation. Specifically, increases in methylation in the 1,140, 1,294 and 1,313 genes and a decrease in methylation in 633, 565 and 532 genes in the hippocampus, cerebellum, and liver, respectively.42 It is noteworthy that the affected genes involve pathways affecting molecular transport, dopamine signaling, nervous system development, and functions in the hippocampus. Functional changes occur in synaptic long-term potentiation in the cerebellum, tissue morphology, and cellular assembly and organization in the liver. They propose that because of these epigenetic effects the drug may also have relevance for amelioration of metabolic syndrome especially in patients with comorbid psychosis. Along these lines, Burghardt et al.43 by controlling for serum folate observed a significant relationship among LINE-1 methylation, methylenetetrahydrofolate reductase (MTHFR), and gender (p = 0.008). Females with the MTHFR 677TT genotype had the lowest methylation (56%) compared with the other groups (75%). Moreover, we are cognizant that high folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Specifically, hypomethylation of the pro-opiomelanocortin (POMC) promoter was observed with high folate pup diet. Furthermore, POMC-specific methylation was positively associated with glucose response to a glucose load.44

Other neuro epigenetics links include Alzheimer’s disease (AD), where a specific SNPs in the gene inositol polyphosphate phosphatase-like1 (INPPL1), encodes for a SH2 domain-containing inositol 5-phosphatase (SHIP2). Inositol 5-phosphatasis involved in insulin signaling is associated with metabolic syndrome.45 In addition, Lahiri and Maloney46 suggested that research targets such as the insulin-degrading enzyme (IDE) and sortilin-related VPS10 domain containing receptor 1 (SORCS1) genes are implicated in both AD and diabetes. The connection is referred to as a metabolic-cognitive syndrome and may involve specific mechanisms for pre-disease remediation and may be a target for nutritional modification of aberrant DNA methylation and oxidation. Similarly, Li et al.47 has shown that early postnatal over-nutrition results in excess adiposity and other components of metabolic syndrome that persist into adulthood including reduction both physical exercise and energy expenditure. This finding may have relevance to dopaminergic tone and as such polymorphisms of the dopamine D2 receptor gene as well as BNDF.48 Similarly, under-nutrition in utero through neuro epigenetics effects causes severe alterations in energy metabolism and birth-weight, which may have similar ramifications throughout adulthood leading to adult metabolic syndrome.49

Of interest, is the role of circadian locomoter output cycles kaput (CLOCK) genes that regulate circadian rhythm. Links have been observed between circadian rhythms and major components of energy homeostasis, thermogenesis, hunger-satiety, rest-activity rhythms, darkness –induced drinking behavior, and the sleep-wake cycle.50,51 Sahar and Sassone-Corsi52 point out that even though the circadian clock regulates multiple metabolic pathways and metabolite availability, conversely, feeding behavior can regulate the circadian clock. These facts may lead to novel therapeutic targets to treat metabolic syndrome. The notion is underscored by the observation that, the network of clock genes, can modify chromatin remodeling.49 One of these is a histone acetyl transferase gene that affects the activity of nuclear receptors and transcription factors.

The largest study to date by Kraja et al.53 found an array of pleiotropic genes for metabolic syndrome and inflammation. The study looked at 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Essentially, they proposed that twenty-five variants (seven loci newly reported) are metabolic syndrome candidates. The candidates include: MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Moreover, others have found roles for many reward genes including: leptin, HTR2C, DRD2, TNF, SNAP-25 MC4R, CNR1, MDR1, ADRA1A and INSIG2 in assessing genetic liability to metabolic syndrome.54,55

A few broad tenets regarding nutritional genomics include the following:

  • Carbohydrate metabolism- The gene called carbohydrate responsive element –binding protein (ChREBP) is a key regulator of glucose metabolism and fat storage. Cyclic AMP and a high fat diet inhibit ChREBP and slow down glucose utilization.56
  • Obesity- overweight female who are carriers of the C polymorphisms of the leptin receptor gene lost more weight in response to a low-calorie diet than the non-carriers.57
  • Body Composition- chromium pic can help body composition Obese subjects were genotyped for the dopamine D2 receptor gene (DRD2). Subjects were separated into two independent groups: those with either A1/A1 or A1/A2 allele and those with only A2/A2 allelic pattern.The subjects were sequenced for scale weight and percent body fat, and then divided into matched placebo and chromium picolinate (CrP) groups. The measures of the change in fat weight, body weight, percent change in weight, and the body weight change in kilograms were all significant for the carriers of the A2/A2 genotype. There was no significance for any other parameter for the cohort possessing an A1 allele.58 One reason for this difference in response may be due to the fact that carriers of the A1 variant have increased risk for carbohydrate binging and may have engaged in overeating during the course of the experiment. This could have masked the benefit of CrP as observed in the carriers of the A2 variant.


