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Curr Oncol Rep (2016) 18:43

DOI 10.1007/s11912-016-0529-6

INTEGRATIVE CARE (C LAMMERSFELD, SECTION EDITOR)

A Novel Approach to the Nutrigenetics and Nutrigenomics


of Obesity and Weight Management
Yael T. Joffe 1,2 & Christine A. Houghton 3

# Springer Science+Business Media New York 2016

Abstract Nutrigenetics and nutrigenomics, as well as diet and cardiovascular disease (CVD), type 2 diabetes, and a number
exercise, play an important role in the development and treatment of cancers [1]. The complexity of this chronic disorder be-
of obesity and its comorbidities. If an individual’s susceptibility comes more apparent, exhibiting a multifactorial etiology
to becoming obese and their responsiveness to weight loss inter- [2]. Lifestyle factors such as diet and exercise continue to be
ventions are to be understood, then it needs to be addressed at a recognized to play an important role in the development and
molecular and metabolic level, including genetic interaction. progression of obesity and its comorbidities. However,
This review proposes a three-pillar approach to more fully com- nutrigenetics and nutrigenomics also contribute to the obese
prehend the complexity of diet-gene interactions in obesity. phenotype, interacting with the genome to regulate the devel-
Peroxisomal proliferating-activated receptor gamma (PPARG) opment and progression of obesity and its comorbidities.
and mitochondrial uncoupling protein-1 (UCP-1) are explored These complex interactions may explain differences observed
in detail. Illustrating how an understanding of nutritional bio- in the obese phenotype that vary both within and across
chemistry, nutrigenomics, and nutrigenetics may be the key to populations [3–6].
understanding differences observed in the obese phenotype that While the interest in obesity by both researchers and
vary both within and across populations. practitioners continues to grow, the approach is at best
disjointed, employing either expansive genome-wide as-
Keywords Nutrigenomics . Nutrigenetics . Nutritional sociation studies (GWAS) or focusing on a few genes, a
biochemistry . Obesity . Weight loss . PPARG . UCP-1 few nutrients, or a single behavioral intervention. This
article does not address whether or not the field of
nutritional genomics is ready for clinical weight man-
Introduction agement. Rather, this article proposes a Bbig picture^
in how researchers and clinicians may better approach
Obesity, a chronic low-grade inflammatory condition, is asso- the complexity of obesity.
ciated with the development of many comorbidities including

This article is part of the Topical Collection on Integrative Care


Nutrigenetics and Nutrigenomics—Know
* Yael T. Joffe the Difference
yael@manukascience.co.za
Many clinicians, and surprisingly, academics as well, are
1
Manuka Science, 17 Roeland Square, Drury Lane, Cape Town, South unable to differentiate between nutrigenetics and
Africa nutrigenomics. What is often referred to as nutrigenomics
2
Department of Nutritional Sciences, School of Health Related is in fact nutrigenetics. In this article, we use the term
Professions, Rutgers School of Dental Medicine, Newark, NJ, USA nutritional genomics to mean both nutrigenetics and
3
School of Human Movement Studies, University of Queensland, nutrigenomics (see the box: Defining the Difference
Brisbane, Queensland, Australia Between Nutrigenetics and Nutrigenomics).
43 Page 2 of 7 Curr Oncol Rep (2016) 18:43

