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MBB334 - Biochemical Basis of Human Disease > Williamson - Obesity etc. > Flashcards

Williamson - Obesity etc. Flashcards

1
Q

What is the worldwide (and UK) leading cause of death?

A
  • heart disease
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2
Q

What are the main causes of heart diseases, and what do they have in common?

A
  • smoking, obesity, high BP

- all treatable and to some extent preventable (but are genetic elements)

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3
Q

Apart from heart disease what are other major causes of death in the UK?

A
  • stroke
  • cancer
  • liver disease
  • dementia
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4
Q

Worlwide, what is the 2nd leading cause of death?

A
  • infectious disease (big effect in causing chronic illness)

- major ones are malaria, TB, HIV

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5
Q

What is the biochemical basis of obesity?

A
  • low level inflam response
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6
Q

What diff processes does inflam induce?

A
  • increased blood flow (to bring in cells with spec roles, eg. leucocytes, and wash out causative agents and dead cells, platelets to cause blood clots, esp in cuts)
  • accum of leucocytes in damaged tissue (so can induce effects)
  • increased permeability of endothelial cells lining blood vessels (blood leaks out into surrounding tissue) –> want leucocytes in tissue
  • enables leucocytes to damaged tissues, kill infection and create barrier (if tissue damage eg. a cut)
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7
Q

What are the 4 signs of inflam?

A
  • oedema (swelling)
  • heat –> due to vasodilation
  • erythema
  • pain
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8
Q

By what cells are PGs prod?

A
  • endothelial cells or leucocytes
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9
Q

Are PGs autocrine, paracrine or endocrine, and why?

A
  • can be either autocrine or paracrine

- not endocrine, as do not originate from endocrine glands but from a wide range of cells

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10
Q

How are PGs prod?

A
  • by oxidation of FAs (usually arachidonic acid) by cyclooxygenase (COX) which cat arachidonic acid –> prostaglandin H2 –> lots of diff products, inc thromboxane and other prostacyclin
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11
Q

What are 2 types of PGs?

A
  • prostacyclin

- thromboxanes

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12
Q

What cells prod prostacyclin, and what is its role?

A
  • vasodilator
  • made by endothelial cells
  • inhibits aggreg of platelets (stops blood clotting as trying to increase blood flow), so stim inflam and migration of leucocytes into tissue
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13
Q

What cells prod thromboxane and what is its role?

A
  • made by platelets
  • have opp effect to prostacyclins
  • vasoconstrictors and promote platelet aggreg (blood clots)
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14
Q

Why are both prostacyclins and thromboxanes req in inflam response?

A
  • initially want to promote blood flow to eg. cut, then want blood clotting
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15
Q

What is the effect of inhibiting synthesis of prostacyclin?

A
  • prevent vasodilation and reduce inflam
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16
Q

What is the effect of inhibiting synthesis of thromboxane?

A
  • opp to prostacyclin

- prevent vasoconstriction and increase inflam

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17
Q

What is blood clotting an essential response to?

A
  • tissue damage
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18
Q

Why does blood clotting need to be tightly reg?

A
  • to prevent unwanted blood clots (=thrombosis) or too much bleeding
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19
Q

What is the process of blood clotting?

A
  • starts w/ platelet activation, form mesh that is blood clot
  • turn from roundish cells that move easily through bloodstream to shape w/ projections (more complex) so stick to each other/other things
  • also release various signals, inc thromboxane A2, activates other platelets
  • signals activate series of proteolytic reactions
  • at same time damaged tissue causes changes in prots circulating in blood
  • ultimately activate prothrombin to thrombin (cleaved) and thus convert fibrinogen to fibrin (=sticks platelets together)
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20
Q

How is blood clotting usually inhibited?

A
  • by various factors released by endo cells

- among which is prostacyclin I2, which inhib platelet activation

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21
Q

What are NSAIDs also known as?

A
  • cyclooxygenase (COX) inhibitors
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22
Q

What do NSAIDs do?

A
  • reduce inflam

- reduce fever and headaches

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23
Q

Why can steroids be used to control inflam?

A
  • natural regulators of inflam

- esp corticosteroids

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24
Q

What is the disadvantage of using steroids?

A
  • lots of side effects, as target lots of cells, lot of LT effects
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25
Q

How does aspirin work?

