Obesity and Genes Recent Developments Pennington Biomedical Research Center

20082 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

20083 Obesity Influenced in the following ways:  Type of food consumed  Environmental factors  Individual response to food and physical activity

20084 The Obesity epidemic  Due to permissive genes and the environment. Obesity reviews (2007) 8 (Suppl. 1)

20085 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.

20086 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.

20087 The Discovery of the Obesity genes  Certain molecules may control energy balance that will be targeted for treatment.

20088 The Discovery of the Obesity genes  Some individuals may benefit from specific diets and/or exercise regimes, drugs or surgery to prevent obesity.

20089 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.

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

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’.

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.

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).

‘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.

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.

Obese phenotype  The visible properties of an organism that are produced by the interaction of the genotype and the environment – such as obesity.

Mendelian Disorders  Phenotype homozygotes heterozygotes  Carriers

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

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

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

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

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

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

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

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

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

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

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

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

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, RD Outreach Coordinator Phillip Brantley, PhD Director, Division of Education Claude Bouchard, PhD Director, Pennington Biomedical Research Center Division of Education Pennington Biomedical Research Center

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