Williamson - Obesity etc. Flashcards
(131 cards)
1
Q
What is the worldwide (and UK) leading cause of death?
A
- heart disease
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)
3
Q
Apart from heart disease what are other major causes of death in the UK?
A
- stroke
- cancer
- liver disease
- dementia
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
5
Q
What is the biochemical basis of obesity?
A
- low level inflam response
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)
7
Q
What are the 4 signs of inflam?
A
- oedema (swelling)
- heat –> due to vasodilation
- erythema
- pain
8
Q
By what cells are PGs prod?
A
- endothelial cells or leucocytes
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
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
11
Q
What are 2 types of PGs?
A
- prostacyclin
- thromboxanes
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
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)
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
15
Q
What is the effect of inhibiting synthesis of prostacyclin?
A
- prevent vasodilation and reduce inflam
16
Q
What is the effect of inhibiting synthesis of thromboxane?
A
- opp to prostacyclin
- prevent vasoconstriction and increase inflam
17
Q
What is blood clotting an essential response to?
A
- tissue damage
18
Q
Why does blood clotting need to be tightly reg?
A
- to prevent unwanted blood clots (=thrombosis) or too much bleeding
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)
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
21
Q
What are NSAIDs also known as?
A
- cyclooxygenase (COX) inhibitors
22
Q
What do NSAIDs do?
A
- reduce inflam
- reduce fever and headaches
23
Q
Why can steroids be used to control inflam?
A
- natural regulators of inflam
- esp corticosteroids
24
Q
What is the disadvantage of using steroids?
A
- lots of side effects, as target lots of cells, lot of LT effects
25
How does aspirin work?
- an NSAID
- inhibits COX, by irreversibly acetylating it
- reduction of thromboxane synthesis reduces clotting
26
Apart from as a painkiller, how can aspirin be used?
- taken at low levels to reduce blood clotting and therefore risk of heart attacks
27
Why are we now moving to other NSAIDs, such as ibuprofen, instead of aspirin?
- aspirin leads to gastric bleeding, as PGs protect stomach lining --> stomach ulcers
- other NSAIDs have less effects on gastric irritation
28
What does paracetamol inhibit?
- COX-2 isoform
29
Why do aspirin and paracetamol have lots of other pharmacological effects?
- don't work just as COX inhibitors, so lots of poss side effects
30
Why do NSAIDs make good drugs?
- small
- soluble
- bind lots of things
- great at getting into body to cause effects
31
How do NSAIDs effects on COX-1/2 differ?
- most inhibit them equally
32
Why is COX-2 a better target than COX-1?
- 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
33
How do roles of COX-1 and 2 differ?
- 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
34
Why was the COX-2 inhibitor Vioxx eventually withdrawn from the market?
- 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
35
What BMI is defined as obese?
- over 30
36
How is BMI calc?
- mass (kg) / height (m)^2
37
Generally what is obesity a consequence of?
- consuming more energy intake than body needs
38
What is the energy value of a calorie?
- 1kcal - 4.2kJ
39
Is most losing/gaining of weight fat?
- no, in the ST gen water
40
What are the main food categories?
- carbs
- fats
- prots
- fibre
- also mineral and vitamins (but v small amounts)
41
What is fibre?
- indigestible food material, mainly plant cellulose, no nutritive value, bulks up food and helps digestion and excretion
42
How do plants store sugars?
- as starch (in fruits and veg)
- lots of glucose in starch
- not easy to digestm so energy released slowly
43
What is our main intake of sugars now?
- sweet food and sugary drinks --> mainly refined sucrose
44
In evo terms, why is the body not set up to deal w/ sugars, esp refined sugars?
- historically low fraction of European diet --> meat/ fish have little, fruit has fructose and some sucrose, milk contains lactose
45
In what foods is fat mainly found?
- meat/fish (and seeds)
46
Why is eating fats important?
- inc cholesterol --> essential for mem function
47
How do fats provide flavours?
- many flavours are fat soluble
48
What is the main fat in animals (and humans), and where is it stored?
