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Adiposity in Health and disease - Coggle Diagram
Adiposity in Health and disease
Part 1: Issues of fat distribution
Adiposity is not just a matter of how much you have, but how well it functions
‘Sick fat’ = adiposopathy concept (dysfunction in AT by adipocyte hypertrophic and visceral adiposity leading to disease= insulin resistance, met. syndrome, CVD). Is sick fat a CVD?
Obesity can lead to accumulation of blood TAG which accumulates in other tissues leading to lipotoxicity (insulin resistance and metabolic syndrome)
Adipogenesis: formulation of AT
Hyperplastic obesity- number of adipocytes increases
Hypertrophic obesity- size of adipocytes increases. Associated with high fat/sugar diet. More glucose/NEFA uptake from blood
Adipocyte size is a reflection of function. The larger the size, the less healthy the function
Adipose tissue expandability - increased AT associated with insulin resistance and other co-morbidities
Leads to impaired storage that leads to TAG spilling out into blood and flowing to other tissues
Leads to more fat which increases adipokines= more inflammation, antagonising insulin action
Larger the adipocyte (hypertrophic adipocyte), the more insulin resistant it becomes (less GLUT 4 which brings glucose into cell)
more FA released by lipolysis (less lipogenesis)= releases lipid into the blood (> lipaemic), reduced insulin sensitivity
Central adipocytes- especially visceral adipocytes are linked to disease because: the adipocytes are larger in size and they drain into the portal system (i.e. direct to liver)
How is VAT formed?
Limited SAT capacity for multiple causes
2.hypertrophic SAT cause lipid to spill out, taken up by liver and formed as VLDL and accumulate around other tissue as VAT
Lipotoxicity occurs: VAT lipids can form diacyglycerol and ceramide which affect insulin function and signalling in these tissues = more insulin resistant = Lipotoxicity
What is VAT linked with? Linked to insulin resistance, ectopic fat, compromised liver function, met. syndrome and cardiometabolic risk
How are VAT different to SAT? VAT are hypertrophic and more inflammatory due to immune cells compared to SAT (smaller and more insulin sensitive)
Portal vein theory:
VAT around organs so supplied by portal system (drains from gut to liver)
As VAT drains into portal, they are hyperlipolytic (sensitive to catecholamine stimulation and poorly responsive to insulin)
They are have a high NEFA flux to liver which increases VLDL synthesis, GNG, and ectopic fat accumulation and insulin increases
VAT only formed when compromised SAT capacity so marker of lipid overload
However, visceral adiposity is not necessarily guaranteed in obesity
Sumo wrestlers and prada-willis syndrome have high BMI but low VAT
some lean individuals have higher VAT than people who are obese (BMI not predictor of VAT storage)
Part 2: Determinants of fat distribution
Gender and ethnicity are clear determinants of fat distribution. Especially during periods of shifting energy balance
women preferentially store fat in lower body and men in upper body
women have higher lipid capacity storage in gluteal and thigh than men
women have higher LPL activity in abdominal, gluteal and thigh regions than men so > capacity to store fat subcutaneously
women have high aLPL (adipose LPL) and mLPL (muscle LPL) activity than men in fed state
Fat storage via LPL
Men have higher turnover / activity / functioning of upper SAT compared to female
women better NEFA turnover in SAT and slightly higher fat oxidation
Men have higher NEFA turnover in visceral
Fat storage difference between gender
women deposit x2 circulating NEFA in SAT compared to men
men more efficient at storing lipid in subcutaneous abdominal adipose tissue
Lipolysis differences between genders
Women: lipolysis is 40% relative to REE, 15% more circulating NEFA, higher lipolysis and fat oxidation rates during exercise, a 72 hour fast results in better SAT lipolysis (into systemic circulation) than men but men have better VAT lipolysis (into portal circulation)
Gender differences in adipose tissue: men have higher SAAT (subcutaneous abdominal AT) and VAT than women (women have more SAT)
Gender differences in weight gain: 1/2 peripheral (gluteal, femoral lower body) and 1/2 SAAT as female but with men, 95% SAAT/VAT
Ethnicity: south asians born with less SAT and greater SAT hypotrophy = leading to lipid overflow theory . Caucasians greater capacity to store fat subcutaneously
Subcutaneous Adipose Tissue capacity and function is key
Dietary NEFA and glucose stored as SAT and once filled, stored as visceral and this can overflow= ectopic fat and lipotoxicity. Females have more ‘buckets’ / SAT capacity
if you remove SAT via lipo. then fat stored as VAT sooner
Changes in menopause are associated with clear changes in fat distribution
increased action of androgen/ reduced estrogen shifts women to male phenotype of fat storage = SAAT / VAT > SAT.