A
  • an NSAID
  • inhibits COX, by irreversibly acetylating it
  • reduction of thromboxane synthesis reduces clotting
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26
Q

Apart from as a painkiller, how can aspirin be used?

A
  • taken at low levels to reduce blood clotting and therefore risk of heart attacks
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27
Q

Why are we now moving to other NSAIDs, such as ibuprofen, instead of aspirin?

A
  • aspirin leads to gastric bleeding, as PGs protect stomach lining –> stomach ulcers
  • other NSAIDs have less effects on gastric irritation
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28
Q

What does paracetamol inhibit?

A
  • COX-2 isoform
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29
Q

Why do aspirin and paracetamol have lots of other pharmacological effects?

A
  • don’t work just as COX inhibitors, so lots of poss side effects
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30
Q

Why do NSAIDs make good drugs?

A
  • small
  • soluble
  • bind lots of things
  • great at getting into body to cause effects
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31
Q

How do NSAIDs effects on COX-1/2 differ?

A
  • most inhibit them equally
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32
Q

Why is COX-2 a better target than COX-1?

A
  • inhibiting COX 2 more likely to affect inflam (as COX-2 mainly found in inflamed tissues)
  • so COX-2 inhibitor should reduce inflam but not cause gastric irritation
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33
Q

How do roles of COX-1 and 2 differ?

A
  • involved diff in synthesis of prostacyclins and thromboxanes
  • COX-2 seems more important for making prostacyclins, but less important for thromboxanes –> so inhibition may increase thrombosis risk
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34
Q

Why was the COX-2 inhibitor Vioxx eventually withdrawn from the market?

A
  • clinical trials showed increased risk of heart attacks w/ high doses
  • small trials showed 3-8x increased risk –> but not stat signif
  • but don’t want to stop making a drug on basis of something that might be a coincidence
  • eventually was withdrawn due to concerns over cardiovascular risk
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35
Q

What BMI is defined as obese?

A
  • over 30
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36
Q

How is BMI calc?

A
  • mass (kg) / height (m)^2
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37
Q

Generally what is obesity a consequence of?

A
  • consuming more energy intake than body needs
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38
Q

What is the energy value of a calorie?

A
  • 1kcal - 4.2kJ
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39
Q

Is most losing/gaining of weight fat?

A
  • no, in the ST gen water
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40
Q

What are the main food categories?

A
  • carbs
  • fats
  • prots
  • fibre
  • also mineral and vitamins (but v small amounts)
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41
Q

What is fibre?

A
  • indigestible food material, mainly plant cellulose, no nutritive value, bulks up food and helps digestion and excretion
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42
Q

How do plants store sugars?

A
  • as starch (in fruits and veg)
  • lots of glucose in starch
  • not easy to digestm so energy released slowly
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43
Q

What is our main intake of sugars now?

A
  • sweet food and sugary drinks –> mainly refined sucrose
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44
Q

In evo terms, why is the body not set up to deal w/ sugars, esp refined sugars?

A
  • historically low fraction of European diet –> meat/ fish have little, fruit has fructose and some sucrose, milk contains lactose
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45
Q

In what foods is fat mainly found?

A
  • meat/fish (and seeds)
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46
Q

Why is eating fats important?

A
  • inc cholesterol –> essential for mem function
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47
Q

How do fats provide flavours?

A
  • many flavours are fat soluble
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48
Q

What is the main fat in animals (and humans), and where is it stored?

A
  • triglycerides

- stored in adipose tissue

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49
Q

Why is protein so important?

A
  • all machinery and most structural components of cells are made of proteins
  • muscle = proteins
  • essential AAs that must come from diet, as can’t make them
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50
Q

How do animal and plant energy stores differ?

A
  • animals store most energy as fat

- plants as carbs (starch)

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51
Q

Why don’t animals store energy as sugars?

A
  • get energy from food by burning it and sugars already have oxygen, so get less energy per gram than from fats
  • so less weight to carry around as fats (not a problem for plants)
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52
Q

Why do plants opt for storage as sugars?

A
  • sugars soluble in water, so simpler way to store
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53
Q

How is saliva important in sugar catabolism?

A
  • prod amylase to break down starch
54
Q

How are prots catabolised?

