Dr. Claude Bouchard. John W. Barton, Sr. Chair in Genetics and Nutrition Louisiana State University

Transcription

1 Dr. Claude Bouchard John W. Barton, Sr. Chair in Genetics and Nutrition Louisiana State University

2 2014 SEC Symposium A GENETIC PREDISPOSITION IS AMONG THE DRIVERS OF THE OBESITY EPIDEMIC: IMPLICATIONS FOR OBESITY PREVENTION PROGRAMS Claude Bouchard Pennington Biomedical Research Center

3 Multiple Drivers of Weight Gain and Obesity

4 A Mile-High View of These Drivers Physics Physiology Behavior Environment

5 Physics: First Law of Thermodynamics Energy can change form but it can not be created or destroyed. The increase in energy of a closed system is equal to the heat supplied to the system (dietary calories) minus the work done by it (energy expenditure). Thus weight gain (a gain in energy) occurs in the presence of increased caloric intake and/or decreased energy expenditure.

6 The Role of Physiology So the laws of physics apply but it is not the whole story. For instance, the processing of metabolic fuel can vary in efficiency depending on hormonal and physiological markers. Insulin, glucorticoids, leptin, steroids and other hormones influence nutrient partitioning and the profile of metabolic fuel oxidized or stored Likewise, hepatic, muscular and adipose tissue metabolic states influence the fate of metabolic fuels

7 A Comprehensive Model

8 Social Environment Physical Environment Energy Intake Energy Expenditure Energy Partitioning Fat Accretion Adipogenesis Obesity Overweight Behaviors Biology Adapted from Bouchard C, Rankinen T, 2008

9 Social Environment More recreational eating Food pricing Pressure to consume Eating on the run Fewer meals at home Larger portions Agricultural policies Society of spectators instead of participants Powerful, constant advertising Food labeling Less access to nutritious foods Pressure to be sedentary Nutrition-poor school meals & snacks Physical Environment Environmental pollutants Urban design Building design Energy Intake Energy Expenditure Peripheral regulators of appetite Metabolic fluxes & futile cycles CNVs, mobile elements, etc. Common & rare SNPs Population density & sprawl Energy Partitioning Fat Accretion Adipogenesis Viruses Biology Absence of sidewalks Reliance on automobiles CNS regulators of appetite RMR Gene gene & gene environment interactions Obesity Gut microbiota Overweight Maternal-fetal nutrition Calorie-dense foods Regulators of adipogenesis Smoking cessation Certain medications PA, metabolic rates Lipid oxidation rates Less time in strenuous activity High-fat diets Epigenetics & programming Corn fructose syrup More time in sedentarism Absence of breast-feeding Behavior Larger portions Bouchard C, unpublished

10 Obesogenic Environment Social Environment Built Environment Obesogenic Behavior Biology: defective or predisposing Energy Intake Energy Expenditure Energy Partitioning Fat Accretion Adipogenesis Obesity Overweight Bouchard C, unpublished

11 A Definition of GxE Interaction A gene-behavior interaction effect is present when the response to an a change in behavior is conditional on the genotype of the individual

12 Weight, kg Body Weight Changes in MZ Twins in Response to Overfeeding Body weight (p < 0.02): F = 3.4; R = 0.55 Fat mass (p < 0.05): F = 3.0; R = 0.50 AVF (p < 0.01): F = 6.1; R = Bouchard C et al, New Engl J Med, Twin A Twin B Weight, kg

13 Weight loss, kg Fat loss, kg Weight & Fat Mass Loss in Obese Twins on a 28-day VLC Diet* Twin A R= 0.85 F=12.8 (p<0.001) Twin B Weight loss, kg *1.6 MJ/day, 14 pairs of female MZ twins Twin A R= 0.88 F=17.0 (p<0.001) Fat loss, kg Twin B Hainer V et al, Int J Obes, 2000

14 Obesogenic Environment Obesogenic Behavior Social Environment Built Environment Biology: defective or predisposing Maternal influences Nutritional state Obesity Diabetes or GDM Smoking, etc. In utero effects Wiring Hormone sensitivity DNA methylation Histone modification Energy Intake Energy Expenditure Energy Partitioning Fat Accretion Adipogenesis Obesity Overweight Bouchard C, unpublished

15 Understanding the Meaning of Heritability Coefficients

16 Heritability Estimates of Obesity Traits Heritability is a population parameter h 2 (narrow sense) is the proportion of the phenotypic variance due to additive genetic factors Then h 2 is the upper limit of a trait variance that can be explained by DNA variants Not to be confounded with H 2 (broad sense), which includes not only the additive genetic variance but also dominance, gene-gene interactions, gene-environment interactions

