Rohde et al_obesity_genetics_2019

Genetics and Epigenetics in Obesity

Introduction

• Obesity is a significant global health burden with increasing prevalence.

• Considered a potentially heritable trait.

• Monogenic obesity is linked to defects in hypothalamic circuits regulating appetite and energy homeostasis, such as leptin mutations which lead to uncontrolled eating.

• Common obesity tends to arise from interactions among genetic, epigenetic, and environmental factors.

Genetic Background of Obesity

Monogenic Syndromic and Non-syndromic Obesity

• Monogenic obesity can be:

  • Syndromic: Associated with other traits (e.g., cognitive impairments).

  • Non-syndromic: Not associated with other conditions; often linked to specific genes like MC4R, LEP, LEPR, PCSK1.

• 79 syndromes identified, with some fully or partially characterized genetically.

Notable Monogenic Syndromes

• Prader-Willi Syndrome: Chromosomal imprinting defect.

• Bardet-Biedl Syndrome: Linked to 19 different genes.

• Homozygous mutations in leptin-related genes can lead to severe obesity, often requiring treatment with recombinant leptin.

Common Obesity

• Most individuals suffer from common (multifactorial) obesity due to interactions among numerous genetic loci, with minor effects on BMI.

• GWAS (Genome-wide Association Studies) have identified over 870 SNPs related to obesity but explain only 5% of BMI variance.

• Major contributors include genes affecting appetite regulation, insulin action, and lipid metabolism.

Gene-Environment Interaction in Obesity

• Genetic factors have considerable interactions with environmental influences, particularly lifestyle and dietary choices.

• Studies show that physical activity can reduce the impact of genetic predispositions, especially related to the FTO gene.

• Dietary habits also significantly modulate how genetic variants influence obesity risk.

Epigenetic Signatures in Obesity

• Epigenetic changes (e.g., DNA methylation) modify gene expression without altering DNA sequences.

• DNA Methylation in Obesity:

  • Recent studies focus on the correlation of DNA methylation changes with obesity traits.

  • Certain methylation patterns in genes associated with metabolism correlate with BMI and metabolic syndrome markers.

Genome-Wide DNA Methylation Studies

• Important studies identify specific genes whose methylation levels correlate with BMI.

• HIF3A found to have significant methylation related to higher BMI across diverse tissues.

Lessons from Intervention Studies

• Behavioral interventions such as exercise and weight loss (e.g., bariatric surgery) lead to notable changes in DNA methylation patterns.

• Exercise and dietary modifications can improve metabolic outcomes and influence gene expression in adipose tissue.

Precision Medicine in Obesity

• Efforts to implement precision medicine strategies that tailor interventions based on genetic and epigenetic profiles are ongoing.

• There is potential for personalized management strategies for monogenic obesity through genetic testing; however, common obesity presents more varied responses to treatment based on individualized risk profiles.

Closing Remarks

• The complexity of obesity's etiology necessitates continued research into genetic and epigenetic interactions with lifestyle factors.

• Understanding these dynamics may lead to improved prevention and treatment strategies.