The Heritability of Obesity


Defining the Difference Between
Nutrigenetics and Nutrigenomics Large family-based studies in different populations have con-
sistently demonstrated a familial correlation in adult body
Genetic variability (nucleotide sequence change) mass index (BMI), at about 0.2 between parents and offspring,
influences how we interact with our environment. and at about 0.3 between siblings [7, 8]. Moustafa and Froguel
Nutrigenetics describes the influence of gene variants (2013) [9••] reported the heritability of human corpulence and
on our ability to interact with bioactive molecules in the adiposity to be between 40 and 70 %. Based on twin studies,
molecular environment surrounding our cells and the the amount of genetic influence on body fatness and body fat
consequences of that interaction. distribution has previously been established to be ~70 % for
In contrast to nutrigenetic interactions where the BMI [7, 10]. However, the contribution varies according to
gene variants act on the environment, with the age of the individual. In childhood, a certain proportion of
Nutrigenomic interactions, the environment influences the BMI variance in twins is explained by shared environmen-
gene expression. Nutrigenomics is concerned with the tal factors, while in adulthood, it is exclusively the non-shared
influence of bioactive molecules interacting with a environmental experiences. Wardle et al. (2008) confirmed a
gene, potentially influencing gene expression, either heritability of 77 % for BMI and waist circumference (WC) in
upregulating or downregulating (turning it up or a UK sample of 5092 twin pairs aged 8–11 years [11]. The
down), or activating or silencing (on or off). most interesting finding from this twin study is the relatively
Nutrigenomic interactions may be direct or indirect. low contribution of the shared-environment. The shared-
In a direct interaction, the molecules are of small environment effect was estimated at just over 10 %. Siblings
molecular weight, carrier-mediated, and lipid-soluble. would have been exposed to similar food offers, similar op-
In an indirect interaction, the molecules are larger and tions for television viewing, and physical activity. They would
hydrophilic. These molecules interact at the cell also have been exposed to the same parent behavior and go to
surface. the same school. All of this should contribute to a more similar
Clinicians are most familiar with the nutrigenetic BMI and WC between siblings. Parents may be the least sur-
interactions available in commercial tests. This has prised by this result, being aware that children differ despite
resulted in a distorted emphasis on single nucleotide having a similar upbringing. Blaming parents may be mis-
polymorphisms (SNPs) and a Bsuperficial^ involve- guided. Excessive weight gain in a child may be due to a
ment with what the science of nutritional genomics child’s genetic susceptibility to an obesogenic environment,
has to offer. To comprehend the complex nature and less likely to be the fault of the parents.
between diet and genetics on obesity requires an under-
standing of the three pillars of nutritional genomics. Missing Heritability
These include the following: nutritional biochemistry,
nutrigenetics, and nutrigenomics. Biochemical Despite the findings that the inter-individual variance in BMI
processes are driven and understood through nutrition- explained by genetic factors is between 40 and 70 %, the
al biochemistry. It is imperative to understand these genetic variability detected by molecular genetic research
pathways and the disruption thereof, which contribute (SNP research) to date explains only around 5 % of inter-
to perturbations in health and potentially the develop- individual BMI variance [12••]. At best, Speliotes et al.
ment of disease. Nutrigenetics provides information on (2010) extrapolate that the analysis of 730,000 GWAS data
genetic sequence variants, SNPs, as well as other sets might reveal that up to 10 to 15 % of the genetically
variations such as copy number variants. These may related BMI variance could be explained [8]. Hebebrand et
(but not always) alter gene expression or enzyme al. (2013) offer possible explanations for the missing herita-
function. By understanding nutrigenomics (nutrient bility, including that heritability is systematically
impact on gene expression), it is possible to identify overestimated. This review cannot address all the reasons,
nutrient and lifestyle changes that may alter gene but these are dealt with in greater detail in the article by
expression. Put together, these three pillars of Hebebrand et al. [12••].
nutritional genomics will empower the practitioner to
construct targeted and clinically useful dietary and
lifestyle recommendations for weight management. Monogenic vs Polygenic Obesity

Monogenic obesity refers to rare forms of severe obesity that


result from polymorphisms that carry a large effect size on an
individual gene or chromosomal region. Despite the rarity of
Curr Oncol Rep (2016) 18:43 Page 3 of 7 43

