Possibilities and limitations in the treatment of overweight and obesity

1. Nutrigenetics:
Possibilities and limitations in the
treatment of overweight and
obesity
Gessner Diana, 0747266
Bachelor-Thesis
supervisor: O.Univ.-Prof. Dr. Hans Goldenberg
Institute of Medical Chemistry, Center of
Pathobiochemistry and Genetics, Vienna, Austria 2012.
Seminar Human Nutrition (330060) SS 2014

2. Learning Objectives
• Be familiar with the evidence for
genetic influences on obesity
• Understand how genetic factors
can influence obesity, both
directly and indirectly
• Have knowledge about
Pharmacological treatment of
obesity
• Be aware of one current
application of genomic
information for public health
practice

3. Topic-Overview
1. Introduction
• Obesity (ob) facts
2. Nutritional genomics
• Definition, classification, the omics cascade
• Methods: Heritability of ob and the search for ob candiate genes
3. Obesity candidate genes
• The GIANT-Study
• Neuroendocrine regulation of food intake
• Leptin Theapy
4. Metabolic gene profiling
• Gene profile illustration
• The Paleolithic diet
• Personal recommendations
• Facts and discussion
5. Conclusion and take home message

4. Introduction
• Worldwide
– 1.7 billion people are
overweight
• Austrian nutritional report
2012
– Children
• Increase of overweight from 11 to
17 % compared to 2008
• stabilization in obesity
– Adults
• Overweight: 40 %
• Obese: 12 %
• Health costs of an obese
person
– 25% higher than for a human
with normal bodyweight
WHO, 2008; OECD, 2010; Elmadfa I et al, 2012.

5. Introduction
• Numerous dietary strategies does
already exist on the market
• Review 2009 - clinical trials of
weight loss maintenance
– between 35% and 80% of
subjects who lost at least 10% of
their body weight do not succeed
in maintaining this weight for over
1 year
• The aim of my work was to
illustrate the current limitations
and possibilities of nutrigenetics
to stop weight cycling and to
combat ,globesity’
Turk et al.,2009

6. • Definition
Study of how foods affect our genes and
how individual genetic differences can
affect the way we respond to nutrients
• Classification
• Nutrigenetics
Examination of the impact of genetic
differences on the response to a
specific dietary model, functional
food or supplementation on health
effects
• Nutrigenomics
Examination of diet or specific
nutrient effects on gene expression
 deals with the gene products
Fenech 2008 ; Costa et al., 2008
Nutritional genomics

7. Nutritional genomics
a multidisciplinary science
• Combines information from
• Genetic, nutrition, Physiology, pathology, molecular biology, bioinformatics, and other disciplines.
Fenech 2008 ; Costa et al., 2008

8. Heritability of Obesity
• obese people: 50% predisposing
gene variants
• Studies of families, adoptees, twins
and adopted twins provide evidence
that obesity is heritable
• incomplete concordance
• difficulty in defining inheritance
patterns
• Obesity: complex genetic diseases
with a multifactorial origin:  Not
single-gene disorder
• Rare monogenetic forms: (Leptin
mutation) do not account for
majority of cases
Speakman 2009; NGFN, 2012

9. The search for candiate genes
“I found
one! I found
one!”
Kenneth M. Weiss & Joseph D. Terwilliger - 2000

10. Nutritional genomics
Methods
• Human Genetic Variation
• 99.9% of our DNA sequences are
the same
• SNPs
Exchanges of single base pairs
• can be used as a marker
•  biallelic
• Genotyping
• Identification of SNPs and their
association with certain disease
scenarios as well as obesity
• Linkage analyze
• deals with a specific genetic
relationship between loci on a
chromosome
• Association study
• describes a statistical relationship
between genes or genetic
variants and the disease of
interest
• individuals and population groups
we’re screened on
polymorphisms related to nutrition
and nutrient metabolism
Klein, 2012; Manilo, 2010