A
  • broken down to monomers, some receycling, then builds back up into prot
  • saliva important
  • stomach and gut contain a variety of enzymes to break proteins into AA and short peptides
  • then transported back into body, circulate in blood and take up in tissue and liver
55
Q

How is BSE caused?

A
  • when protein taken in by mouth isn’t broken down, so intact protein into bloodstream - so prot catabolism isn’t 100% efficient, but is generally v good
56
Q

Why is fat catabolism complicated?

A
  • insoluble
57
Q

How are triacylglyerides form diet catabolised and transported in body?

A
  • emulsified by bile salts, broken down by lipases and transported into mucus cells
  • reassembled into triacylglycerides (transp round body in blood, need to be enclosed in micelle as insoluble), so packaged into apolipoprotein bound chylomicrons
  • shorter chain FAs (< 14) do not need esterifying and transp as free FAs (in chylomicrons etc.)
58
Q

What is the structure of triacylglerides?

A

DIAG

59
Q

What level is blood glucose kept at?

A
  • around 5mM
60
Q

How are sugars in the diet catabolised in the body?

A
  • broken down to monosaccharides in gut
  • transp to epithelial gut cells and then into blood
  • in liver rapidly converted to glucose
61
Q

How is any excess glucose stored?

A
  • where poss as glycogen (until stores fill up) –> eg. muscle and liver cells have glycogen stores
62
Q

How is uptake, storage and release of sugars reg?

A
  • by insulin and glucagon
63
Q

What does prolonged excess glucose in diet affect?

A
  • insulin control –> TIID
64
Q

How does glucose reach the TCA cycle, and how is storage as fat related?

A
  • DIAG*
  • excess sugars converted to fat via acetyl CoA
  • can’t convert fat back to sugar –> so fat is final deposit for excess energy
  • only burn fat if don’t have sugars to burn, as body will burn sugars first
65
Q

How is fat important in evo terms?

A
  • as store of energy
  • needed for insulation
  • protection of body parts
  • source of hormones
66
Q

What is the thrifty gene hypothesis?

A
  • ST buildup of fat good, but chronic nutritional excess is bad (+ve selection for glucose and lipid metabolism)
67
Q

Why are sugars always preferred as energy source?

A
  • easier and quicker to use
68
Q

Are tissues limited to 1 energy source?

A
  • most can use range of energy sources
69
Q

How are energy needs met in ‘slow’ non-skeletal muscle, and why is this advantageous?

A
  • most energy needs met by conversion glucose to pyruvate
  • provides v little energy
  • but adv is pyruvate converted to lactate in muscle (makes bit more energy), which is then converted back to glucose = efficient recycling
70
Q

How are energy needs met in skeletal muscle?

A
  • can use glucose (= PREFERRED, from blood or glycogen)
  • or free FA (taken up directly or broken down from triacylglycerol)
  • or ketone bodies
71
Q

How are energy needs met for ‘fast twitch’ muscle (eg. in sprinting)?

A
  • almost entirely glucose to glycogen, as faster
72
Q

What tissues can only use glucose, and why?

A
  • erythrocytes, as no nucleus/mt and v little metabolism except glycolytic pathway
  • brain, if blood glucose drops below approx 3mM, stops working and go into coma
73
Q

What happens in starvation?

A
  • fat can be converted back to acetyl CoA and turned to ketone bodies, which can keep processes going, except brain, which is supplied glucose by breaking down prot (last resort as prot never intended as energy store)
74
Q

How much of obesity is genetically linked, and what does this mean?

A
  • twin and other genetic studies showed 70% obesity is genetically determined
  • 70% genetically determined = 70% variation in pop due to genetics (not about the indiv)
  • doesn’t mean cannot control fat, but is much easier for some people than others
75
Q

How might birth weight be linked to obesity risk?

A
  • low birth weight assoc w/ overweight children and also in adults
76
Q

What evidence is there that obesity is programmed early?

A
  • 75% obese children become obese adults, comp to 10% normal children
77
Q

What kind of interaction does the gut microbiome have w/ host?

A
  • metagenomic interactions
78
Q

How does the gut microbiome affect digestion, and how could this be relevant to obeisty ?

A
  • most digestion is by MOs in gut
  • affects efficiency at which food absorbed/digested
  • obese people have diff microbiomes, so extract more energy from food
79
Q

What evidence is there for the role of the gut microbiome in obesity?

