Genetic Determinants of Obesity

Question 1

What is obesity?

Answer 1

A metabolic disorder which is consequence of an imbalance between energy intake and usage.

Question 2

What is obesity a risk factor for?

Answer 2

Cardiovascular diseases

Type 2 Diabetes

Several cancers

Question 3

What are some causes of obesity?

Answer 3

– Genetic
– Epigenetic
– Environmental

Question 4

What are the obesity-related traits?

Answer 4

– ↑BMI (Body Mass Index)
– Unhealthy weight gain
– ↑waist circumference
– Excess of body fat

Question 5

What is dylipidemia?

Answer 5

High cholesterol

Question 6

What is hypertension?

Answer 6

High blood pressure

Question 7

What is BMI?

Answer 7

mass (kg) / height (m2)

Question 8

What is considered underweight?

Answer 8

Less than 18.5

Question 9

What is considered a healthy BMI?

Answer 9

18.5-25

Question 10

What is considered an overweight BMI?

Answer 10

25-30

Question 11

What is considered an obese BMI?

Answer 11

More than 30.

Question 12

What is the correlation between BMI and obesity?

Answer 12

A high BMI increases cancer risk.

Question 13

How is obesity an adaptive response?

Answer 13

An adaptive response to famine, analogous to fat storage observed in other animals in preparation for periods of food scarcity.

Question 14

How was obesity proved to most probably not be positive selection?

Answer 14

In Western world despite plenty food supply, ~70% population not obese.

Question 15

What is the evidence for genetic contribution for obesity?

Answer 15

Inter-individual variation on BMI and body fatness

Animal model: ob/ob mice

Question 16

What kind of people were used in Inter-individual variation on BMI and body fatness tests?

Answer 16

Twins, adoptees and
family.

Question 17

What percentage of obesity was proved to be down to genetics through inter-individual variation?

Answer 17

25-40%

Question 18

What percentage of obesity was proved to be down to non-hereditary factors through inter-individual variation?

Answer 18

60 – 75%

Question 19

What was the major breakthrough found through the use of animal models on obesity?

Answer 19

Mutation of the ob (obese) gene results in severe obesity and type 2 diabetes.

Question 20

What is the ob gene?

Answer 20

Leptin

Question 21

What is the role of leptin?

Answer 21

Decreases appetite, body fat stores & insulin production.

Question 22

What is Leptin?

Answer 22

Satiety hormone.

Question 23

Where is Leptin produced?

Answer 23

Adipose tissue.

Question 24

Where is the adipose tissue?

Answer 24

Body Fat

Question 25

What are the 2 main types of obesity?

Answer 25

Monogenic Polygenic

Question 26

What is monogenic obesity?

Answer 26

Mendelian obesity, is inherited through a gene mutation.

Question 27

What is polygenic obesity?

Answer 27

Common obesity.

Question 28

How common is monogenic obesity?

Answer 28

Rare

Question 29

When does monogenic obesity start?

Answer 29

Early onset (childhood)

Question 30

When does polygenic obesity start?

Answer 30

Later onset

Question 31

What causes polygenic obesity?

Answer 31

Environment and slightly SNPs.

Question 32

How do monogenic mutations lead to obesity?

Answer 32

Defect in the satiety centres in the brain Defect in the appetite control centres in the brain

Question 32

What does a defect in the satiety centres in the brain lead to?

Answer 32

Loss of Leptin signalling.

Question 33

What is Congenital Leptin Deficiency?

Answer 33

Extremely rare mutations in the LEP gene– no leptin.

Question 34

What is Leptin Receptor deficiency?

Answer 34

Rare mutations in LEPR gene – no response to leptin

Question 35

What kind of inheritance do monogenic obesity diseases follow?

Answer 35

Autosomal recessive.

Question 36

What is the consequence of Loss of Leptin signalling?

Answer 36

Excessive hunger leads to severe obesity Decrease in the production of hormones directing sexual development and reproductive function Hyperinsulinemia

Question 37

What is Hyperinsulinemia?

Answer 37

Insulin Resistance

Question 37

What do monogenic mutations that lead to a defect in the brain appetite control centres?

Answer 37

POMC pathway defects.

Question 38

What is the POMC pathway?

Answer 38

The melanocortin pathway The fed state is signalled by the abundance of circulating hormones such as leptin and insulin Bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote the processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH).

Question 39

What is ACTH?

Answer 39

Adrenocorticotropic hormone

Question 40

What is the role of ACTH?

Answer 40

Stimulates cortisol release by adrenal glands

Question 41

What are α-MSH and β-MSH?

Answer 41

Melanocyte-stimulating hormone

Question 42

What is the role of α-MSH and β-MSH?

Answer 42

Weight regulation & energy balance maintenance Skin pigmentation (melanin production)

Question 43

What are β-endorphin?

Answer 43

Endogenous opiates

Question 44

What are Met-encephalin?

Answer 44

Endogenous opiates

Question 45

What is POMC?

Answer 45

Proopiomelano cortin

Question 46

What is the role of POMC?

Answer 46

Extensively cleave into multiple peptide hormones

Question 47

What happens when mutations occur in POMC?

Answer 47

Damaged versions or absence of POMC Decreased levels (or loss) of ACTH, α-MSH, and β-MSH Dysregulation of body's energy balance Excessive hunger→ excessive feeding & severe obesity

Question 48

What happens when an individual has POMC deficiency?

Answer 48

An autosomal recessive disorder causing severe obesity, red hair and pale skin.

Question 49

What are POMC-neurons activated by?

Answer 49

Leptin and Insulin

Question 50

What is the role POMC-neurones produce?

Answer 50

Produce α-MSH which activates melanocortin (MC4R & MC3R) receptors & increase the satiety signal.

Question 51

What is the role of Neurons (NPY /AGRP)?

Answer 51

Express NPY & AGRP Inhibit MC4R and POMC neurons signalling resulting in an increased appetite.

Question 52

What is NPY?

Answer 52

Neuropeptide Y

Question 53

What is AGRP?

Answer 53

Agouti-related protein

Question 54

What are Neurons (NPY/AGRP) activated by?

Answer 54

Ghrelin (‘hunger hormone’)

Question 55

How is leptin affected in mendelian obesity?

Answer 55

Mutations reduce signalling Obesity Leptin gene affected and there's a decrease in circulating leptin LEPR gene which is resistance to leptin

Question 56

How is Leptin affected in common/polygenic obesity?

Answer 56

High circulating concentrations of leptin and are ‘leptin resistant’. This means there is an issue with access to the brain or of downstream signalling pathway.

Question 57

What genetics association in common obesity?

Answer 57

Genetic associations exist between candidate genes and obesity-related phenotypes.

Question 58

What SNPs involved in the leptin/melanocortin pathway have a positive genetic association with the risk of obesity?

Answer 58

* AGRP * LEPR * MC4R * NPY * POMC

Question 59

What is the fat mass and obesity-associated protein?

Answer 59

mRNA demethylase

Question 60

Where is the FTO?

Answer 60

Highly expressed in hypothalamus

Question 61

What is the SNP(rs9939609) in FTO gene, risk allele linked to?

Answer 61

Decrease in Satiety Increase in food intake Increase Ghrelin expression and leptin resistance

Question 62

What is an Odds ratio?

Answer 62

Relative probabilities of the occurrence of the outcome given a particular genotype for an SNP.