DNA-BASED INDIVIDUALIZED MEDICINE

The example related to CrP links both gene variations to nutritional solutions. The results of the CrP double blind placebo controlled study suggest that the therapeutic effect of CrP in terms of weight loss and change in body fat is genotype dependent.58  In this scenario, carriers of the DRD2A1 allele have aberrant glucose cravings which could lead to abnormal adiposity. The craving for carbohydrates is indeed a very important antecedent for obesity. Thus, low DRD2 receptor density due to carrying the DRD2A1 allele is a major culprit and must be addressed.  Dopamine activation may be accomplished by the utilization of a complex nutritional known as KB220, which has demonstrated enhanced fMRI resting state functional connectivity in both humans and animal models59  and putatively increases the release of neuronal dopamine.Thus utilizing nutrigenomic principles to assist in the induction of “homeostasis” in carriers of the A1 allele of the DRD2 gene (low D2 receptor density) requires significantly higher doses of KB220 to reduce aberrant glucose craving behavior compared to carriers of the DRD2 A2 allele (normal D2 receptor density).60 In-vitro studies show that continued activation of Dopamine D2 receptors by D2 agonists induce significant proliferation of D2 receptor density61 and as such reduction of carbohydrate craving behavior  and the slow continued activation of dopamine may lead to the proliferation of DRD2 receptors.

LG839 a KB220 variant is the first DNA–personalized anti-obesity nutraceutical introduced in the global marketplace. There are 30,000 genes in the human genome and over 600 genes that have been identified to associate with obesity and related sequel and over 17,000 genes that could affect gene expression in obesity. We have conservatively selected 13 candidate genes that have a major impact on both the CNS and peripheral control of both craving behavior and fat production. Moreover, each of these candidate genes has been researched and includes numerous peer-reviewed published articles providing evidence-based associations with obesity (Table 4). Interestingly, it is known that signals from the brain regulate whole body metabolism and may trigger fat cells to burn fat. Perino et al discovered that mice expressing catalytically inactive forms of two-phosphoinositide 3-kinases (P13KBeta and P13KGamma) were leaner and therefore burned more fat.62 Inhibitors of the P13Kbeta and P13Kgamma delivered specifically into the brain significantly lost fat in adipose cells.


Reward Deficiency Syndrome

Understanding that low dopamine function leads to impulsive, compulsive and addictive behaviors, paves the way to defining addiction as a brain disorder involving impairments in so called “reward circuitry.”  This new definition of addiction has been now adopted by the American Society of Addiction Medicine (ASAM) founded by the San Franciscan visionary David E. Smith.64 This new definition which is based in part on the initial conceptualization of one of us (KB) who in 1995 coined “Reward Deficiency Syndrome” (RDS)65 a term to define common genetic antecedents for a predisposition for aberrant substance and behavioral seeking.  This list is remarkable and it may lead to: alcoholism, opiate dependence; psycho-stimulant abuse (e.g. cocaine), nicotine dependence, glucose bingeing and overeating, inability to focus (ADHD and other spectrum disorders), pathological gambling, excessive internet gaming, sex addiction, obsessive compulsive disorder, among other repetitive known behaviors.

Finding potential therapeutic targets is of extreme interest and some important factors include:

  • The consumption of alcohol in large quantities or carbohydrates bingeing stimulates the brain’s production of and utilization of dopamine
  • In the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors
  • When calcium channels are activated by highly concentrated glucose dopamine release from P12 cells is stimulated
  • There is a significant correlation between blood glucose and cerebrospinal fluid concentrations of the dopamine metabolite homovanillic acid
  • The glucose analog, 2-deoxyglucose (2DG), in pharmacological doses is associated with enhanced dopamine turnover and causes acute gluco-privation
  • Many studies show that early postnatal overfeeding is linked to an altered functioning of the mesolimbic dopamine pathway. Altered function is associated with changes in insulin signaling in the VTA, and suggests increased sensitivity, and expression of important proteins of the dopaminergic system.23


