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Molecular Biology of Disease > Obesity > Flashcards

Obesity Flashcards

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1
Q

Can obesity effect likelihood of other disease occurrence?

A

Yes - it predisposes us to a wide range of mental and physical diseases.

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2
Q

What is obesity?

A

A disproportionate body weight for height, with an excessive accumulation of adipose tissue. BMI > 30 (weight in kg / height in m^2).

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3
Q

How does fat accumulate in obesity?

A

Once adipose tissue has reached its limit for accumulating excess fat, there is a spill over of lipid into other tissues e.g. the liver.

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4
Q

What are implications of pear shaped obesity?

A
  • Increased subcutaneous fat (hips and thighs)
  • Low risk of diabetes
  • Low risk of metabolic syndrome
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5
Q

What are implications of apple shaped obesity?

A
  • Increased visceral fat (around middle / internal organs)
  • High risk of diabetes
  • High risk of metabolic syndrome
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6
Q

When does obesity occur?

A

When there is greater energy intake than expenditure, or the body is not able to properly regulate the energy balance.

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7
Q

What impacts our energy intake?

A
  • Diet (high carb, high fat foods contribute a lot of calories)
  • Nervous system
  • Endocrine system
  • Microbiota
  • Stress or emotional factors
  • Medications
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8
Q

What impacts our energy expenditure?

A
  • Exercise level (impacted by our surroundings, e.g. city vs country, gyms available etc)
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9
Q

What impacts our susceptibility to obesity?

A
  • Genetics - 30-60% of weight gain is due to genetic factors.
  • Hypothalamic tumours or lesions (cause obesity development).
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10
Q

Why was obesity not taken seriously as a genetic condition?

A

It was thought that it could easily be controlled by lifestyle until the 1950s.

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11
Q

How did we discover genetics has a large impact on obesity?

A

Twin studies - identical twins exposed to different environments still have similar weight gain. i.e. environment had little influence.

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12
Q

What is parabiosis?

A

Surgical union of two organisms allowing sharing of the blood circulation

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13
Q

What did parabiosis experiments in db/db and WT rats reveal?

A

db/db mutations produce a circulating factor that causes starvation in a WT animal.

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14
Q

Which mutations predispose mice to obesity?

A

ob/ob and db/db (recessive)

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15
Q

What symptom does ob/ob and db/db genotypes cause?

A

Hyperphagia (extreme hunger / never feeling full).

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16
Q

What did parabiosis experiments in rats with hypothalamic lesions and WT rats reveal?

A

Hypothalamic lesions produce a circulating factor that causes starvation in a WT animal.

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17
Q

What did parabiosis experiments in ob/ob and WT rats reveal?

A

The WT rats produce a circulating factor that causes the ob/ob rats to decrease food intake, lose weight and become healthier. The ob/ob mice did not lose weight to the point of death.

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18
Q

What did parabiosis experiments in ob/ob and db/db rats reveal?

A

ob/ob mice are responsive to a circulating satiety factor that db/db mice overproduce but are not responsive to themselves.

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19
Q

Why do db/db mice become obese?

A

They are unresponsive to a circulating satiety factor they produce (mutation in receptor).

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20
Q

Why do ob/ob mice become obese?

A

They do not produce a circulating satiety factor (in sufficient quantities to regulate its weight).

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21
Q

How does the ob mutation affect leptin?

A

It is a non-sense mutation so produces a truncated, non-functional form of leptin.

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22
Q

How does the db mutation affect leptin?

A

Leptin is overproduced because there is no response to it due to mutated receptor.

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23
Q

Where is the leptin receptor located?

A

The arcuate nucleus of the hypothalamus.

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24
Q

What is leptin?

A

A hormone secreted by adipocytes, which circulates at levels in proportion to fat mass and is an indicator of nutritional state. It regulates body weight.

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25
Q

What happens when the NPY/AgRP neurons in the arcuate nucleus are targeted by leptin?

A

They are inhibited so appetite is not stimulated (NPY/AgRP are orexigenic).

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26
Q

What happens when the POMC neurons in the arcuate nucleus are targeted by leptin?

A

They are activated and appetite is suppressed (POMC are anorexigenic).

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27
Q

Where are signals from the arcuate nucleus sent?

A

Paraventricular nucleus then onto higher brain function.

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28
Q

How are NPY/AgRP neurons orexigenic?

A

When activated they secrete AgRP, which stimulates food intake through blocking of the melanocortin 4 receptor (MC4R).

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29
Q

How are POMC neurons anorexigenic?

A

When activated they secrete α-melanocyte-stimulating hormone (α-MSH), which activates MC4R to inhibit food intake.

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30
Q

What kind of system is body weight homeostasis by leptin?

A

Negative feedback

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31
Q

Is appetite drive on or off or finely balanced?

A

Finely balanced - the α-MSH agonism and AgRP antagonism of MC4R, in response to peripheral nutritional cues such as leptin can alter appetite drive in subtle ways.

32
Q

What can the MC4R receptor be thought of as?

A

A rheostat; activation is adaptive to conditions.

33
Q

Mutations in which genes can be linked to obesity?

A

Any genes in the melanocortin pathway e.g. POMC, MC4R. Not just leptin and leptin receptor.

34
Q

What is the melanocortin pathway?

A

A neural system that regulates many bodily functions, including energy homeostasis, food intake, and body weight.

35
Q

Why are labradors and retrievers often used as service dogs?

A

They have a mutation in their POMC gene so their appetite is always stimulated, they have greater food motivation and are therefore easier to train.

35
Q

Do appetite controlling hormones from the intestine confer short or long term appetite control?

A

Short term

35
Q

Which appetite controlling hormones are secreted by the intestine?