estrogens decrease so less BAT (BAT increases energy expenditure)
Physically removing subcutaneous fat either has no impact or detrimental impact on health
liposuction to reduce SAAT has no change in metabolic / CV risk factors
thigh fat removal (thigh lipectomy) remains removed 1 year later but VAT increases compared to before lipectomy (redistribution of SAT to central AT) , with potential impact on metabolic and CV risk factors
Increased abdominal adipogenesis in response to lipo? decreased femoral LPL activity
Femoral lipectomy and postprandial lipaemia- decreased LPL activity femorally after lipo. which increases post-prandial lipaemia (diminished ability to remove dietary lipid)= increasing met. syndrome risk
Exercise can dissipate lipid plus adapt muscle as a functioning temporal store of lipid
Muscle (fat oxidation) can be seen as a ‘drain’ of VAT- lipid can be oxidised in muscle. Exercise can dissipate lipid plus adapt muscle as a functioning temporal store of lipid. VAT stores first to reduce when weight lost.
athlete paradox- athletes have lipid in muscle and obese people have lipid in muscle but compromised.(ceramide and diaglycerol releasing)
Part 3: Regulation and function of adipose tissue
Adipogenesis is the process of creating new adipocytes and is key to adipose tissue expandability (PPARy is a key regulator of this)
What is Sequential model of weight gain and insulin resistance? : either high proliferation and differentiation of fat cells or low profile ration and differentiation capacity
What is a key regulator of adipogenesis? PPARy
Why is the function of adiposity important? if obese and have lipodystrophy (not enough adipocytes) = more lipids in blood= ectopic fat= insulin resistance and met. syndrome
Lipid steal hypothesis concerns the ability to increase number of adipocytes (especially subcutaneous fat) in order to then more favourably redistribute fat
what is the Lipid steal hypothesis ? increase in PPARy increases adipose tissue capacity to store fatty acids. can give drugs (TZDs) which act as agonists (ligan activators), helping PPARy to increase AT mass (hyper plastic- increased number of AT) = store more lipid as SAT= decreased plasma FFA = less ectopic fat
What changes happened to body fat distribution in the 6 month troglitazone therapy trial (TZD). BMI increased but TAG lowered, glucose tolerance improved, VAT reduced and SAT increased
What effect do growth hormone and IGF-1 have on adipose tissue? if too much, AT unable to mature and if too little, AT becomes hypertrophic (‘sick fat’). Need normal GH signalling for healthy fat cells
Cortisol in combination with insulin is a key influence on storage or breakdown
How does the HPA axis affect fat distribution/ adiposity? 1. cortisol released from HPA axis firing. 2. VAT has high glucocorticoid receptors 3. central obesity associated with hyper sensitised HPA axis ? cause / effect 4. we know cortisol can stimulate fat storage and fat release
Where is HPA axis evidenced to affect fat distribution? evidenced in cushing syndrome (high cortisol synthesis= more central fat), obesity (elevated cortisol), stress increases HPA axis so ? if stress affects fat distribution?
What are the gender differences in HPA pathway activation? HPA axis more controlled in women. In men, cortisol release less controlled ? why women better SAT storers
What controls the action of cortisol?