CONCLUSION

Obesity, the result of overeating as well as a number of well described eating disorders, has been accurately considered to be a world-wide epidemic. Recently, a number of theories backed by a plethora of scientifically sound genetic and neurochemical studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Our laboratory has published on the Reward Deficiency Syndrome (RDS) concept. Genetic and epigenetic phenomena lead to impairment of the brain reward circuitry resulting in a hypo-dopaminergic function. Abnormal craving behavior is the result of genetic polymorphisms or epigenetic changes due to habituation or stress that effect the interactions of powerful neurotransmitters. Important factors which could help indicate potential therapeutic targets include: (1) consumption of alcohol in large quantities or carbohydrates bingeing stimulates the brain’s production of and utilization of dopamine; (2) in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; (3) when calcium channels are activated by highly concentrated glucose dopamine release from P12 cells is stimulated; (4) there is a significant correlation between blood glucose and cerebrospinal fluid concentrations of the dopamine metabolite homovanillic acid; (5) the glucose analog, 2-deoxyglucose (2DG), in pharmacological doses is associated with enhanced dopamine turnover and causes acute gluco-privation. (6) many studies show that early postnatal overfeeding is linked to an altered functioning of the mesolimbic dopamine pathway. Altered function is associated with changes in insulin signaling in the VTA, and suggests increased sensitivity, and expression of important proteins of the dopaminergic system.24

Evidence from animal studies and fMRI in humans support the hypothesis that multiple similar brain circuits are disrupted in obesity,metabolic syndrome, and drug dependence. For the most part, DA-modulated reward circuits are implicated in pathologic eating behaviors. Treatment for both glucose and drug addiction, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy in contrast to current practices that use dopamine antagonistic therapy. Considering the failure of the clinical utilization of powerful dopamine D2 agonists due to chronic down regulation of D2 receptors, newer targets based on novel less powerful D2 agonists that up-regulate D2 receptors seem prudent.  New strategies targeted at improving DA function in the treatment and prevention of obesity, a subtype of reward deficiency, are called for and encouraged.


ACKNOWLEDGEMENTS

We appreciate the expert edits of Margaret A. Madigan, BScN


CONFLICT OF INTEREST

Kenneth Blum through his companies Synaptamine Inc. and KenBer LLC holds a number of US and foreign patents issued and pending on both genetic testing and solutions to RDS. Kenneth Blum is on the Dominion Diagnostic, LLC., Scientific Advisory Board and is a paid consultant. Gozde Agan and James Fratantonio are employed by Dominion Diagnostics. The preparation and review of the manuscript was supported in part by funds from the National Institutes of Health, NIAAA (R01-AA07112 and K05-AA00219) and the Medical Research Service of the US Department of Veterans Affairs (Marlene Oscar-Berman). There are no other conflicts.


AUTHOR CONTRIBUTION

All authors contributed equally.