A
  • in genetically identical mice, feed some on high fat diet and others on low fat diet, microbiome dev diff, subsequent switch to identical diets and obesity persists, as does microbiome
  • faecal transplants can change obesity markers (in mice)
80
Q

What is 1 suggestion for how microbiome becomes alt?

A
  • increased antibiotic use in children alt microbiome, increasing chance of obesity
81
Q

What do obese and people w/ IBD have in common?

A
  • reduced microbial complexity

- so could use faecal transplants to repop bowel after antibiotics?

82
Q

What do probiotics do?

A
  • introd diff bacteria into gut-

- evidence can change IR

83
Q

What are prebiotics?

A
  • nutrients that alt microbiome
84
Q

What are some diff health consequences of obesity, and how do they arise?

A
  • TIID = insulin resistance arising from high FFA
  • liver failure = increased circulating FFA
  • high BP = poss from insulin resistance (and other causes) → 50% of overweight people
  • cardiovascular disease = high LDL cholesterol, high BP
  • reduced fertility (males) = decreased testosterone, increased oestrogen (due to effect of fat on signalling)
  • polycystic ovaries (females)
  • breast and other cancers = increased oestrogen
    osteoarthritis = greater weight on joints
  • accidents and suicide = weight, body image, depression
  • obstructive sleep apnoea = fat deposits in neck and pharynx
  • gallstones = high circulating cholesterol
85
Q

Why can obesity be referred to as a metabolic syndrome?

A
  • essentially changes metabolism –> as lots going wrong at same time
86
Q

Apart from a fat store, what is adipose tissue?

A
  • an endocrine organ (secretes signals/hormones)
87
Q

What is the role of adipose tissue as a releaser of inflam mediators, in obestity?

A
  • obesity is essentially chronic low level inflam at all times –> blood conc of inflam markers lower after weight loss, suggesting adipose tissue releases inflam mediators
  • gen called adipokines, inc IL-6 → causes chronic ‘low grade’ inflam
88
Q

How can constant low grade inflam be a bad thing, eg. in relation to adipokines?

A
  • adipokines promote infiltration of immune cells (eg. macrophages) into adipose tissue
  • which can start vicious circle of inflam –> effectively like an autoimmune response, as adipose tissue is self
89
Q

What is a consequence of obesity increasing insulin resistance?

A
  • leads to changes in lipid metabolism, eg. higher LDL, increases risk of atherosclerosis
90
Q

How might adipose tissue contrib to insulin resistance and atherosclerosis?

A
  • also releases TNFα (chronic inflam signal)
  • also increases release of FFA from adipocytes, may be involved in insulin resistance
  • increases ROS prod (released by macrophages), causes oxidative stress and endothelial dysfunction (eg. reduction in NO release) → further increases risk of atherosclerosis
91
Q

Apart from IL-6, what is another adipokine released by adipose tissue, and what is its role?

A
  • leptin

- reduces appetite

92
Q

How do levels of inflam mediators alt after a meal, and how does this differ in obese people?

A
  • acute rise in inflam mediators - greater in obese people
93
Q

How do diff food effect inflam mediators released?

A
  • more antioxidants in food reduce inflam mediators (eg. vit C, E, carotenoids)
94
Q

How does reg of IS alt w/ age, and what is the consequence of this?

A
  • worsens, so chronic inflam arising from obesity likely to have more serious consequences as age
95
Q

What type of fat causes the most health problems?

A
  • visceral
96
Q

What are the 2 forms of adipocyte?

A
  • white adipose tissue (WAT)

- brown adipose tissue (BAT)

97
Q

What is the role of WAT, and how much of body weight does it make up?

A
  • stores energy in fat

- up to 25% of body weight in non-obese people

98
Q

What is the role of BAT?

A
  • lots of mito, burns fat to reg thermogenesis
99
Q

What animals have lots of BAT?

A
  • ones that hibernate
100
Q

How does BAT proportion change in humans as they age?

A
  • decreases
101
Q

Why is BAT prob healthier than WAT?

A
  • takes fat from WAT and burns it

- more BAT have the better, as metabolically active, prop between them affects health

102
Q

What stim BAT usage, and what might this mean?

A
  • stim by low external temp, so central heating could be bad (western problem, contrib to more obesity?)
  • also stim by fasting, which also alt gut microbiota
103
Q

What is BAT made up of, and where is this derived?

