Two Major US Trends - Kaeberlein Lab
Transcript of Two Major US Trends - Kaeberlein Lab
Life Expectancy in the US
Two Major US Trends
Obesity Trends* Among U.S. Adults
BRFSS, 1985
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1986
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1987
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1988
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1989
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1990
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1991
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1992
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1993
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1994
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1995
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1996
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1997
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1998
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 1999
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 2000
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 2001
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 2002
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 2003
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 2004
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 2005
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
Obesity Trends* Among U.S. Adults
BRFSS, 2006
No Data <10% 10%–14% 15%–19% 20%-24% 25%-29% ?30%
What is Obesity?
Metabolic disordercharacterized by chronicexcess of energy intakeover expenditure, leadingto the accumulation offat.
N Engl J Med 355:763, August 24, 2006
Underweight = <18.5Normal weight = 18.5-24.9Overweight = 25-29.9Obese > 30
BMI correlates with mortality
Methods
• Genetic Approaches– Genome-wide Linkage Studies– Candidate Gene Association Studies
• Objective: to determine whether anassociation exists between a gene’sallelic variation and obesity-relatedtraits
Methods
• Genome-wide Linkage Studies– A systematic examination of all chromosomes in obese
families using polymorphic markers in order to detectincreased allele sharing in obese sibpairs
– Regions located on nearly all the chromosomes(except Y) have been linked to different obesity-related phenotypes
• BMI, distribution of adipose tissue, occurrence of ametabolic syndrome, resting energy expenditure, energyand macronutrient intake, weight variation, the levels ofcirculating leptin and insulin
– Limitations• Lack of replication and inconsistency between studies• Population heterogeneity limits power to detect true
linkage signals
Methods
• Candidate Gene Association Studies– Hypothesis driven approach used to detect
genetic variants that influence susceptibility tocommon disease
– Limitations• High proportion of false positive results published• False negative results may arise in small studies if
genetic effects are modest• True association in one population might not be true
in another due to heterogeneity in genetic orenvironmental background
Variables InfluencingHuman Obesity
• Monogenic Disorders– Leptin/Melanocortin Pathway
• Polygenic Susceptibility Factors– Gene-Gene Interaction– Gene-Environment Interaction
• Diet• Physical Activity
Table 1.Rare monogenic forms of human obesity.
Mutch, D.M. and K. Clement. Best Practice & Research ClinicalEndocrinology & Metabolism 2006, 20(4): 647-664
Leptin Melanocortin Pathway
Oswald and Yeo, Obesity Reviews 8:293-306
FOOD INTAKE
ENERGY METABOLISM
Obesity Gene Candidates
ADIPOSE TISSUE METABOLISM
LIPID AND GLUCOSE METABOLISM
Obesity Gene Candidates
Gene-Gene Interaction• PPARG2 – ADRB3
– Pro12Ala of PPARG2 gene - Trp64Arg of ADRB3 gene• Significantly higher BMI, insulin, and leptin levels
• ADRs– Gly/Gly genotypes of ADRB1 plus at least one β3- Arg allele
• Increases in BMI
– ADRB1/ADRB3 gene with UCP-1 gene and/or LPL
• LEP-LEPR– LEP-G2548A and LEPR Q223R
• May promote immune dysfunction associated with obesity
• Chromosome region interaction between obesity susceptibility loci– Chromosome regions 2p25-p24 and 13q13-21– 20q and chromosome 10 centromere– TBC1 domain family member 1 gene (TBC1D1) and 4q34-q35 region
Gene-Environment Interaction• Gene and Diet interaction
– Genes regulating energy homeostasis and thermoregulation• Neuropeptide Y (NPY), agouti-related protein (AGRP), melanocortin
pathway factors (MC4R), uncoupling proteins (UCPs), fatty acid bindingfactors (FABP)
– Diet intake control may be affected by genes encoding tastereceptors and peripheral signaling peptides
• Insulin (INS), leptin (LEP), ghrelin (GHRL), cholecystokinin (CCK)
– Protein levels may be altered during starvation or overfeeding• UCP-2 and UCP-3 genes, LEPR genes
– Genes involved in digestion of starch may be linked tocarbohydrate and protein intakes
• α-amylase genes (AMY1A, AMY2A, and AMY2B) insulin-like growth factor 1gene (IGF1)
– Genes controlling eating behavior• MC4R gene and neuromedin beta gene (NMB)
– Variable responses to diet in lipoprotein metabolism pathway• APOE, APOB, APOA4, APOC3, LDLR, FABP, LPL, MTP, CETP, HPL
Gene-Environment Interaction• Gene and Physical Activity Interaction
– Genes influence physical performance and physicalactivity
• Improved duration of exercise• II and ID genotype of ACE but not in DD genotype
• Maximal oxygen consumption after aerobic exercise training• HIF1 and TTN
• Maximal oxygen uptake in the sedentary state in response totraining
• CKMM, SGCB, SNTB1, SGCG, DAG1, LMNA, PYGL, GCH1,SUR
• Other genes that have been reported: GNB3, ADRB2, MC4R,CART, UCP-2, UCP-3
FTO Papers
• Genome-wide linkages study– Strong association between SNPs in FTO,
diabetes and obesity incidence– ~20,000 adults, ~10,000 children
• Gene-Environment Interaction– DNA demethylase
• DNA repair or transcriptional regulator?• Found in hypothalamus – energy control center of
brain• mRNA levels sensitive to food intake