Genetic Determinants of Obesity Flashcards

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1
Q

What is obesity?

A

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

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2
Q

What is obesity a risk factor for?

A

Cardiovascular diseases

Type 2 Diabetes

Several cancers

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3
Q

What are some causes of obesity?

A

– Genetic
– Epigenetic
– Environmental

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4
Q

What are the obesity-related traits?

A

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

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5
Q

What is dylipidemia?

A

High cholesterol

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6
Q

What is hypertension?

A

High blood pressure

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7
Q

What is BMI?

A

mass (kg) / height (m2)

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8
Q

What is considered underweight?

A

Less than 18.5

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9
Q

What is considered a healthy BMI?

A

18.5-25

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10
Q

What is considered an overweight BMI?

A

25-30

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11
Q

What is considered an obese BMI?

A

More than 30.

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12
Q

What is the correlation between BMI and obesity?

A

A high BMI increases cancer risk.

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13
Q

How is obesity an adaptive response?

A

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

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14
Q

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

A

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

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15
Q

What is the evidence for genetic contribution for obesity?

A

Inter-individual variation on BMI and body fatness

Animal model: ob/ob mice

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16
Q

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

A

Twins, adoptees and
family.

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17
Q

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

A

25-40%

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18
Q

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

A

60 – 75%

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19
Q

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

A

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

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20
Q

What is the ob gene?

A

Leptin

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21
Q

What is the role of leptin?

A

Decreases appetite, body fat stores & insulin production.

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22
Q

What is Leptin?

A

Satiety hormone.

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23
Q

Where is Leptin produced?

A

Adipose tissue.

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24
Q

Where is the adipose tissue?

A

Body Fat

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25
Q

What are the 2 main types of obesity?

A

Monogenic

Polygenic

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26
Q

What is monogenic obesity?

A

Mendelian obesity, is inherited through a gene mutation.

27
Q

What is polygenic obesity?

A

Common obesity.

28
Q

How common is monogenic obesity?

A

Rare

29
Q

When does monogenic obesity start?

A

Early onset (childhood)

30
Q

When does polygenic obesity start?

A

Later onset

31
Q

What causes polygenic obesity?

A

Environment and slightly SNPs.

32
Q

How do monogenic mutations lead to obesity?

A

Defect in the satiety centres in the brain

Defect in the appetite control centres in the brain

32
Q

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

A

Loss of Leptin signalling.

33
Q

What is Congenital Leptin Deficiency?

A

Extremely rare mutations in the LEP gene– no leptin.

34
Q

What is Leptin Receptor deficiency?

A

Rare mutations in LEPR gene – no response to leptin

35
Q

What kind of inheritance do monogenic obesity diseases follow?

A

Autosomal recessive.

36
Q

What is the consequence of Loss of Leptin signalling?

A

Excessive hunger leads to severe obesity

Decrease in the production of hormones directing sexual development and reproductive function

Hyperinsulinemia

37
Q

What is Hyperinsulinemia?

A

Insulin Resistance

37
Q

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

A

POMC pathway defects.

38
Q

What is the POMC pathway?

A

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).

39
Q

What is ACTH?

A

Adrenocorticotropic hormone

40
Q

What is the role of ACTH?

A

Stimulates cortisol release by adrenal glands

41
Q

What are α-MSH and β-MSH?

A

Melanocyte-stimulating hormone

42
Q

What is the role of α-MSH and β-MSH?

A

Weight regulation & energy balance maintenance

Skin pigmentation (melanin production)

43
Q

What are β-endorphin?

A

Endogenous opiates

44
Q

What are Met-encephalin?

A

Endogenous opiates

45
Q

What is POMC?

A

Proopiomelano cortin

46
Q

What is the role of POMC?

A

Extensively cleave into multiple peptide hormones

47
Q

What happens when mutations occur in POMC?

A

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

48
Q

What happens when an individual has POMC deficiency?

A

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

49
Q

What are POMC-neurons activated by?

A

Leptin and Insulin

50
Q

What is the role POMC-neurones produce?

A

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

51
Q

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

A

Express NPY & AGRP

Inhibit MC4R and POMC neurons signalling resulting in an increased appetite.

52
Q

What is NPY?

A

Neuropeptide Y

53
Q

What is AGRP?

A

Agouti-related protein

54
Q

What are Neurons (NPY/AGRP) activated by?

A

Ghrelin (‘hunger hormone’)

55
Q

How is leptin affected in mendelian obesity?

A

Mutations reduce signalling

Obesity Leptin gene affected and there’s a decrease in circulating leptin

LEPR gene which is resistance to leptin

56
Q

How is Leptin affected in common/polygenic obesity?

A

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.

57
Q

What genetics association in common obesity?

A

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

58
Q

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

A
  • AGRP
  • LEPR
  • MC4R
  • NPY
  • POMC
59
Q

What is the fat mass and obesity-associated protein?

A

mRNA demethylase

60
Q

Where is the FTO?

A

Highly expressed in hypothalamus

61
Q

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

A

Decrease in Satiety

Increase in food intake

Increase Ghrelin expression and leptin resistance

62
Q

What is an Odds ratio?

A

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