REFERENCES

  1. World Health Organization Fact Sheet August 2014 http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed November 24 2014.
  2. Statistics by country for Metabolic Syndrome http://www.rightdiagnosis.com/m/metabolic_syndrome/stats-country. Accessd November 24 2014.
  3. Blum K, Thanos PK, Gold MS. Dopamine and glucose, obesity, and Reward Deficiency Syndrome. Front Psychol. 2014;5:919.
  4. Downs BW, Chen AL, Chen TJ, et al., Nutrigenomic targeting of carbohydrate craving behavior: can we manage obesity and aberrant craving behaviors with neurochemical pathway manipulation by Immunological Compatible Substances (nutrients) using a Genetic Positioning System (GPS) Map? Med Hypotheses. 2009;73:427-434..
  5. Zheng J, Xiao X, Zhang Q, et al., DNA methylation: the pivotal interaction between early-life nutrition and glucose metabolism in later life. Br J Nutr. 2014;20:1-8.
  6. Goni L, Milagro FL, Cuervo M, et al. Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity and regulation of body weight. Nutr Rev. 2014.
  7. Hidalgo B, Irvin MR, Sha J, et al. Epigenome-wide association study of fasting measures of glucose, insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network study. Diabetes. 2014;63:801-807.
  8. Oben JE, Ngondi. JL, Blum K. Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene. Lipids Health Dis. 13:7-44.
  9. Blum K, Chen AL, Chen TJ, et al., LG839: anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome. Adv Ther. 2008;25:894-913.
  10. Grether U, Bénardeau A, Benz J, et al., Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists. Chem Med Chem. 2009;4:951-956.
  11. Warrier M, Hinds TD, Ledfrod KJ, et al., Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice. Endocrinology. 2010;151:3225-3236.
  12. Heerwagen MJ, Miller MR, Barbour LA, et al., Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol Regul Integr Comp Physiol. 2010;299:R711-22.
  13. Gabory A, Attig L, Junien C, Epigenetic mechanisms involved in developmental nutritional programming. World J Diabetes. 2011;2:164-175.
  14. Paparoet L, di Costanzo M, di Scala C, et al., The Influence of Early Life Nutrition on Epigenetic Regulatory Mechanisms of the Immune System. Nutrients. 2014;6:4706-4719.
  15. Remely M, Lovrecic L, de la Garza AL, et al., Therapeutic perspectives of epigenetically active nutrients. Br J Pharmacol. 2014.
  16. Gerhauser C., Cancer chemoprevention and nutriepigenetics: state of the art and future challenges. Top Curr Chem. 2013;329:73-132.
  17. Janesick As, Shioda T, Blumberg B, Transgenerational inheritance of prenatal obesogen exposure. Mol Cell Endocrinol. 2014.
  18. Nakagami H, Pang Z, Shimosato T, et al., The dipeptidyl peptidase-4 inhibitor teneligliptin improved endothelial dysfunction and insulin resistance in the SHR/NDmcr-cp rat model of metabolic syndrome. Hypertens Res. 2014;37:629-635.
  19. Guénard F, Tchernof A, Deschaies Y, et al., Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances. Physiol Genomics. 2014;46:216-222.
  20. Kawarazaki W, Fujita T, Aberrant Rac1-mineralocorticoid receptor pathways in salt-sensitive hypertension. Clin Exp Pharmacol Physiol. 2013;40:929-936.
  21. Drummond EM, Gibney ER, Epigenetic regulation in obesity. Curr Opin Clin Nutr Metab Care. 2013;16:392-397.
  22. DelCurto H, Wu G, Satterfield MC, Nutrition and reproduction: links to epigenetics and metabolic syndrome in offspring. Curr Opin Clin Nutr Metab Care. 2013;16:385-391.
  23. Nakagami H, The mechanism of white and brown adipocyte differentiation. Diabetes Metab J. 2013;37:85-90.
  24. Portella AK, Silveira PP, Laureano DP, et al., Litter size reduction alters insulin signaling in the ventral tegmental area and influences dopamine-related behaviors in adult rats. Behav Brain Res. 2014;278C:66-73.
  25. Turcot V, Tchernof A, Deshaies Y, et al., LINE-1 methylation in visceral adipose tissue of severely obese individuals is associated with metabolic syndrome status and related phenotypes. Clin Epigenetics 2012;4:10.
  26. Ruemmele FM, Garnier-Lengliné H, Why are genetics important for nutrition? Lessons from epigenetic research. Ann Nutr Metab. 2012;3:38-43.
  27. Hulsmans M, Holvoet P, MicroRNAs as early biomarkers in obesity and related metabolic and cardiovascular diseases. Curr Pharm Des. 2013;19:5704-5717.
  28. Ramírez CM, Goedeke L, Fernández-Hernando C, “Micromanaging” metabolic syndrome. Cell Cycle. 2011;10:3249-3252.
  29. Jufvas A, Stralfors P, Vener AV, Histone variants and their post-translational modifications in primary human fat cells. PLoS One. 6. (2011).
  30. Wang J, Wu Z, Li D, et al., Nutrition, epigenetics, and metabolic syndrome. Antioxid Redox Signal. 2012;17:282-301.
  31. Sugii S, Evans RM, Epigenetic codes of PPARγ in metabolic disease. 2011;585:2121-2128.
  32. Lillycrop KA, Effect of maternal diet on the epigenome: implications for human metabolic disease. Proc Nutr 2011;70:64-72.
  33. Okamura M, Inagaki T, Tanaka T, et al., Role of histone methylation and demethylation in adipogenesis and obesity. Organogenesis. 2010;6:24-32.