A

GLP1, CCK, PYY, GIP

36
Q

Does leptin confer short or long term appetite control?

A

Long term

37
Q

Which appetite controlling hormone is secreted by the stomach?

A

Ghrelin

38
Q

Which appetite controlling hormones are secreted by the pancreas?

A

Insulin, glucagon

39
Q

What does GLP1 do?

A

Activates POMC neurons - suppresses appetite (satiety signal). Also reduces metabolism. Targets a range of organs.

40
Q

What does ghrelin do?

A

Activates NPY/AgRP neurons – stimulates appetite (hunger signal).

41
Q

What does PYY do?

A

Inhibits NPY/AgRP neurons - suppresses appetite (satiety signal).

42
Q

What does GIP do?

A

Its function is not fully characterised.

43
Q

What is monogenic obesity?

A

Early-onset, severe obesity.
- Genetic cause (single mutation on 1 gene)
- Rare
- High penetrance
- No environmental influence

44
Q

What is polygenic obesity?

A

Common obesity.
- Smaller genetic contribution (each variant has a small effect)
- Hundreds of variants in or near many genes
- Common
- Low penetrance
- Environment is a key determinant

45
Q

Which appetite regulating genes were characterised first?

A

Those expressed in the brain.

46
Q

How do we study the genetics of polygenic obesity?

A

GWAS.

47
Q

Why can genes like leptin be implicated in mono and polygenic obesity?

A

Different types of mutation e.g. non sense vs substitution. Some have a more minor effect than others.

48
Q

How does GWAS work?

A

Investigates if the allele of a genetic variant is found more often than expected (also do a control) in individuals with the disease being studied.

49
Q

Which locus is commonly associated with obesity?

A

The FTO locus, but we cannot yet define the mutated genes within it (FTO gene, loci nearby and trans-acting elements are implicated) and the mechanisms they impact that cause obesity. Many results suggest different things.

50
Q

Can epigenetic regulation change likelihood of obesity?

A

Yes - there is epigenetic regulation of many obesity related genes.

51
Q

Can epigenetic changes in a mother impact the child’s likelihood of becoming obese / experiencing metabolic disease?

A

Yes - children conceived during famine are much more likely to experience metabolic disease - inherited epigenetic changes from mother.
In other cases children can be protected by their parent’s epigenetic marks that they have inherited.

52
Q

How do we treat (monogenic) leptin deficiency?

A

Administer synthetic leptin.

53
Q

Can leptin be used to target obesity which doesn’t have genetic origin?

A

No - people who are obese overproduce leptin anyway! Usually the problem is with the response to leptin in these cases.

54
Q

What happens when there is too much circulating leptin?

A

The brain becomes overwhelmed and develops a resistance, signalling low leptin levels and hunger. This creates the obesity cycle.

55
Q

How do we treat POMC deficiency?

A

Setmelanotide; used as a replacement for MSH (binds MC4R) (which can’t be produced by POMC) to signal for a decreased appetite.

56
Q

How do we treat leptin receptor deficiency?

A

Setmelanotide; leptin receptor is essential for POMC function so treated the same as POMC deficiency.

57
Q

How do we treat morbid polygenic obesity?

A

Bariatric (gastric bypass) surgery.

58
Q

What is bariatric surgery?

A

Creation of a small pouch from the stomach and connecting it to the small intestine. Makes patient feel full after eating less, plus their body doesn’t absorb all the calories from their food.

59
Q

What are short term risks of bariatric surgery?

A

Risks associated with surgery.

60
Q

What are long-term risks associated with bariatric surgery?

A
  • Bowel obstruction
  • Stomach perforation
  • Ulcers
  • Vomiting
61
Q

Why has finding anti obesity drugs been so challenging?

A

They are often accompanied by dramatic side effects e.g. cardiotoxicity, stroke risk, cancer risk

62
Q

What are recent obesity breakthrough drugs manufactured using biological understanding?

A

Ozempic and wegovy.

63
Q

What are ozempic and wegovy?

A

A peptide called semaglutide that is orthologous to GLP1. They mimic GLP1 effects (lower blood sugar, suppress appetite, produce faster sense of fullness).

64
Q

What type of hormone are GLP1 and GIP?

A

Incretins

65
Q

How is semaglutide different to GLP1

A

It has been modified e.g. fatty acid chain added, to have a longer half life (GLP1 degraded within 1.5-5 minutes).

66
Q

How much does ozempic reduce body weight by?

A

15% over 68 weeks (2.4mg dose per week). In obese / overweight people without diabetes.

67
Q

What are ozempic side effects?

A

Nausea / vomiting, diarrhoea, constipation

68
Q

What is the problem with using GWAS to identify genetic contributions to obesity?

A

We are finding lots of rare variants in lots of different genes - not helpful for developing a widespread effective treatment.

69
Q

Which simple model organism can be utilised for diabetes study?

A

Drosophila melanogaster! They have lots of human disease genes conserved.

70
Q

What happens when flies are raised on a high fat diet?

A

They become obese; develop cardiomyopathy and diabetic phenotypes. They have analogous metabolic systems and hormones to us.

71
Q

How do we use Drosophila melanogaster to understand the genetic basis of obesity?

A
  • Identify human genes with rare variants in severe obesity
  • Identify orthologous Drosophila genes
  • Drosophila functional screens
72
Q

Which pathway has Drosophila study implicated as a contributor to obesity?

A

Hippo pathway

73
Q

What factors can contribute to the development of obesity?

A
  • Individual
  • Social and family environment
  • Organisations and institutions
  • Communities
  • Public policies

Molecular Biology of Disease (4 decks)

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