Obesity and Genes Recent Developments

Pennington Biomedical Research Center

Publication # 7

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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 (6q16.3–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 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 ASP levels.

--The Human Obesity Gene Map

2009 25--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, MBA, RDOutreach CoordinatorPhillip Brantley, PhDDirector, Division of EducationSteven Heymsfield, MDDirector, Pennington Biomedical Research CenterBeth Kalicki, BS

Division of EducationPennington Biomedical Research Center

Edited: October 2009

About Our CompanyThe Pennington Biomedical Research Center is a world-renowned nutrition research center. Mission:

To promote healthier lives through research and education in nutrition and preventive medicine. The Pennington Center has several research areas, including: Clinical Obesity ResearchExperimental ObesityFunctional FoodsHealth and Performance EnhancementNutrition and Chronic DiseasesNutrition and the BrainDementia, Alzheimer’s and healthy agingDiet, exercise, weight loss and weight loss maintenance The research fostered in these areas can have a profound impact on healthy living and on the prevention of common chronic diseases, such as heart disease, cancer, diabetes, hypertension and osteoporosis. The Division of Education provides education and information to the scientific community and the public about research findings, training programs and research areas, and coordinates educational events for the public on various health issues. We invite people of all ages and backgrounds to participate in the exciting research studies being conducted at the Pennington Center in Baton Rouge, Louisiana. If you would like to take part, visit the clinical trials web page at www.pbrc.edu or call (225) 763-3000.

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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