Insulin and cortisol= increase LPL activity and lipogenesis= replenish fat
GH/IGF-1 and catecholamines + cortisol= decrease LPL activity and lipogenesis = mobilize fat stores
Cortisol promoters (11bHSD1, StAR) and inhibitors (11bHSD2, 5a reductase) = regulate cortisol activity
Cortisol, (Insulin) and PPARy action is governed by circadian rhythm (i.e. time of day) and is different in VAT and SAT
-SAT= store during day, release at night
what is adipose tissue rhythmicity in relation to VAT and SAT? The rhythmicity of cortisol promoters and inhibitors (periods of more or less action) in VAT and SAT changes over 24 hour period = VAT and SAT activity not the same
What change occurs in insulin signalling in SAT across a day? Insulin signaling highest in morning for peak fat storage in early hours = designed so that can be released during overnight fast
Adipokines are also key influences on adipose tissue and function, esp. adiponectin (leptin) and are influenced by adipocyte location and size
What changes occur in leptin, PPARy, adiponectin and cortisol action across a day in VAT and SAT?
VAT: PPARy and cortisol action greatest in middle of night (VAT stored in evening). As VAT is not designed to store, released FFA during day as reservoir of lipid
SAT stores in day vs VAT stores at night.
variations explain shift worker fat storage
What are adipokines? Bio active molecules released by adipose tissue (forms a cytokines)
what is the difference between adipokine release in SAT vs VAT?
SAT: low level anti-inflammatory
VAT: low level pro-inflammatory
What do chemokines and cytokines do in hypertrophic adipocytes? Contribute to increased macrophages by release of MCP-1 in muscle AT which increases TNFa (impairs adipose tissue to take up fat) and contributes to localized muscle insulin sensitivity
Describe the characteristic of a hypertrophic adipocyte the larger it gets? Becomes more inflammatory and in turn, antagonizes insulin receptor function
What is meant by hypoxia in relation to AT? Larger the AT, more hypoxic it becomes (less oxygen diffused into cell), less HIF-1 broken down which will trigger inflammation, impairing storage ability of AT
What does hypoxia do to AT function? Impairs ability to take up glucose and store lipid
Part 4: Measuring adiposity
Having established high visceral fat and/or ectopic fat are risk factors for metabolic disease, they are not easy to measure
This presents a 'missing risk' for a significant proportion of lean individuals who may have: normal BMI, normal body fat, normal waist circumference
Why is there a 'missing risk'? Despite association between obesity and risk of insulin resistance, DM and CVD (specifically abdominal obesity), not guaranteed at an individual level. This is because not every obese person has an increased risk / non-obese individuals may also have an increased risk VAT difficult to measure
VAT is strong predictor of metabolic and CVD risk independent of BMI.
Loss of intra-abdominal AT (VAT/IAAT)is associated with improvements in insulin sensitivity, BP, and circulating lipids. when negative energy balance created through diet / exercise, VAT first to reduce as designed to have high turnover.
Hence those who are lean cannot be complacent in thinking they are healthy by default
Measuring ectopic fat difficult as can only use MRI but Can look at other markers of risk independent of adiposity e.g. metabolic markers, functional test in response to meal
How do you measure IAAT/VAT? Via MRI
What are the pros and cons of MRI? Only way to quantify body comp. and ectopic fat accurately. Can look at frequency and quantify ectopic fat in liver and pancrease based on MRS (magnetic resonance spectroscopy). but expensive and time consuming.
If you know ectopic fat, this is even better as this is what will compromise insulin actionn and give rise to lipotixicity
What would be difference between healthy fat storage and patient with lipodystrophy (not enough adipose tissue)? Little SAT and VAT combined
What changes would you see with ageing and disease ? Ageing: Less muscle mass (sarcopenia- break down of muscle) with more fat infiltration Degenerative muscle disease: less muscle in comparison to fat
Can use to determine TOFI phenotype (thin on outside, fat on inside) = high levels of VAT. Characterised as those with IAAR to SAAT ratio with 2SD > mean for healthy population
BMI and waist circumference not adequate markers of risk! VAT/ASAT ratio important. Total 'trunk' / abdominal fat not adequate marker as will have different proportions of ASAT and VAT