these monogenic forms of obesity, they have provided great 1. Weight loss maintenance: Successful weight loss and
insight into our understanding of several pathways and mech- maintenance over 24 months.
anisms involved in the development of a more polygenic obe- 2. Rebound: Lost weight in the first 6 months, but regained
sity. Moustafa and Froguel (2013) in their article BFrom obe- most of it over the 24 months.
sity genetics to the future of personalized obesity therapy^ 3. Slow weight loss: Weight loss was slower than the first
describe the most common monogenic obesity conditions two groups but the group achieved a successful weight
and observed phenotypes [9••]. loss at 24 months.
4. Weight loss resistance: Almost no weight was lost, despite
Understanding Polygenic Obesity compliance to the diet and exercise program over
24 months.
In this review, we are concerned only with polygenic Almost a decade ago, Adamo and Tesson (2007)
obesity which can best be explained by the common suggested that identifying individuals responsive to
disease—common variant hypothesis. This proposes that lifestyle modification to control body mass would be
frequent alleles of several genes, each with a small ef- extremely advantageous [15]. Despite this, most
fect on the BMI (or other phenotype), determine an health practitioners have not yet been able to com-
individual person’s weight by the sum of the variants prehend and clinically manage the variable nature of
present [12••]. weight gain and weight loss.
For clinicians, one of the most useful classifications
of genetic obesity is by Loos and Bouchard [13]. This
proposes four levels of genetic determination of obesity:
genetic obesity, strong genetic predisposition, slight ge-
netic predisposition, and genetically resistant. Genetic Factors Involved in Obesity Susceptibility
and Weight Regulation
& Genetic obesity represents at least 5 % of obesity cases and
a large percentage of the severely obese. Variation in a Traditionally, clinical management of obesity has fo-
single gene causes obesity in spite of the environment. cused on energy balance, most times ascribing any re-
& Strong genetic predisposition results from a number of sistance to losing weight as due to excess calories, in-
susceptibility alleles at a number of loci. In a non- adequate energy expenditure, or a low metabolic rate.
obesogenic environment, individuals would likely be This is clearly a simplistic and outdated interpretation.
overweight, but would become obese and potentially se- If an individual’s susceptibility to obesity and respon-
verely obese in an obesogenic environment. siveness to weight loss interventions is to be under-
& Slight genetic predisposition suggests that in a restrictive stood, then it needs to be addressed at a molecular
(non-obesogenic) environment, individuals will likely be and metabolic level, including genetic interactions.
normal weight or slightly overweight. However, in an Researchers have grouped genes in a number of
obesogenic environment, there is a strong likelihood that ways. In a recent review article by Martinez and
individuals will become overweight or obese. Milagro [16••], the first grouping considered genetically
& Genetically resistant individuals remain at normal weight regulated processes and mechanisms that contribute to
or almost normal weight in a wide range of obesogenic body weight homeostasis. They included physical activ-
conditions. ity, appetite, adipocyte differentiation, insulin signaling,
mitochondrial functions, lipid turnover, thermogenesis,
This classification is well illustrated by this study by and energy efficiency. They then grouped genes accord-
Masuo et al. (2005) [14]. A 24-month weight loss pro- ing to how they regulate metabolic functions, in which
gram enrolled 154 overweight Japanese men. The diet there are polymorphisms that have been related to ge-
consisted of a low calorie, low fat, and low sodium diet netically mediated differences to dietary weight loss in-
(1600 kcal/day, 55 % CHO, 30 % protein, 15 % fat, 7 g terventions, these include the following:
NaCl per day). Participants performed at least 1 h of
aerobic exercise daily calculated as steps. Compliance & Regulating energy intake (e.g., MC3R, MC4R, POMC,
to diet and exercise was considered excellent and con- LEP, LEPR, FTO)
sistent based on diet and activity records. At the end of & Lipid metabolism and adipogenesis (e.g., PLIN1,
the 24 months, the men were grouped into four groups APOA5, LIPC, FABP2)
according to their weight loss. All groups maintained & Thermogenesis (e.g., ADBRs, UCPs)
the reduced calorie intake and high physical activity & Adipocytokine synthesis (e.g., ADIPOQ, IL6), as well as,
over 24 months. The groups included the following: & Transcription factors (e.g., PPARG, TCF7L2, CLOCK)
43 Page 4 of 7 Curr Oncol Rep (2016) 18:43

