Nutrigenetics:

Possibilities and limitations in the treatment of overweight and obesity Gessner Diana, 0747266

Bachelor-Thesissupervisor: O.Univ.-Prof. Dr. Hans GoldenbergInstitute of Medical Chemistry, Center of Pathobiochemistry and Genetics, Vienna, Austria 2012.

Seminar Human Nutrition (330060) SS 2014

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

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

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.

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 nutrigeneticsto stop weight cycling and to combat ,globesity’

Turk et al.,2009

• 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

Nutritional genomicsa multidisciplinary science

• Combines information from• Genetic, nutrition, Physiology, pathology, molecular biology, bioinformatics, and other disciplines.

Fenech 2008 ; Costa et al., 2008

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: (Leptinmutation) do not account for majority of cases

Speakman 2009; NGFN, 2012

The search for candiate genes

“I found

one! I found

one!”

Kenneth M. Weiss & Joseph D. Terwilliger - 2000

Nutritional genomicsMethods

• Human Genetic Variation

• 99.9% of our DNA sequences are

the same

• SNPsExchanges 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

Nutritional genomicsGenome 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

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

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

• Ob candidate genes

Schwartz et al., 2000; Schwartz and Morton, 2002; Morton et al., 2006

Neuroendocrine regulation of food intakeThe 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

Neuroendocrine regulation of food intakeThe 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.

• 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 subjectson 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

• 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 obesitycoadministration with leptin sensitizer - amylin

• 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

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

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

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

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

PPAR GammaPeroxisome 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

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

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