A
  • mixture of true BAT derived from monocyte precursor cells, plus beige adipose tissue derived from adipocyte precursor cells
104
Q

What enz stim BAT activity?

A
  • sirtuin
105
Q

What is the role of sirtuin?

A
  • deacetylase, removes acetyl groups eg. in histones, so changes gene reg, affects epigenetics
106
Q

What response is sirtuin thought to be involved in?

A
  • response to starvation

- as upreg during low calorie intake and lead to enhanced β-ox of fats and increased gluconeogenesis

107
Q

The correl between what 2 things may be due to sirtuin?

A
  • strong +ve correl between long life and low calorie intake
108
Q

What is the result if leptin KO?

A
  • overweight
109
Q

What is the role of leptin?

A
  • reg appetite, by reducing it and leading to increase in FA ox, increase in insulin sensitivity and increased energy expenditure
110
Q

How does leptin reg appetite?

A
  • -ve feedback mech –> increased adipose tissue reduces fat accum
111
Q

Why can’t leptin be given as a drug?

A
  • pro inflam and increases risk of atherosclerosis
112
Q

Are leptin mutations a major problem in obese people?

A
  • no, as obesity not caused by 1 gene and most obese people have lots of leptin
113
Q

How does leptin affect BAT?

A
  • stim thermogenesis in BAT via mt uncoupling
114
Q

What is the result of defects in leptin receptor?

A
  • cause similar phenotype to leptin KO
115
Q

What are some other genes that have been linked w obesity?

A

MCR4
Various others in same pathway –> all affect appetite
Mt uncoupling prots

116
Q

What is the most common single gene form of obesity?

A
  • MCR4

- in 2-6%

117
Q

What was the 1st gene identified by GWAS to be assoc w/ BMI?

A
  • FTO (fat mass and obesity related)
118
Q

What is the role of FTO?

A
  • encodes an α-ketoglutarate dep dioxygenase –> cat demeth of mRNA
119
Q

What role does FTO play in obesity?

A
  • increases obesity risk by 20% and affects what kind of obesity you have –> but only accounts for about 1% of heritability, so not common cause
  • stim dev of precursor adipose cells to WAT rather than beige
120
Q

Why can’t we just downreg FTO, if its deficiency protects against obesity?

A
  • fams w/ LoF change in FTO have severe dev problems
121
Q

What is nearly 18% of heritable variance in gene exp in obesity due to, and how?

A
  • not SNPs, but changes in copy no. (ie. copt no. variants)
  • lots of CNVs in humans
  • increased copy no. of obesity related genes may increase risk of obesity
122
Q

By what mech does ER deal w/ unfolded or partially unfolded prots?

A
  • unfolded protein response (UPR)
123
Q

What does UPR consist of?

A
  • halt prot translation
  • degrade unfolded prots (eg. by proteasome)
  • induce expression of chaperones (help folding of badly folded prots)
124
Q

How does chronic high calorie intake lead to UPR?

A
  • leads to high levels circulating FAs –> messes up ER, leads to ‘ER stress’, leads to UPR
125
Q

How is ER stress implicated in insulin sensitivity?

A
  • ER stress prod insensitivity to insulin signalling –> also prod range of inflam signals designed to help stressed cells to cope
126
Q

When is UPR good, and when is it a bad thing?

A
  • gen UPR useful as ST response, but leads to inflam and insulin resistance when permanently over activated
  • doesn’t help that cells that have apoptosed recruit inflam mediators, eg. macrophages
127
Q

Are anti-obesity drugs available?

A
  • several are, but not v effective in most cases
128
Q

What is the best method to combat obesity?

A
  • reduction in calorie intake and exercise –> ie. lifestyle changes
129
Q

What are the disadvs of anti obesity drugs?

A
  • often side effects, eg. cardiovascular
130
Q

What is VLDL, and what does it contain?

A
  • VLDL = packages of fat that get transp round body in blood, also contain cholesterol
131
Q

How are lipids catabolised?

A
  • lipids pass into lymph system and then into blood
  • when reach target (where stored/needed), broken down again
  • attached to CoA for beta-ox or re-esterified for storage
  • liver can oxidise FAs to ketone bodies which are soluble 4-C molecules and used eg. by muscle

MBB334 - Biochemical Basis of Human Disease (7 decks)

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