17 Overview of the Heritability Estimates for BMI or Adiposity Heritability, % Nuclear families Adoption studies Twin studies 50-90

18 Heritability of an Aggregated Trait Has Poor Actionable Potential As we have seen, BMI level or risk of obesity is the end product of a constellation of influences. Hence the advantage to focus instead on endophenotypes or intermediary traits

19 Heritability Estimates for Intermediate Traits Relevant to Obesity Heritability in % Energy intake / kg 5-20 Fat intake (%) 20 RMR / kg FFM 40 TEM (%) 40 Level of activity 25 Energy partitioning 20

20 Genes and Obesity

21 Current Compendium of Obesity Genes Derived from GWAS (October 2013) Common Form from GWAS ADAMTS9 GNPDA2 LRP1B NRXN3 SPRY2 BDNF GP2 LY86 NUDT3 TBX15 CADM2 GPRC5B LYPLAL1 OLFM4 TFAP2B CDKAL1 GRB14 MAF PCSK1 THNSL2 CPEB4 HECTD4 MAP2K5 PRKD1 TMEM160 DNAJC27 HOXB5 MC4R PTBP2 TMEM18 DNM3 HOXC13 MSRA QPCTL TNNI3K ETV5 IRS1 MTCH2 RPL27A VEGFA FAIM2 ITPR2 MTIF3 RSPO3 ZNF608 FANCL KCTD15 NEGR1 SEC16B ZNRF3 FLJ35779 KLF9 NFE2L3 SH2B1 FTO LINGO2 NISCH SLC39A8

22 Number of individuals Combined Effect of Risk Alleles at 32 SNPs on Average BMI Atherosclerosis Risk in Communities (ARIC) study, n = 8,120 individuals of European descent Mean BMI (kg/m 2 ) Speliotes EK et al, Nature Genetics, 2010 Number of weighted risk alleles

23 Effect of Maternal or Fetal Homozygosity for a Minor Allele at Candidate Genes on Birth Weight HNF1B < 900 g GCK > 600 g Transcription HNF4A > 790 factor g CRHBP When the < 148 GCK g hepatocyte nuclear Corticotrophin-releasing mutation is factor GCK Transcription 1B < 550 is critical g for hormone-binding present in protein the development Glucokinase factor hepatocyte ADCY5 + CCNL1 of serves as < 113 g pancreas. In 21 babies participates mother in the but not a nuclear glucose factor sensor 4A is ADCY5 MTCH2 in with mutated HNF1B, regulation in of the the fetus, the involved encodes pancreas in < regulation 26 g adenylate and is a birth weight was low hypothalamic-pituitaryadrenal axis. birth weight is Mitochondrial rate-limiting FTO of insulin > 22 secretion. cyclase g enzyme carrier 5, in 2 and in all cases. In 13 of higher When by about gene glucose Accounts sequence metabolism. for about the variants Fat mass was have and tested obesity in about them with unaffected mother is 600 homozygous g. 24,000 GCK 4% of mutations MODY cases. been associated with mothers, 69% with gene birth SNP weights was in were for the minor However, allele when present Birth weight the fetus at a higher investigated normal SGA at fasting in range. more than Homozygotes birth. SNP, birth the weight mutation is is glucose but increased not carried by 790 by g the in SNPs in both genes were associated with birth 28,000 newborns. for the minor and T2DM. in the weight in three ethnic groups. reduced In whites, on present average 9% in both are mother HNF4A homozygotes reduce birth by CCNL1 Homozygosity allele had fetus results encodes The for a in birth low the lower and rare birth homozygotes high birth weights for birth reflect weight-lowering 148 g but mother is also alleles and weight for a mutation. by about 54% 550 g. reduced cyclin-l1, allele weight resulted by weight of carriers reduced which were variation in about by plays a 22 in g 26 g. at fetal two insulin SNPs, secretion resulting resulting a all birth three weight fetus, ethnic 113 birth groups g a higher about macrosomic. role 900 in birth RNA weight. g. from splicing. the GCK lower fetal than genotype the 24% and with the investigated. one fetal allele weight or less. is response to maternal hyperglycemia. normal.

24 Take-Home Messages

25 In Summary Observational data suggest that there is a significant genetic component to obesity There are significant genetic components to multiple intermediate traits causally related to body weight and adiposity Several gene defects can cause obesity; they are rare and account for <10% of the early-onset, severe obesity cases. About 100 DNA variants with small effect sizes have been associated with obesity In brief, genetic predisposition not genetic determinism

26 In Closing Observational and experimental data strongly suggest that the response to manipulations of energy balance by: caloric restriction, reduced sugar and dietary fat, reduction of sedentary behavior and increased PA level is conditioned by genomic variants that remain to be identified and mechanisms that are unknown at this time

27 Pennington Biomedical Research Center