Obesity & Inflammation Flashcards
what exists in overweight + obese people?
low grade chronic inflammation
What is the definition of obesity in terms of BMI?
BMI >30
What are the risk factors for obesity?
-Excessive food consumption
-Reduced physical activity
What percentage of obesity cases does genetics account for, and what is the implication of the main cause of obesity?
- only <2% of cases
- therefore most likely due to gene/environmental interactions
What is epigenetics?
study of how the environment affects which genes are expressed
What are the 2 types of modifications that can occur in epigenetics?
DNA and histone modifications… impact on RNA transcription
Epigenetics - Gene environment interactions leading to….
heritable changes in gene expression via DNA modifications
what DNA modifications can make a person more prone to obesity?
Cytosine methylations
What histone modifications can be made to make a person more prone to obesity?
Methylation/acetylation
- histone marks which effect mRNA transcription
what are histones?
proteins that allow organisation of DNA -> chromatin
What are the epigenetic regulators?
long non-coding RNAs (>200 nucleotides)
How are long non-coding RNAs epigenetic regulators?
they act as scaffolds for the assembly of RNA transcripts and proteins
how are lncRNAs identified?
by Next Generation sequencing
how are lncRNAs identified?
by Next Generation sequencing
What are the 3 main causes of obesity?
- genetics
- diet
- physical activity
What is metabolic syndrome? How does obesity fit into its definition?
at least 2 factors that -> multiple chronic diseases - 1 of these factors is obesity
Name the 3 factors responsible for metabolic syndrome.
- insulin resistance/ hyperinsulinaemia
- obesity (leading to) dyslipidaemia
- hypertension
4 examples of chronic diseases that can be caused by metabolic syndromes?
- diabetes
- CVD
- atherosclerosis
- heart failure/strokes
obesity: associated with risk of developing….
OA
most px undergoing joint replacement therapy are overweight
particular risk factor for OA, aside from BMI?
WHR.
higher = apple shape = high risk
lower = pear shape = low risk
(summary)
effect of overeating on adipose tissue?
leads to pathological inflammatory adipose tissue
- Hyperplasia of adipocytes (overgrowth of cells)
- Increased immune cell infilitration
-> change in adipose tissue phenotype
-> secretion of cytokines (adipokines)
What are the functions of adipose tissue?
- stores lipid
- immunological tissue
What are adipokines?
cytokines secreted by adipose tissue
How does overeating affect adipocytes?
hyperplasia - adipocytes become bigger
Hyperplasia of adipocytes causes them to do what?
- secrete cytokines known as adipokines
- change their phenotype
- both of these result in increased pro-inflammatory immune cell infiltration
what specific type of tissue is a major source of inflamm proteins + cytokines? where from?
abdominal adipose tissue from wieght gain and less exercise
what do adipocytes produce and how?
chemokines (proteins that recall immune cells into tissue)
after they accumulate lipids + get bigger and stretch
how does obese adipose tissue differ to lean. (BMI<25)?
Lean: high adiponectin
low leptin
obese: lowadiponectin
high leptin
what is leptin?
hormone that regulates food intake in body
resident immune cell population (for lean adipose tissue) is comprised of what and role?
mostly immune suppressive.
T regs/ resident macrophages… keep adipose tissue in check
adipose tissue acc important for what?
immune response
What causes loss of cartilage in obese people?
increases the release of adipokines which have a pro-inflammatory effect
What is an issue with too many T-regs at adipose tissue?
At normal levels, regulate adipose tissues but too much: increase chemokines in blood -> low grade chronic inflammation
What is adiponectin and role?
An adipokine secreted by adipocytes
regulates glucose levels + lipid metabolism
What is leptin and role?
- Hormone tin fat cells
- If fat cell size increases, levels will increase
- speeds up metabolism +inhibits appetite
adiponectin in obese tissue: LOW, meaning?
ess regulation of food intake - decrease insulin sensitivity meaning increased glucose levels and metabolism
What are the levels of leptin in obese adipose tissue?
Levels of this adipokine will be high in
adiponectin in obese tissue: LOW, meaning?
less regulation of food intake - decrease insulin sensitivity … increased glucose levels and metabolism
leptin in obese tissue: HIGH, meaning?
metabolsim is slowed and appetite increases
They also reduce insulin sensitivity meaning increased glucose levels
Once released, adipokines enter blood and have distal effects on (5)?