The length and scope of this review limit the number Classified as an endocrine organ, white adipose tissue
of genes and SNPs that can be discussed. Rather, the (WAT) has long been considered an energy storage organ,
intention is to illustrate how applying a three-pillar ap- forming large lipid droplets in white adipocytes in response
proach can provide a useful model to more fully com- to excessive food-derived energy input. However, the distinc-
prehend the complexity of diet-gene interactions in tion between these two types of adipose tissue is not quite as
obesity. clear as first thought. In response to cold exposure or beta-
adrenergic stimulation, brown adipocytes have been detected
in WAT, showing that formation of brown adipocytes may be
inducible by the local environment.
Example 1. Cell Regulation and PPARG
PPAR gamma is a key regulator in both WAT and BAT,
with many key genes under PPAR gamma control. These
The lipid-sensing PPAR family is both complex and fascinat-
include genes associated with lipid transport and metabolism,
ing in the way it regulates a number of key cellular functions.
adipokine production, and insulin signaling. As part of PPAR
The name peroxisomal proliferating-activated receptors pro-
gamma’s insulin-sensitizing role, it increases synthesis of the
vides little clue to the diverse actions of this family of ligand-
adipokine adiponectin in adipocytes and at the same time
activated nuclear transcription factors. Activated by fatty acids
decreases resistin and TNF-alpha; and these effects coordi-
and their derivatives, PPARs closely link lipid chemistry to
nately regulate insulin sensitivity [19].
metabolic disease and innate immunity [17]. In so doing, they
integrate various intra-cellular signaling pathways such that
PPPARs—an Evolutionary Solution to a Cellular
PPARs effectively contribute to whole-body homeostasis by
Conundrum?
mediating regulatory crosstalk between organs and systems.
The diversity of PPAR biochemical functions is appar-
Lipids are an important fuel in human cells, being a concen-
ent when considering that, among other actions, it partic-
trated source of energy when Bburnt^ in oxygen.
ipates not only in adipogenesis but also in regulation of
Mitochondrial involvement in the Bburning^ of fatty acids
cell survival, osteoblast, skin and gut cell differentiation
results in increased flux of oxygen in the mitochondria with
and more. It is the PPAR family’s wide-reaching actions
consequent generation of superoxide radicals. Essentially,
at the biochemical level that enable it to integrate a num-
whenever fat is burned as fuel, the production of reactive
ber of signaling pathways to coordinate inter-organ
oxygen species (ROS) increases. This situation has been de-
crosstalk. These multiple levels of inter-organ crosstalk
scribed as the Bhypoxia-lipid conundrum^ in that whenever
implicate PPARs in carcinogenesis, inflammation, athero-
fat stores are oxidized as fuel, the cell’s redox balance swings
sclerosis, tissue repair, and immunomodulation [18].
to the oxidative side [20].
Discovered in 1990, early research into the PPAR family
PPARs may in effect provide a solution to this conundrum
accelerated when it was shown that PPAR gamma played a
via several mechanisms: (1) modulation of mitochondrial
key role in adipogenesis; it was subsequently described as a
uncoupling protein (UCP) expression to reduce the synthesis
Bmaster controller of the thrifty gene response,^ tying its func-
of ROS, (2) optimization of forkhead box class O factor
tion to energy storage, and ultimately to obesity. The develop-
(FOXO) activity by the induction of enzymes that breakdown
ment of synthetic PPAR gamma ligands displayed insulin-
ROS such as MnSOD and catalase [21], and (3) suppression
sensitizing effects, which saw thiazolidinediones released as
of the pro-inflammatory transcription factor NFkB. Figure 1
a new class of pharmaceutical for treatment of type 2 diabetes,
graphically illustrates this important cell survival relationship
a condition closely associated with excessive adiposity.
[20]. PPARs promote mitochondrial proton gradient
uncoupling, reduce ROS, and increase heat generation, while
PPAR Gamma—Relationship to White and Brown ensuring safe lipid storage and burning (reducing
Adipocytes lipotoxicity), safe carbohydrate storage, and reducing need
for insulin [22].
The synthesis of adipose tissue is dependent on the coordina-
tion of numerous transcription factors and their associated co- Clinical Relevance of PPAR Activity
activators and co-repressors. PPAR gamma is considered to be
one of the master regulators of adipocyte differentiation in the PPAR gamma activity may be compromised by the presence
process of adipogenesis. Mitochondria-dense brown adipo- of PPARG polymorphisms. In addition, its activity decreases
cyte tissue (BAT) is specialized to enable non-shivering ther- with age, a process that can be slowed by caloric restriction
mogenesis. Here, fatty acids are oxidized to generate heat, a [23]. Aging is also known to be associated with constitutive
process that can both enhance tolerance to low environmental activity of the pro-inflammatory transcription factor, NFkB.
temperature and prevent the storage of excess energy as fat. As a consequence, the protective effects of PPAR gamma are
Curr Oncol Rep (2016) 18:43 Page 5 of 7 43