11. Nutritional genomics
Genome wide studies
Klein, 2012; Manilo, 2010
• Genome-wide screens
• Comprehensive scan of the genome
in an unbiased fashion
• Previously unrecognized genes can
be identified
• Observable traits: Fat mass, WHR,
BMI
• SNP Maps
• Comprehensive map of hundreds of
thousands of selected SNPs
• Disadvantages
• Association does not imply
causation!
• Linkage disequilibrium
• Confounder: population stratification

12. McCarthy et al., 2010
Genomic Locations of Proven Signals of Body-Mass Index (BMI), Obesity,
and Related Phenotypes
Obesity gene map
• Located on all chromosomes except Y
• More than 600 genes, markers, and chromosomal regions related to
human obesity phenotypes

13. The GIANT study
Speliotes et al., 2010 , Heid et al., 2010
• Association analyses of
249,796 individuals reveal
18 new loci associated
with BMI
• Meta-analysis identifies 13
new loci associated with
WHR and reveals sexual
dimorphism in the genetic
basis of fat distribution
• merely a share of up to 4.5% of the BMI variance
accounts to the genetic risk variance
• 90% of the overweight risk is still due to the lifestyle
• FTO fat mass and obesity related gene:
• the risk variation in the FTO gene is responsible
for less than 0.5% of the total variance of BMI
• difference of 2 - 3 kg

14. • Ob candidate genes
Schwartz et al., 2000; Schwartz and Morton, 2002; Morton et al., 2006
Neuroendocrine regulation of food intake
The Leptin/Melanocortin Pathway
• involvement in the
neuroendocrine cycle of energy
homeostasis
• dysfunction caused by mutations
in these pathways will disrupt
energy homeostasis and can
lead to obesity
• energy expenditure and food
intake: affected by the
individual’s genetic background

15. Neuroendocrine regulation of food intake
The Leptin/Melanocortin Pathway
GHR ghrelin receptor; ISR,insulin receptor; LepR leptin receptor; NPY,
neuropeptide Y; POMC, proopiomelanocortin, melanocortin (α-MSH)/cocaine
and amphetamine-regulated transcript (CART) Agouti-related Peptide (AgRP)
Schwartz et al., 2000; Schwartz
and Morton, 2002; Morton et
al., 2006
• Insulin and leptin,
• Antagonist of the
orexigenic NPY and
AgRP neurons
• Agonist of the
anorexigenic neurons
of the melanocortin
(α-MSH)/cocaine and
amphetamine-
regulated transcript
(CART) pathways
• food intake↓↓
• energy ↑↑
expenditure.

16. • R-metHuLeptin improves
– metabolic abnormalities of leptin-
deficient patients
– induces a dramatic weight loss in
obesity due to leptin mutations
• Weight loss is not significant in
obese hyperleptinemic subjects
on r-metHuLeptin
– r-metHuLeptin administration of
10 mg twice daily (20 mg/d) for
16 weeks did not alter body
weight in obese patients with
type 2 diabetes
Leptin therapy in common obesity
Ravussin et al. 2009 http://www.myalept.com/index.aspx

17. • A double-blinded randomized
study conducted by Amylin
Pharmaceuticals, Inc.
– participants lost significantly
more weight on the combination
of r-metHuLeptin and
pramlintide (analog of amylin)
– mean weight loss of 12.7% than
on treatment with either agent
alone (mean 8.2% for r-
metHuLeptin and 8.4% for
pramlintide)
– Problems
• irritation in injection area
• antibody formation
• Induction of autoimmune reactivity's
against liver and kidney
Amylin Pharmaceuticals, Inc.
Leptin therapy in common obesity
coadministration with leptin sensitizer - amylin

