Obesity and Genes Recent Developments

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Obesity and Genes Recent Developments
Pennington Biomedical Research Center
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Overview

• Genetic basis for obesity
• The obesity epidemic
• The discovery of the obesity genes
• Monogenic obesity
• Associations with obesity
• Animal models of obesity
• Conclusions

--The Human Obesity Gene Map
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Obesity

• Influenced in the following ways
• Type of food consumed
• Environmental factors
• Individual response to food and physical activity

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The Obesity epidemic

• Due to permissive genes and the environment.

Obesity reviews (2007) 8 (Suppl. 1)
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The Obesity epidemic

• Obesity is very heritable.
• It is an interplay between
• Food intake, and
• Physical activity
• How your body uses/acquires food and expends
  energy determines our weight.

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The Discovery of the Obesity genes

• Once genes are identified that are linked to
  obesity, treatment can begin.
• Some may have defective genes and providing the
  missing protein will be effective in treating
  obesity.

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The Discovery of the Obesity genes

• Certain molecules may control energy balance that
  will be targeted for treatment.

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The Discovery of the Obesity genes

• Some individuals may benefit from specific diets
  and/or exercise regimes, drugs or surgery to
  prevent obesity.

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Obesity due to genetic disorders

• Helped to de-stigmatize human obesity
• Seen as a biomedical disorder and not simply a
  moral frailty.
• Has led to dramatically successful therapy in a
  few individuals.
• One gene mutation, the melanocortin 4 receptor,
  may be responsible for tens of thousands of cases
  of obesity.

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Monogenic obesity

• Monogenic genetic defect in one gene
• This type of genetic mutation can result in
  severe forms of obesity that run in families.

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Monogenic obesity

• As of now, obesity due to genetic changes is due
  to
• Defect is in the satiety centers in the brain.
• Affects appetite control centers in the brain.
• Obesity is not due to slow metabolism.

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Monogenic obesity

• A very small chemical change in the DNA has been
  found to be associated with obesity-related
  variables.
• Subtle variants in genes can result in severe
  early onset obesity, and are likely to contribute
  to susceptibility to obesity in the general
  population.

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Monogenic obesity

• A single chromosome may be linked with obesity in
  several populations (10p12).
• Another chromosomal region may be associated with
  obesity and diabetes (6q16.3q24.2).
• A gene for an enzyme is associated with childhood
  obesity and also with insulin resistance (ENPP1).
  
• A modification in a gene increases the odds ratio
  for obesity by 1.21.3 (Insig2).

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Polygenic contribution to obesity

• Polygenic contribution to obesity could be
• Relatively common genetic changes common
  variant common disease model, or the
• Rare genetic changes in the multiple rare
  variantscommon disease model. This may be true
  in certain populations.

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Mendelian Disorders or monogenic mutations

• Mendelian disorders - single mutant genes.
• There are four main patterns of inheritance
• autosomal dominant,
• autosomal recessive,
• X-linked dominant, or
• X-linked recessive.
• 6,000 known single gene disorders
• Frequency lt 1 in 200 births.

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Obese phenotype

• The visible properties of an organism that are
  produced by the interaction of the genotype and
  the environment such as obesity.

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Mendelian Disorders

• Phenotype
• homozygotes
• heterozygotes
• Carriers

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Mendelian Disorders

• Cushings Syndrome, two loci CNC1 and CNC2,
  mutations in PRKAR1A or MEN1 genes
• Cortisone Reductase Deficiency, mutations in
  HSD11B1 and the H6PD gene
• Isolated Growth Hormone Deficiency
• X-Linked Syndromic Mental Retardation 16, MECP2
  gene
• Bardet-Biedl Syndrome, (14q32.1) genes BBS8, BBS3
  and BBS5
• Abright Hereditary Osteodystrophy-Like Syndrome

--The Human Obesity Gene Map
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Monogenic Mutations

• Mutations associated with obesity are
• Cohen syndrome
• Leptin deficiency
• Leptin receptor deficiency
• Prohormone convertase -1 deficiency
• Propopiomelanocortin deficiency

--The Human Obesity Gene Map
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Monogenic Mutations

• Mutations associated with obesity cont.
• Melanocortin 4 receptor mutation
• Melanin concentrating hormone receptor 1 (GPR24)
• ADRB2 gene
• ADRB3 gene
• Corticotrophin-releasing hormone receptors 1 and
  2 (CRHR1-2

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Non Mendelian Complex Traits

• Associations exist between candidate genes and
  obesity- related phenotypes.
• More than 400 studies covering 113 candidate
  genes have reported significant associations.

--The Human Obesity Gene Map
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Associations found in humans

• Body weight, BMI, Overweight, and Obesity 43
  genes
• Body composition 13 genes, Fat distribution
  12 genes, and Energy expenditure 4
  genes
• Changes in Body weight and Body composition 7
  genes
• Negative Associations with Obesity-Related
  Phenotypes

--The Human Obesity Gene Map
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Other Obesity-Related Phenotypes

• Metabolic syndrome waist circumference, dietary
  intakes, and resting energy expenditure.
• Metabolic syndrome BMI, waist-to-hip ratio, and
  sub scapular skinfolds.

--The Human Obesity Gene Map
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Multivariate Genome-Wide Scans

• There are linkages involving BMI and blood
  pressure
• systolic blood pressure,
• diastolic blood pressure, and
• ASP levels.

--The Human Obesity Gene Map
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Currently

• 135 different candidate genes linked with
  obesity-related phenotypes.
• Obesity related associations are shown in 18
  different genes in at least five studies.

--The Human Obesity Gene Map
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Obesity in the mouse model

• Mouse model is used to research the effect of
  genetic changes on metabolism
• In the rodent DNA, 166 genes have been identified
  that, when mutated or expressed as transgenes in
  the mouse, result in phenotypes that affect body
  weight and adiposity.

--The Human Obesity Gene Map
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Obesity in the mouse model

• Obesity in rodents may be due to hepatic lipase
  activity
• Some obesity is due to influences on food intake.

--The Human Obesity Gene Map
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Obesity in the mouse model

• Genetic influences may lead to late-onset (Fob3a)
  or early-onset (Fob3b) obesity in laboratory
  animals.
• Gene mutations may influence insulin and lipids
  or otherwise influence body weight.
• Leptin level or receptors may be influenced
  leading to obesity.

--The Human Obesity Gene Map
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In Conclusion

• Obesity is related to food intake and energy
  balance.
• Obesity is also related to subtle genetic changes
  that can profoundly change the bodys response.
• It is becoming clear that some genes appear to be
  more important than others based on the numbers
  of replication from independent studies.

--The Human Obesity Gene Map
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In Conclusion

• About 20-30 of genetic associations are real and
  do have modest effects on the risk of common
  diseases.
• The goal still remains to identify the right
  combination of genes and mutations that are
  associated with this increased risk for
  overweight and obesity, and determine how
  environmental factors interact with these genes
  and mutations to determine the risk.

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Division of Education Pennington Biomedical
Research Center

• Heli J. Roy, PhD, RD
• Outreach Coordinator
• Phillip Brantley, PhD
• Director, Division of Education
• Claude Bouchard, PhD
• Director, Pennington Biomedical Research Center

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References

• http//obesitygene.pbrc.edu/
• http//www.endotext.org/obesity/obesity8/obesityfr
  ame8.htm
• http//diabetes.niddk.nih.gov/dm/pubs/pima/pathfin
  d/pathfind.htm
• http//www.niddk.nih.gov/health/endo/pubs/cushings
  /cushings.htm