Fig. 1 Transcriptional triad of


survival. Adapted from [20]
©2007 Nunn et al.

likely to diminish with age in all individuals but more so Example 2. Thermogenic Processes, ADRB2,
in those who carry particular PPARG polymorphisms and and UCP
those who are overweight or type 2 diabetic; these latter
conditions are pro-inflammatory states. Given the critical We referred earlier to the hypoxia-lipid conundrum in relation
role of PPAR gamma in protecting the cell against the to the modulation of mitochondrial UCP. UCPs are mitochon-
lipid catabolism vs redox balance conundrum, solutions drial transporters present in the inner mitochondrial mem-
which can reactivate PPARs may help restore metabolic brane, with UCP-1 uniquely present in brown adipocytes.
balance. UCP-1 is activated by free fatty acids and creates a shunt
between complexes of the respiratory chain and the adenosine
triphosphate (ATP)-synthesizing enzyme, ATP synthase.
Although physical activity is the primary mechanism used
Why Cells Need PPAR Gamma Modulation and Not by humans for dissipating excess energy, an evolutionary sys-
Activation tem of thermogenesis evolved to protect the body from hypo-
thermia; this system is reliant on diverting energy synthesis
The pharmaceutical PPAR gamma agonists were initially towards heat generation when required.
hailed as the answer to the developing type 2 diabetes epidem- When UCP-1 is activated (coupled), respiration is en-
ic, but the expected benefits were not without associated risks. hanced, but when it is uncoupled, oxidation energy is dissi-
The effects of PPAR gamma activation are not all beneficial, pated as heat. In this way, UCP-1 acts as a Bcontrol point^ in
so that even though metabolic and immune effects are gener- energy synthesis. UCP-1 polymorphisms can affect energy
ally desirable, prolonged activation in other systems can lead regulation and temperature sensitivity and as such have impli-
to disturbances in cardiac and renal status as well as degrada- cations for individuals who have difficulty in regulating adi-
tion of bone. posity and in adapting to a cold environment. Aberrant UCP-1
The pharmaceutical PPAR gamma agonist, rosiglitazone, genes (both hetero- and homozygous) express enzymes of
exemplifies the dual action of PPAR activators. A 2010 lower activity, resulting in decreased ability to burn body fat
study concluded: Bprescription of rosiglitazone was asso- for heat. Not surprisingly, the thyroid hormone, triiodothyro-
ciated with an increased risk of stroke, heart failure, and nine (T3), induces the expression of UCP-1 and enhances
all-cause mortality, and an increased risk of the composite mitochondrial biogenesis in human adipocytes [25].
of AMI, stroke, heart failure, or all-cause mortality in Furthermore, these authors suggest that Bbrown-like adipo-
patients 65 years or older^ [24]. It is for this reason that cytes in WAT and skeletal muscle play a crucial role in the
PPAR Bmodulation^ is considered to be a more appropri- regulation of body weight and that understanding of the mech-
ate action than Bactivation.^ Pharmaceuticals lack the anism underlying the increase in UCP-1 expression level in
specificity to target a single action, and in the case of these organs should, therefore, provide an approach to man-
PPAR gamma, activation will result in adverse as well aging obesity.^ In adipose tissue, thyroid hormone (TH) reg-
as beneficial effects as illustrated in the 2010 findings ulates multiple aspects of lipid metabolism, including lipogen-
described above. In contrast to pharmaceuticals, dietary esis, lipolysis, and thermogenesis. TH treatment induces
interventions are typically less potent in their effects, with UCP-1 expression in brown adipocytes, suggesting a link be-
human cells adapted to such food-derived compounds. tween lowered thyroid function and tendency to adiposity.
43 Page 6 of 7 Curr Oncol Rep (2016) 18:43