- triglycerides
| - stored in adipose tissue
49
Why is protein so important?
- 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
50
How do animal and plant energy stores differ?
- animals store most energy as fat
| - plants as carbs (starch)
51
Why don't animals store energy as sugars?
- 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)
52
Why do plants opt for storage as sugars?
- sugars soluble in water, so simpler way to store
53
How is saliva important in sugar catabolism?
- prod amylase to break down starch
54
How are prots catabolised?
- 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
How is BSE caused?
- 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
Why is fat catabolism complicated?
- insoluble
57
How are triacylglyerides form diet catabolised and transported in body?
- 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
What is the structure of triacylglerides?
*DIAG*
59
What level is blood glucose kept at?
- around 5mM
60
How are sugars in the diet catabolised in the body?
- broken down to monosaccharides in gut
- transp to epithelial gut cells and then into blood
- in liver rapidly converted to glucose
61
How is any excess glucose stored?
- where poss as glycogen (until stores fill up) --> eg. muscle and liver cells have glycogen stores
62
How is uptake, storage and release of sugars reg?
- by insulin and glucagon
63
What does prolonged excess glucose in diet affect?
- insulin control --> TIID
64
How does glucose reach the TCA cycle, and how is storage as fat related?
* 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
How is fat important in evo terms?
- as store of energy
- needed for insulation
- protection of body parts
- source of hormones
66
What is the thrifty gene hypothesis?
- ST buildup of fat good, but chronic nutritional excess is bad (+ve selection for glucose and lipid metabolism)
67
Why are sugars always preferred as energy source?
- easier and quicker to use
68
Are tissues limited to 1 energy source?
- most can use range of energy sources
69
How are energy needs met in 'slow' non-skeletal muscle, and why is this advantageous?
- 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
How are energy needs met in skeletal muscle?
- can use glucose (= PREFERRED, from blood or glycogen)
- or free FA (taken up directly or broken down from triacylglycerol)
- or ketone bodies
71
How are energy needs met for 'fast twitch' muscle (eg. in sprinting)?
- almost entirely glucose to glycogen, as faster
72
What tissues can only use glucose, and why?
- 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
What happens in starvation?
- 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
How much of obesity is genetically linked, and what does this mean?
- 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
How might birth weight be linked to obesity risk?
- low birth weight assoc w/ overweight children and also in adults
76
What evidence is there that obesity is programmed early?
- 75% obese children become obese adults, comp to 10% normal children
77
What kind of interaction does the gut microbiome have w/ host?
- metagenomic interactions
78
How does the gut microbiome affect digestion, and how could this be relevant to obeisty ?
- 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
What evidence is there for the role of the gut microbiome in obesity?
- 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
What is 1 suggestion for how microbiome becomes alt?
- increased antibiotic use in children alt microbiome, increasing chance of obesity
81
What do obese and people w/ IBD have in common?
- reduced microbial complexity
| - so could use faecal transplants to repop bowel after antibiotics?
82
What do probiotics do?
- introd diff bacteria into gut-
| - evidence can change IR
83
What are prebiotics?
- nutrients that alt microbiome
84
What are some diff health consequences of obesity, and how do they arise?
- 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
Why can obesity be referred to as a metabolic syndrome?
- essentially changes metabolism --> as lots going wrong at same time
86
Apart from a fat store, what is adipose tissue?
- an endocrine organ (secretes signals/hormones)
87
What is the role of adipose tissue as a releaser of inflam mediators, in obestity?
- 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
How can constant low grade inflam be a bad thing, eg. in relation to adipokines?
- 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
What is a consequence of obesity increasing insulin resistance?
- leads to changes in lipid metabolism, eg. higher LDL, increases risk of atherosclerosis
90
How might adipose tissue contrib to insulin resistance and atherosclerosis?
- 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
Apart from IL-6, what is another adipokine released by adipose tissue, and what is its role?
- leptin
| - reduces appetite
92
How do levels of inflam mediators alt after a meal, and how does this differ in obese people?
- acute rise in inflam mediators - greater in obese people
93
How do diff food effect inflam mediators released?