18. • potential role of r-metHuLeptin treatment in weight loss maintenance
• falling leptin levels due to weight loss activate neuroendocrine
mechanisms that may drive patients to regain weight
Rosenbaum et al., 2005
• increasing energy intake, by
increasing hunger
• decreasing energy expenditure, by
decreasing thyroid hormone levels
• subsequently slowing metabolism
• r-metHuLeptin therapy
• may avoid these neuroendocrine
deleterious responses and
prevent “yo-yo” dieting
• may have major implications in
weight loss management
Leptin therapy in weight loss maintenance

19. Current metabolic gene profiling
• Goal
– Improving health and preventing
disease through tailored diet and
lifestyle prescriptions
Form-Med ®, 2010
• Form-Med ® - Gene –
Metabolic- Analyze
• Material
– Blood
– samples of the oral mucosa
– detailed questionnaire completed
on diets
– Costs: 500 euros
• Information from Analyzed
genes
– individual perfect macronutrient
distribution
– inflammation tendency
– optimal exercise/training
programs

20. Current metabolic gene profiling
Central topic
• Am I genetically more of a "farmer"
or do I belong to "hunter-
gatherers"?
– Paleolithic diet: human genome has
not changed since the Stone Age
– Stone Age (Paleolithic) diet is the
only, appropriate nutrition for humans
– human organism have perfectly
adapted on this diet over millions of
years
– Paleolithic foods:
Fruits, nuts, seeds, wild meat, fish
– non-Paleolithic foods :
Milk and milk products, cereals,
potato's, sweets
Macronutrient ratio of the Paleolithic diet according to different authors; Ströhle and Hahn, 2006
Voegtlin,1975

21. Metabolic gene profiling
FormMed GSA: model analysis, FormMed, 2010
‚farmer‘ ‚hunter-gatherer‘
higher CH
less fat
less CH
higher fat and protein
• ‘PPAR-gamma
• homozygous wild-type (wt / wt)
• this genotype is more likely to be
overweight and to develop the
metabolic syndrome.
• The metabolism of carbohydrates
tends to work lesser than in
people with other variants of this
gene '[FormMed Health Care,
2010].’
• Model genotype:
hunter-gatherer

22. Metabolic gene profiling
• Recommendations for the macronutrient distribution related to the
genotype in the model analyze by FormMed
FormMed GSA: model analysis, FormMed, 2010; DGE, 2014
• recommended macronutrient
distribution during weight
reduction
DGE: CH: >50 E%; Fat: 30 E%; Protein: 9-11 E%
 The recommended macronutrient distribution for a healthy diet does
not differ very much from the general recommendations of the DGE!
• recommended macronutrient
distribution for a long-term,
healthy diet

23. PPAR Gamma
Peroxisome proliferator - Activated receptor
• PPAR Gamma:
• member of the peroxisome
proliferator-activated receptor
(PPAR) subfamily of nuclear
receptors
• regulate transcription of various
genes
• fatty acid storage and glucose
metabolism, adipocyte
differentiation
• PPARG Pro12Ala polymorphism
– the results of several studies suggest that the Pro12Ala polymorphism is
associated with increased insulin sensitivity
– further studies:
– the Pro12Ala mutation was associated with DM II and juvenile obesity
contrary to the previous results

24. Conclusion
• So far the concept of candidate
genes not led to convincing
successes although there are
results from candidate gene
studies that could identify clear
associations between obesity
and genetic predisposition
• the practical relevance of these
associations is rather low
• Pharmacological treatment and
side effects with e.g. Leptin and
Leptin synthesizers has to be
investigated in further studies
• Any specific diet, based on
individual DNA analysis, like
gen-metabolic-analyses, which
are already performed by
companies like FormMed cannot
be pronounced yet
• Further knowledge has to be
gained to curb ,globesity’ using
nutrigenetics

25. Take home message
• A better understanding about the influences of genetic
variations and the regulation of candidate genes may lead to
more individualized strategies in the treatment of overweight
and obesity
• an active lifestyle and a well-balanced diet can certainly
influence genetic predisposition for developing overweight
positively and leads to a slim and healthy life