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Genobesity 2005

Genobesity 2005. Bottero. The “ thrifty genotype ” hypothesis James Neel, 1962. Since, energy storage in the form of fat is an important adaptation for survival, it is likely that combination of genes have been selected during evolution to favor energy storage.

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Genobesity 2005

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  1. Genobesity 2005

  2. Bottero

  3. The “thrifty genotype” hypothesisJames Neel, 1962 • Since, energy storage in the form of fat is an important adaptation for survival, it is likely that combination of genes have been selected during evolution to favor energy storage.

  4. “Adults of present-day industrialized countries have a hunter-gatherer genome but live in a sedentary, food-abundant society” Eaton et al. Am J Med 84:739, 1088

  5. The threshold model for Polygenic multifactorial Inharitance of common complex disorders

  6.  Four levels of genetic susceptibility to become obese

  7.  Diagram of the determinants of positive energy balance andfat deposition

  8. Pima Indians of the ‘restrictive’ remote Mexican Sierra Madre mountains have a muchlower prevalence of obesity and type II diabetes mellitus than those living in the ‘obesogenic’ environment of Arizona.

  9. Evidence from genetic epidemiology - Heritabilty • MZ and DZ twins and MZ twins reared apart studies– around 70% heritability • Adoption studies – around 30% heritability • Family studies – intermediate between the above

  10. Evidence from geneticepidemiology–familial risk • National Health and Nutrition Examination Survey III – 2-8 times higher risk for 1st degree relatives • Canada Fitness Survey – 5 times higher risk for relatives (but also increased for spouses of probands)

  11.  Intra-pair resemblance in the response of identical twins to long-term changes in energy balance

  12. Genetic syndromes associated with obesity • At least 25 • Most common Prader Willi Bardet-Biedl Cohen Albright Alstrom

  13. Bardet-Biedl Syndrome (BBS) • Obesity • Diabetes/ hypertension • Retinopathy • Polydactyly • Mental Retardation • Renal Anomalies • Hypogonadism • Heart defects

  14. Mean BMI of Bardet-Biedl patients according to the 3 chromosome loci Chromosome 3 28.6 (CI 22.4-34.7) Chromosome 15 34.3 (CI 28.0-40.6) Chromosome 16 22.5 (CI 19.8-25.2)* * P<0.001

  15. Locus heterogeneity in BBS -BBS1 - Leppert et al., 1994 - BBS2 - Kwitek-Black, 1993 - BBS3 - Sheffield et al., 1994 - BBS4 - Carmi et al., 1995 - BBS5 - Young et al., 1999 - BBS6 - Slavotinek et al., 2000 - BBS7 - Badano et al., 2003 - BBS8 - Ansley et al.,2003

  16. Katsanis et al. Science 293, 2256 (2001)

  17.  Central pathways contributing towards the regulation of energy intake and energy expenditure. Modified from: Loos & Bouchard, J Int Med 254:401, 2003 PC-1 α-MSH

  18. Human monogenic obesity genes Leptin and leptin receptormutations–about 7 cases at present: • Homozygous loss of function mutation in the leptingene causes early onset morbid obesity with hypogonadotropic hypogonadism and central hypothyroidism. In one case recombinant human leptin RT resulted in a significant and sustained fat mass loss.

  19. Human monogenic obesity genes • Homozygous mutation in the leptinreceptorgene (one family) results in a phenotype similar to that of leptin deficiency, although more severe, associated with growth retardation due to impaired GH secretion.

  20. Human monogenic obesity genes • Melanocortin pathway Homozygous or compound heterozygous loss of function mutations in POMC (2 cases) result in obesity, red hair, adrenal insufficiency. Mutations in PC-1 result in the above phenotype + hyperinsulinemia

  21. Human monogenic obesity genes • At least 27 mutations in MC4Rgenein about 68individuals cause dominant and recessive inherited nonsyndromic obesity with incomplete penetrance and variable expression: earlier onset with a trend towards childhood obesityand excessive food-seeking behavior from age 6-8 months.

  22. Identifying susceptibility genes for common forms of obesity • Candidate genes - Regulation offood intake Studies suggest that sequence variations in the leptin gene may account for the variation in circulating leptin levels and thus could modify the ability of the brain to sense the amount of fat stored in white adipose tissue.

  23. Identifying susceptibility genes for common forms of obesity • Candidate genes - Regulation ofenergy intake • Some evidence for POMC involvement in common childhood obesity. • Inconclusive evidence for other candidate neuropeptides involved in control of food intake.