  34. Kirk H, Cefalu WT, Ribnicky D, et al., Botanicals as epigenetic modulators for mechanisms contributing to development of metabolic syndrome. Metabolism. 2008;57:S16-23.
  35. Mariman EC, Epigentic manifestations in diet-related disorders. J Nutrigenet Nutrigenomics. 1:232-239.
  36. Tamashiro KL, Moran TH. Perinatal environmental and its influences on metabolic programming of offspring. Physiol Behav. 2010;100:560-566.
  37. Cocores JA, Gold MS, The Salted Food Addiction Hypothesis may explain overeating and the obesity epidemic. Med Hypotheses. 2009;73:892-899.
  38. Campion J, Milagro FL, Martinez JA, Individuality and epigenetics in obesity. Obes Rev. 2009;10:382-392.
  39. Gallou-Kabani C, Junien C, Nutritional epigenomics of metablic syndrome: new perspective against the epidemic. Diabetes. 2005;54:1899-1906.
  40. Simmons R. Epigenetics and maternal nutrition: Nature v. Nurture. Proc Nutr Soc. 2010;29:1-9.
  41. Misiak B, Frydecka D, Piotrowski P, et al., The multidimensional nature of metabolic syndrome in schizophrenia: lessons from studies of one-carbon metabolism and DNA methylation. Epigenomics. 2013;5:317-329.
  42. Melka MG, laufer BI, McDonal P, et al., The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum. Clin Epigenetics. 2014;6:1.
  43. Burghardt KJ, Pilsner JR, Bly MJ, et al., DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences. Epigenomics. 2012;4:261-268.
  44. Cho CE, Sánchez-Hernández D, Reza-López SA, et al., High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics. 2013;8:710-719.
  45. Accardi G, Caruso C, Colonna-Romano G, et al., Can Alzheimer disease be a form of type 3 diabetes? Rejuvenation Res. 2012;15:217-221.
  46. Lahiri DK, Maloney B, The “LEARn” (latent early-life associated regulation) model: an epigenetic pathway linking metabolic and cognitive disorders. J Alzheimers Dis. 2012;30:S15-30.
  47. Li G, Kohorst JJ, Zhang W, et al., Early postnatal nutrition determines adult physical activity and energy expenditure in female mice. Diabetes. 2013;62:2773-83.
  48. Leckie RL, Weinstein AM, Hodzic JC, et al., Potential Moderators of Physical Activity on Brain Health. J Aging Res. 2012.
  49. Roth CL, Sathyanarayana S, Mechanisms affecting neuroendocrine and epigenetic regulation of body weight and onset of puberty: potential implications in the child born small for gestational age (SGA). Rev Endocr Metab Disorder. 2012;13:129-140.
  50. Blum K, Oscar-Berman M, Badgaiyan R, et al., Hypothesizing Darkness Induced Alcohol Intake Linked to Dopaminergic Regulation of Brain Function. Psychology. 2014;5:282-288.
  51. Gallou-Kabani C, Vigé A, Junien C, Lifelong circadian and epigenetic drifts in metabolic syndrome. Epigenetics. 2007;2:137-146.
  52. Sahar S, Sassone-Corsi P, Regulation of metabolism: the circadian clock dictates the time. Trends Endocrinol Metab. 2012;23:1-8.
  53. Kraja AT, Chasman DI, North KE, et al., Pleiotropic genes for metabolic syndrome and inflammation. Mol Genet Metab. 2014;112:317-338.
  54. Brandl EJ, Frydrychowicz C, Tiwari AK, et al., Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:134-141.
  55. Lett TA, Wallace TJ, Chowdhury NI, et al., Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry. 2012;17:242-266.
  56. Uyeda K, Yamashita H, KawaquchiTi., Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. BiochemPharmacol. 2002;63(12):2075-80.
  57. Mammes O, Aubert R, Betoulle D, et al., LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women. Eur J Clin Invest. 2001;31(5):398-404.
  58. Chen TJH, Blum K, Kaats G, et al., Chromium Picolinate (CrP) a putative anti-obesity nutrient induces changes in body composition as a function of the Taq1 dopamine D2 receptor polymorphisms in a randomized double-blind placebo controlled study.Gene Therapy and Molecular Biology. 2007;11B:161-170. (2007).
  59. Blum K, Febo M, McLaughlin T, et al., Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)™ as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric. J Behav Addiction. 2014;3(3):149-156.
  60. Cameron JD, Riou ME, Tesson F, et al., The Taq1A is associated with attenuated intervention-induced body weight loss and increased carbohydrate intake in post-menopausal obese women. Appetite. 2012;60(1):111-116.
  61. Hiramoto T, Kanda Y, Satoh Y, et al., Dopamine D2 receptor stimulation promotes the proliferation of neural progenitor cells in adult mouse hippocampus. Neuroreport. 2007;7(352).
  62. Perino A, Beretta M, Kilic A, et al., Combined inhibition of PI3Kβ and PI3Kγ reduces fat mass by enhancing α-MSH-dependent sympathetic drive. Sci Signal. 2014; 18(7).
  63. Smith DE. The process addictions and the new ASAM definition of addiction J Psychoactive Drugs. 2012;44(1):1-4.
  64. Blum K, Gardner E, Oscar-Berman M, Gold M. “Liking” and “wanting” linked to Reward Deficiency Syndrome(RDS): hypothesizing differential responsivity in brain reward circuitry. Curr Pharm Des. 2012;18(1):113-8.


TABLES

blum table 1

 

 

 

 

 

 

 

 

blum table 2

 

 

 

 

 

 

 

blum table 3

Posted in Vol 1 Issue 1 Tagged with: , , , , ,