How UCP-1 and ADRB2 Are Inter-Related 2. Bray MS. Implications of gene-behavior interactions: prevention
and intervention for obesity. Obesity (Silver Spring). 2008;16
Suppl 3:S72–8.
Thermogenesis by UCP-1 in brown adipocytes is controlled 3. Joffe YT et al. Tumor necrosis factor-alpha gene -308 G/A poly-
directly by sympathetic nerves principally through the beta- morphism modulates the relationship between dietary fat intake,
adrenergic action of norepinephrine. Cold exposure activates serum lipids, and obesity risk in black South African women. J
the sympathetic nervous system, releasing noradrenaline Nutr. 2010;140(5):901–7.
4. Joffe YT et al. The -308 G/A polymorphism of the tumour necrosis
which binds to the surface of adipocytes. This action at the factor-alpha gene modifies the association between saturated fat
adipocyte surface promotes the conversion of thyroxine (T4) intake and serum total cholesterol levels in white South African
toT3 by binding to the promoter region of the deiodinase gene. women. Genes Nutr. 2011;6(4):353–9.
5. Joffe YT, et al. The tumor necrosis factor-alpha gene -238 G>A
polymorphism, dietary fat intake, obesity risk and serum lipid con-
centrations in black and white South African women. European
Conclusion journal of clinical nutrition. 2012.
6. Stryjecki C, Mutch DM. Fatty acid-gene interactions, adipokines
These examples illustrate that it is not enough to be told or and obesity. Eur J Clin Nutr. 2011;65:285–97.
7. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors
even to know what impact a SNP may or may not have on in relative body weight and human adiposity. Behav Genet.
enzyme function and what disease associations have been 1997;27(4):325–51.
reported in the scientific literature. Nutrigenetics must exist 8. Speliotes EK et al. Association analyses of 249,796 individuals
in the context of nutritional biochemistry to provide a deeper reveal 18 new loci associated with body mass index. Nat Genet.
2010;42(11):937–48.
understanding of the biochemical pathways that have been
9.•• Moustafa JSE-S, Froguel P. From obesity genetics to the future of
impacted. An understanding of nutritional biochemistry and personalized obesity therapy. Nat Rev Endocrinol. 2013;9(7):402–
nutrigenomics is the key to developing effective weight man- 13. An excellent review article that documents the differences
agement interventions. between monogenic and polygenic obesity. As well as clearly
The three-pillar approach demands that researchers en- describing the different kinds of genetic studies used, and their
contribution to the increasing understanding of the relationship
deavor to understand the biochemical environment within between genetics and obesity.
which functional gene variants are situated. And practitioners 10. Schousboe K et al. Twin study of genetic and environmental influ-
will acquire the skills and knowledge to independently con- ences on adult body size, shape, and composition. Int J Obes
struct diet and lifestyle recommendations that surpass the rec- (Lond). 2004;28(1):39–48.
11. Wardle J et al. Evidence for a strong genetic influence on childhood
ommendations currently offered by commercial nutrigenetic
adiposity despite the force of the obesogenic environment. Am J
tests. Clin Nutr. 2008;87(2):398–404.
12.•• Hebebrand J et al. Molecular genetic aspects of weight regulation.
Deutsch Aerzteblatt Int. 2013;110(19):338. A review of the cur-
Compliance with Ethical Standards rent molecular genetic research. Defining monogenic and poly-
genic obesity and exploring the discrepancy between the genetic
Conflict of Interest Yael T. Joffe is the director of Manuka Science, an variability seen to date in genetic studies and the inter-
educational company that teaches nutrigenetics and nutrigenomics based individual variability of BMI.
on the ideas expressed in this article.
13. Loos RJ, Bouchard C. Obesity—is it a genetic disorder? J Intern
Christine A. Houghton is a co-author of a Manuka Science course that
Med. 2003;254(5):401–25.
teaches nutrigenetics and nutrigenomics based on ideas expressed in this
14. Masuo K et al. Rebound weight gain as associated with high plasma
article.
norepinephrine levels that are mediated through polymorphisms in
the β2-adrenoceptor. Am J Hypertens. 2005;18(11):1508–16.
Human and Animal Rights and Informed Consent This article does 15. Adamo KB, Tesson F. Genotype-specific weight loss treatment ad-
not contain any studies with human or animal subjects performed by any vice: how close are we? Appl Physiol Nutr Metab. 2007;32(3):351–
of the authors.
66.
16.•• Martínez JA, Milagro FI. Genetics of weight loss: a basis for per-
sonalized obesity management. Trends Food Sci Technol.
2015;42(2):97–115. A systematic review of nutrigenetic data.
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