!!
joints, OA
skeletal muscle, sarcopenia
pancreas, diabetes
liver, steatosis
heart, CVD
-> inflammation
What 2 additional CV risk factors do those with high WHR/central adiposity present with?
- high HCL cholesterol levels
- elevated triglycerides
What is meant by atherogenic?
generates plaque in arteries
Name five examples of adipokines
- adiponectin
- leptin
- TNF-alpha
- IL-6
- PAI-1 (plasminogen activator inhibitor 1)
What is the ‘good’ adipokine? why
adiponectin. only one that decreases with obesity
What are the 3 functions of adiponectin?
- Anti-atherogenic
- Anti-inflammatory?
- Increases insulin sensitivity
what T2DM risk factor do those with high WHR/central adiposity present with?
elevated fasting glucose levels
what are adipokines produced by (excess)??
obese adipose tissue
effect of increasing adiposity/ obesity on leptin, tnfa, IL6, PAI1?
all increase
What are the 2 functions of leptin?
- Reduces insulin sensitivity
- Pro-inflammatory (OA and RA joints)
What are the 2 functions of TNF-alpha?
- pro-inflammatory cytokine
- reduces insulin sensitivity
What are the 3 functions of IL-6?
- pro-inflammatory
- pro-atherogenic
- increases vascular inflammation
What are the 2 functions of PAI-1?
- pro-atherogenic
- pro-thrombotic
What key adipokines are elevated in OA and RA synovium/serum?
TNF-alpha, IL-6 (OA only)
2 things that increase risk of CHD?
BMI and WHR
especially both together
relationship between age and inflammatory cytokines?
age increases: inflammatory cytokines increase
Summarise how adipose tissue -> inflammation. Include: effect of over-eating, effect of adipokines, 5 key adipokines and their roles.
image/ drawing p70
What is sarcopenia?
the age-related loss of muscle mass, strength, power and performance
What is sarcopenia associated with?
age related increase in adiposity
What does obesity lead to an accumulation of within skeletal muscle?
triglycerides
How does insulin work at the cellular level?
- binds to receptor
- activates PI3K pathway
- leads to transcription of GLUT4 transporter (into membrane)
- GLUT4 uptakes excess glucose in blood, causing glucose in blood to go down
How does obesity/adiposity lead to insulin resistance?
- fatty acids are taken up in cell and block PI3K pathway
…get insulin resistance - prevents GLUT4 transporter transcription so glucose cannot enter cell and stays in blood
how does adiposity impact glucose levels in blood?
get insulin resistance
and blood glucose stays high
with increased adiposity
impact of skeletal muscle tissue change in age + obesity on GLUT4 expression?
reduces expression
obesity + skeletal muscle + insulin resistance… isolated myotubes in obesity are …
obese myotubes (w adiposity) = intrinsically insulin resistance
BMI and central adiposity (WHR) impact on T2DM risk?
increases
How does obesity cause skeletal muscle atrophy?
- pro-inflammatory cytokines (adipokines) promote atrophy of myotubes
- TNF-a induces muscle E3 ligases MAFbx, MURF1
Summarise the issues obesity leads to within skeletal muscle.
(image p73)
…
what do muscle cells (myoblasts) cultured in OBESE adipose media develop into?
thinner myotubes (muscle fibres)
in obesity, the adipokine resistin is INC/DEC?
significantly increased.
if BMI >25
myoblasts cultured in presence of adipokine resistin exhibit what?
2 specifc things?
impaired myogenesis
…
redcued myotube thickness
reduced nuclear fusion index
what is myogenesis?
formation of skeletal muscular tissue
obesity therapeutic: Lorcaserin is a…
selective serotonin 2C receptor agonist
obesity therapeutic: Lorcaserin works on…
5-HT2c-R
incWhat is the current treatment for obesity?/ adipokine modulation
exercise and low calorie diet
benefits of incorporatingcombination of exercise and low calorie diet to manage obesity?
inc good genes e.g. adiponectin and decrease leptin, TNFa etc. :)
key risk factor for metabolic syndrome disorders eg CVD T2DM
central adiposity
pathological changes to adipose tissue in obese px ->? 2
infiltration of immune cells
secretion of pathological cytokines (adipokines)
obesity + pathological adipokines are associated with… 2
insulni resistance and T2DM
(reduced glucose uptake and obese myotubes)
adipokines can drive X and impair Y
drive muscle atrophy
impair myogenesis
OA link with obesity occurs from…
obese synovial fibroblast inflamm phenotype