  24. Identifying susceptibility genes for common forms of obesity • Candidate genes –regulation ofenergy expenditure Specific allelic combination of variants in the insulin gene was shown among 615 obese children, to induce a higher insulin secretion and a higher risk for developing juvenile obesity

  25. Identifying susceptibility genes for polygenic/common forms of obesity • Genome wide scan for chromosomal regions showing linkage with obesity (QTL’s) in a large collection of nuclear families (mostly adult-sibling pairs): about 70 putative loci affecting obesity-related phenotypes have been found, no gene characterized yet.

  26. Identifying susceptibility genes for polygenic/common forms of obesity • Tissue-specific gene expression profile comparing lean versus obese individuals and other informative samples.

  27. Interactions Between Variants in the ß3-Adrenergic Receptor and Peroxisome Proliferator–Activated Receptor- 2 Genes and Obesity Wen-Chi Hsueh, PHD1, Shelley A. Cole, PHD1, Alan R. Shuldiner, MD2, Brock A. Beamer, MD3, John Blangero, PHD1, James E. Hixson, PHD1, Jean W. MacCluer, PHD1 and Braxton D. Mitchell, PHD1 OBJECTIVE—Previous studies have reported modest associationsbetween measures of obesity and the Trp64Arg variant of theß3-adrenergic receptor (ADRß3) and the Pro12Alavariant of the peroxisome proliferator–activated receptor(PPAR)- 2. We hypothesized that these single gene variants maymark mutations that act through convergent pathways to producesynergistic effects on obesity. RESEARCH DESIGN AND METHODS—The sample included 453 subjectsfrom 10 large Mexican-American families participating in thepopulation-based San Antonio Family Heart Study. The effectsof each gene variant singly and jointly were estimated as fixedeffects using the measured genotype approach framework. Analyseswere conditioned on the pedigree structures to account for thecorrelations among family members. Statistical significancewas evaluated by the likelihood ratio test with adjustment forage, sex, and diabetes status. RESULTS—The allele frequencies for the ADRß3Trp64Arg and PPAR - 2 Pro12Ala variants were 18 and 12%, respectively.The ADRß3 variant was not significantly associatedwith any of the obesity-related traits, but subjects with thePPAR - 2 variant (n = 98) had significantly higher levels of fastinginsulin (P = 0.03), leptin (P = 0.009), and waist circumference(P = 0.03) than those without. Subjects with both gene variants(n = 32) had significantly higher BMI, insulin, and leptin levelsthan those with only the PPAR- 2 variant (n = 66) (P for interaction:0.04, 0.02, and 0.01 for BMI, fasting insulin, and leptin, respectively). CONCLUSIONS—Our results suggest that epistatic modelswith genes that have modest individual effects may be usefulin understanding the genetic underpinnings of typical obesityin humans. Diabetes Care 24:672–677, 2001

  28. Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation Robert A. Waterland and Randy L. Jirtle* Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710 Early nutrition affects adult metabolism in humans and other mammals, potentially via persistent alterations in DNA methylation. With viable yellow agouti (Avy) mice, which harbor a transposable element in the agouti gene, we tested the hypothesis that the metastable methylation status of specific transposable element insertion sites renders them epigenetically labile to early methyl donor nutrition. Our results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B12, choline, and betaine alter the phenotype of their Avy/a offspring via increased CpG methylation at the Avylocus and that the epigenetic metastability which confers this lability is due to the Avytransposable element. These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans. From: Molecular and Cellular Biology (Aug 2003) 23: 5293-5300

  29.  Chromosomal location of some obesity-related genes From: Loos & Bouchard, J Int Med, 254:401, 2003 Monogenic mutations Selected obesity candidate genes QTL’s syndromes

  30. Can genetics be utilized in the practice of obesity management and prevention?

  31. NOT YET!

  32. We are yet unable to: • Define the predictive risk related to obesity for gene variations or mutations in candidate genes • Specifically treat or prevent obesity in carriers of allelic variants or mutations conferring (even) a defined risk

  33. The only exception may be the MC4R gene MC4R mutations represent a significant cause of obesity in morbidly obese children and adults (0.5-6%). In individuals with MC4R mutations, the frequency and relative risk for morbid obesity is about 100-fold higher

  34. The only exception may be the MC4R gene • MC4R agonists are under development and may be used in the future in patients with decreased melanocortinergic activity

  35. HOWEVER: • The expression of the disease in mutation carriers is variable and the penetrance is incomplete MC4R genes environment

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