obesity and genes recent developments pennington biomedical research center
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Obesity and Genes Recent Developments
Pennington Biomedical Research Center
2008 2
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
2008 3
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 (6q16.3–q24.2). 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 1.2–1.3 (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
variants–common 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: < 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 Cushing’s 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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--The Human Obesity Gene Map
135 different candidate genes linked with obesity-related phenotypes. Obesity related associations are shown in 18 different genes in at least
five studies.
Currently
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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 body’s 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.
Heli J. Roy, PhD, RDOutreach CoordinatorPhillip Brantley, PhDDirector, Division of EducationClaude Bouchard, PhDDirector, Pennington Biomedical Research Center
Division of EducationPennington Biomedical Research Center
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References
http://obesitygene.pbrc.edu/ http://www.endotext.org/obesity/obesity8/obesityframe8.htm http://diabetes.niddk.nih.gov/dm/pubs/pima/pathfind/pathfind.htm http://www.niddk.nih.gov/health/endo/pubs/cushings/cushings.htm