- more antioxidants in food reduce inflam mediators (eg. vit C, E, carotenoids)
94
How does reg of IS alt w/ age, and what is the consequence of this?
- worsens, so chronic inflam arising from obesity likely to have more serious consequences as age
95
What type of fat causes the most health problems?
- visceral
96
What are the 2 forms of adipocyte?
- white adipose tissue (WAT)
| - brown adipose tissue (BAT)
97
What is the role of WAT, and how much of body weight does it make up?
- stores energy in fat
| - up to 25% of body weight in non-obese people
98
What is the role of BAT?
- lots of mito, burns fat to reg thermogenesis
99
What animals have lots of BAT?
- ones that hibernate
100
How does BAT proportion change in humans as they age?
- decreases
101
Why is BAT prob healthier than WAT?
- takes fat from WAT and burns it
| - more BAT have the better, as metabolically active, prop between them affects health
102
What stim BAT usage, and what might this mean?
- 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
What is BAT made up of, and where is this derived?
- mixture of true BAT derived from monocyte precursor cells, plus beige adipose tissue derived from adipocyte precursor cells
104
What enz stim BAT activity?
- sirtuin
105
What is the role of sirtuin?
- deacetylase, removes acetyl groups eg. in histones, so changes gene reg, affects epigenetics
106
What response is sirtuin thought to be involved in?
- response to starvation
| - as upreg during low calorie intake and lead to enhanced β-ox of fats and increased gluconeogenesis
107
The correl between what 2 things may be due to sirtuin?
- strong +ve correl between long life and low calorie intake
108
What is the result if leptin KO?
- overweight
109
What is the role of leptin?
- reg appetite, by reducing it and leading to increase in FA ox, increase in insulin sensitivity and increased energy expenditure
110
How does leptin reg appetite?
- -ve feedback mech --> increased adipose tissue reduces fat accum
111
Why can't leptin be given as a drug?
- pro inflam and increases risk of atherosclerosis
112
Are leptin mutations a major problem in obese people?
- no, as obesity not caused by 1 gene and most obese people have lots of leptin
113
How does leptin affect BAT?
- stim thermogenesis in BAT via mt uncoupling
114
What is the result of defects in leptin receptor?
- cause similar phenotype to leptin KO
115
What are some other genes that have been linked w obesity?
MCR4
Various others in same pathway --> all affect appetite
Mt uncoupling prots
116
What is the most common single gene form of obesity?
- MCR4
| - in 2-6%
117
What was the 1st gene identified by GWAS to be assoc w/ BMI?
- FTO (fat mass and obesity related)
118
What is the role of FTO?
- encodes an α-ketoglutarate dep dioxygenase --> cat demeth of mRNA
119
What role does FTO play in obesity?
- 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
Why can't we just downreg FTO, if its deficiency protects against obesity?
- fams w/ LoF change in FTO have severe dev problems
121
What is nearly 18% of heritable variance in gene exp in obesity due to, and how?
- 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
By what mech does ER deal w/ unfolded or partially unfolded prots?
- unfolded protein response (UPR)
123
What does UPR consist of?
- halt prot translation
- degrade unfolded prots (eg. by proteasome)
- induce expression of chaperones (help folding of badly folded prots)
124
How does chronic high calorie intake lead to UPR?
- leads to high levels circulating FAs --> messes up ER, leads to ‘ER stress’, leads to UPR
125
How is ER stress implicated in insulin sensitivity?
- ER stress prod insensitivity to insulin signalling --> also prod range of inflam signals designed to help stressed cells to cope
126
When is UPR good, and when is it a bad thing?
- 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
Are anti-obesity drugs available?
- several are, but not v effective in most cases
128
What is the best method to combat obesity?
- reduction in calorie intake and exercise --> ie. lifestyle changes
129
What are the disadvs of anti obesity drugs?
- often side effects, eg. cardiovascular
130
What is VLDL, and what does it contain?
- VLDL = packages of fat that get transp round body in blood, also contain cholesterol
131
How are lipids catabolised?
- 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
