Genetics of obesity

Question 1

What is the cause of obesity?

Answer 1

Greater energy intake than expenditure

Genes, environment, appetite control and endocrinology all play a role

Question 2

How much of total energy expenditure does physical exercise account for?

Answer 2

30-50%

Resting metabolic rate does not predict weight gain

Question 3

How much do people under report energy intake?

Answer 3

Normal weight -20%

Obese as much as -30 to -50%

Question 4

What study suggests a genetic role in obesity?

Answer 4

Obese women isolated in a country house
Calorie restricted diet for 3 weeks
30% maintained weight within 1kg

Question 5

Describe twin studies in obesity

Answer 5

Adoptive parents and twins
No BMI correlation between parents and child
Dizygotic BMI varied
Monozygotic BMI very similar

Question 6

What are the three types of genetic obesity?

Answer 6

Syndromic monogenic obesity
Non-syndromic monogenic obesity
Polygenic obesity

Question 7

What is syndromic monogenic obesity?

Answer 7

Exceptionally rare
Obesity and mental retardation
Dysmorphic features
Organ specific abnormalities
>30 cases reported

Question 8

What is Prader-Willi syndrome?

Answer 8

1 in 15,000 to 30,000
Hyperphagia, childhood obesity, short stature, cognitive disability
Maternally imprinted, mutations in several genes

Question 9

What is Bardet-Biedl syndrome?

Answer 9

1 in 140,000 to 160,000
Retinal degradation, cognitive disability, polydactyly, genital and renal abnormalities, obesity, type 2 diabetes
Autosomal recessive, 19 genes identified

Question 10

What is Alstrom syndrome?

Answer 10

~300 cases
Hyperphagia, obesity, short stature, round facies, skeletal abnormalities, mental disability
Autosomal dominant mutation in GNAS

Question 11

What is non-syndromic monogenic obesity?

Answer 11

Single gene disorder
Identification of mutations by studying extreme obesity
Often genes involved in appetite control
Rare

Question 12

How is the appetite controlled by the CNS?

Answer 12

Complex system that involves the hypothalamus and CNS

Question 13

What two areas of the hypothalamus control appetite?

Answer 13

Ventromedial nucleus
Lateral hypothalamus
Not anatomically defined
Neurotransmitter and neurone specific

Question 14

What is the ventromedial nucleus?

Answer 14

Satiety centre

Stimulation leads to decreased food intake, ablation leads to increased food intake

Question 15

What is the lateral hypothalamus?

Answer 15

Hunger centre
Stimulation leads to increased food intake
Ablation leads to decreased food intake

Question 16

Describe the activating mechanism of leptin

Answer 16

Acitivates POMC neurons
POMC neutrons are anorexigenic
Decreases appetite

Question 17

Describe the inhibiting mechanism of leptin

Answer 17

Inhibits NPY neurons
NPY neurons are orexigenic
Decreases appetite

Question 18

Describe leptin monogenic obesity

Answer 18

Mutation in the leptin gene
Severly obese from a young age
Hyperphagia and aggressive behaviour if food is denied
Impaired satiety
Undetectable levels of leptin
Treated with injections of recombinant human leptin

Question 19

How does leptin relate to BMI?

Answer 19

Increases with BMI
Cannot be used as a treatment for common obesity
Might even be suffering from leptin resistance

Question 20

What are MC4R mutations?

Answer 20

The receptor which binds alphaMSH and betaMSH in leptin signalling (POMC neurons)
When activated, decreases appetite
Defects or mutations increase body weight

Question 21

What is polygenic obesity?

Answer 21

Multiple gene defects with modest effect
Interact with the environment
Single nucleotide polymorphisms
Discovered by genome wide association studies (GWAS)

Question 22

What is FTO?

Answer 22

Fat mass and obesity associated gene
Discovered by Frayling, May 2007 by GWAS
Predisposes individuals to type II diabetes through increased BMI
Homozygosity: +3kg body weight, x1.67 obesity
Exact function unclear