DR SUJAYA RAGHAVENDRA POST GRADUATE GENERAL MEDICINE

Obesity determinants : genetics or epigenetics

Introduction

Heritability BMI is the surrogate marker of obesityPopulation groups eg: South Asians have

higher adiposity – metabolic syndromes and complications

Obesity (phenotype ) is closely influenced by genetic makeup which is further modulated by epigenetic factors

Epigenetics : variation in gene expression due to external factors example the environment , or heritable changes like X – activation and imprinting

Activation or silencing of gene expression

Obesity determinants

BMI and fat distribution ( predisposition to visceral ) – heritable

Is it genetics or epigeneticResearch on the human genome map and

human obesity – still an ongoing quest!!!

Role of genetics

polygenic , very few monogenic Genome wide association studies and

candidate gene study 11 single gene mutations , 50 loci related to

mendalian syndromes , 244 knockout genes or transgenic models and 127 candidate genes – obesity

< 20 % were replicated in 5 studies

FTO locus – non syndromic obesityExplains Around 1% BMI heritabilityPeople who are homozygous for Risk allele

have a 2-3 kg higher weight compared to non risk allele homozygous.

NEJM study : SNVrs1421085 in the FTO region relationship with obesity

SNV DISRUPTS EARLY DIFFERENTIATION OF MESENCHYMAL PROGENITORS INTO ADIPOCYTES SUBTYPES

SHIFT FROM WHITE ADIPOCYTE(FAT STORING )BROWNING GENE EXPRESSION TO LIPID – STORAGE GENE EXPRESSION

DEVELOPMENT OF FAT STORING WHITE ADIPOCYTES INSTEAD OF BEIGE ADIPOCYTES

QUEBAC family study : 1. 56 % heritability abdominal visceral fat 2. 45 % heritability subcutaneous fat Candidate genes : ADRB3, GR,LPL PAI1,RBP4-

genetic variants predispose to ectopic fat distribution.

But still all these genetic research could only explain miniscule portion of heritability of BMI and fat distribution.

Epigenetics

Genetic predisposition is not always expressed and is expressed mostly in presence of an environment that favors epigenetic modifications .

DNA methylation or histone modification – natures ‘ s mechanism of adapting the genome to the environment

Modifies long term gene expression and the ultimate phenotypic expression.

Fetal origin of adult diseases:maternal health , environment and epigenetics

Maternal nutrition(over and under nutrition ) modifies fetal genomic expression- increased risk of adiposity and ectopic fat deposition

Maternal obesity- obese off spring –hyperinsulinemic –risk of obesity and diabetes

Maternal malnutrition – epigenetic mechanisms- “thrifty phenotype”

A phenotype in which there is growth of more immediately important organs at the expense of other organs and tissues (adipose tissue, pancreas, liver kidney etc)

Diminished functional reserve – accelerated failure in post natal life

Huang et al. positive correlation between IGF2-H19 DNA methylation levels and USG derived measures of subcutaneous fat thickness in young adults

Variants of SLC16A11- associated with TypeIIdiabetes-

Epigenetic modification of the gene – tendency to fat storage

Early life environment and epigenetic modification

Gut microbiome of the obese is very different from the lean

Human gut – hosts 100 trillion bacteria Determinants : genetic background, early

life development (formula feeding , antibiotic use , cesarean section )and high fat diet.

Contribution in the phenotypic expression including obesity

Epigenetic modification in adult life

High fat diet and circadian rhythm and metabolism- closely linked .

In a study Lu et al. mice was given fat diet- reprogramming of hepatic clock – disruption of normal circadial oscillations – affecting metabolism

Silencing of Clock-Bmal 1 network(involved in circadian rhythm and metabolism and PPAR GAMMA induction of a novel gene set

Mechanism of obesity in night shift workers .

Conclusion

Phenotypic expression of obesity and fat distribution is heritable – South Asian , Latin and other ethnic groups

Gene polymorphisms – explain increased riskEpigenetics explain it fullyMany of the factors are modifiable.Target epigenetics- obesity prevention and

management .

Thank you