Obesity & Inflammation

Question 1

what exists in overweight + obese people?

Answer 1

low grade chronic inflammation

Question 2

What is the definition of obesity in terms of BMI?

Answer 2

BMI >30

Question 3

What are the risk factors for obesity?

Answer 3

-Excessive food consumption

-Reduced physical activity

Question 4

What percentage of obesity cases does genetics account for, and what is the implication of the main cause of obesity?

Answer 4

• only <2% of cases
• therefore most likely due to gene/environmental interactions

Question 5

What is epigenetics?

Answer 5

study of how the environment affects which genes are expressed

Question 6

What are the 2 types of modifications that can occur in epigenetics?

Answer 6

DNA and histone modifications… impact on RNA transcription

Question 7

Epigenetics - Gene environment interactions leading to….

Answer 7

heritable changes in gene expression via DNA modifications

Question 8

what DNA modifications can make a person more prone to obesity?

Answer 8

Cytosine methylations

Question 9

What histone modifications can be made to make a person more prone to obesity?

Answer 9

Methylation/acetylation

• histone marks which effect mRNA transcription

Question 10

what are histones?

Answer 10

proteins that allow organisation of DNA -> chromatin

Question 11

What are the epigenetic regulators?

Answer 11

long non-coding RNAs (>200 nucleotides)

Question 12

How are long non-coding RNAs epigenetic regulators?

Answer 12

they act as scaffolds for the assembly of RNA transcripts and proteins

Question 13

how are lncRNAs identified?

Answer 13

by Next Generation sequencing

Question 13

how are lncRNAs identified?

Answer 13

by Next Generation sequencing

Question 14

What are the 3 main causes of obesity?

Answer 14

• genetics
• diet
• physical activity

Question 15

What is metabolic syndrome? How does obesity fit into its definition?

Answer 15

at least 2 factors that -> multiple chronic diseases - 1 of these factors is obesity

Question 16

Name the 3 factors responsible for metabolic syndrome.

Answer 16

• insulin resistance/ hyperinsulinaemia
• obesity (leading to) dyslipidaemia
• hypertension

Question 17

4 examples of chronic diseases that can be caused by metabolic syndromes?

Answer 17

• diabetes
• CVD
• atherosclerosis
• heart failure/strokes

Question 18

obesity: associated with risk of developing….

Answer 18

OA
most px undergoing joint replacement therapy are overweight

Question 19

particular risk factor for OA, aside from BMI?

Answer 19

WHR.
higher = apple shape = high risk
lower = pear shape = low risk

Question 20

(summary)
effect of overeating on adipose tissue?

Answer 20

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)

Question 21

What are the functions of adipose tissue?

Answer 21

• stores lipid
• immunological tissue

Question 22

What are adipokines?

Answer 22

cytokines secreted by adipose tissue

Question 23

How does overeating affect adipocytes?

Answer 23

hyperplasia - adipocytes become bigger

Question 24

Hyperplasia of adipocytes causes them to do what?

Answer 24

- secrete cytokines known as adipokines - change their phenotype - both of these result in increased pro-inflammatory immune cell infiltration

Question 25

what specific type of tissue is a major source of inflamm proteins + cytokines? where from?

Answer 25

abdominal adipose tissue from wieght gain and less exercise

Question 26

what do adipocytes produce and how?

Answer 26

chemokines (proteins that recall immune cells into tissue) after they accumulate lipids + get bigger and stretch

Question 27

how does obese adipose tissue differ to lean. (BMI<25)?

Answer 27

Lean: high adiponectin low leptin obese: lowadiponectin high leptin

Question 28

what is leptin?

Answer 28

hormone that regulates food intake in body

Question 29

resident immune cell population (for lean adipose tissue) is comprised of what and role?

Answer 29

mostly immune suppressive. T regs/ resident macrophages... keep adipose tissue in check

Question 30

adipose tissue acc important for what?

Answer 30

immune response

Question 31

What causes loss of cartilage in obese people?

Answer 31

increases the release of adipokines which have a pro-inflammatory effect

Question 32

What is an issue with too many T-regs at adipose tissue?

Answer 32

At normal levels, regulate adipose tissues but too much: increase chemokines in blood -> low grade chronic inflammation

Question 33

What is adiponectin and role?

Answer 33

An adipokine secreted by adipocytes regulates glucose levels + lipid metabolism

Question 34

What is leptin and role?

Answer 34

- Hormone tin fat cells - If fat cell size increases, levels will increase - speeds up metabolism +inhibits appetite

Question 35

adiponectin in obese tissue: LOW, meaning?

Answer 35

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

Question 35

adiponectin in obese tissue: LOW, meaning?

Answer 35

less regulation of food intake - decrease insulin sensitivity ... increased glucose levels and metabolism

Question 36

leptin in obese tissue: HIGH, meaning?

Answer 36

metabolsim is slowed and appetite increases They also reduce insulin sensitivity meaning increased glucose levels

Question 37

Once released, adipokines enter blood and have distal effects on (5)? !!

Answer 37

joints, OA skeletal muscle, sarcopenia pancreas, diabetes liver, steatosis heart, CVD -> inflammation

Question 38

What 2 additional CV risk factors do those with high WHR/central adiposity present with?

Answer 38

- high HCL cholesterol levels - elevated triglycerides

Question 39

What is meant by atherogenic?

Answer 39

generates plaque in arteries

Question 40

Name five examples of adipokines

Answer 40

- adiponectin - leptin - TNF-alpha - IL-6 - PAI-1 (plasminogen activator inhibitor 1)

Question 41

What is the 'good' adipokine? why

Answer 41

adiponectin. only one that decreases with obesity

Question 42

What are the 3 functions of adiponectin?

Answer 42

- Anti-atherogenic - Anti-inflammatory? - Increases insulin sensitivity

Question 43

what T2DM risk factor do those with high WHR/central adiposity present with?

Answer 43

elevated fasting glucose levels

Question 44

what are adipokines produced by (excess)??

Answer 44

obese adipose tissue

Question 45

effect of increasing adiposity/ obesity on leptin, tnfa, IL6, PAI1?

Answer 45

all increase

Question 46

What are the 2 functions of leptin?

Answer 46

- Reduces insulin sensitivity - Pro-inflammatory (OA and RA joints)

Question 47

What are the 2 functions of TNF-alpha?

Answer 47

- pro-inflammatory cytokine - reduces insulin sensitivity

Question 48

What are the 3 functions of IL-6?

Answer 48

- pro-inflammatory - pro-atherogenic - increases vascular inflammation

Question 49

What are the 2 functions of PAI-1?

Answer 49

- pro-atherogenic - pro-thrombotic

Question 50

What key adipokines are elevated in OA and RA synovium/serum?

Answer 50

TNF-alpha, IL-6 (OA only)

Question 51

2 things that increase risk of CHD?

Answer 51

BMI and WHR especially both together

Question 52

relationship between age and inflammatory cytokines?

Answer 52

age increases: inflammatory cytokines increase

Question 53

Summarise how adipose tissue -> inflammation. Include: effect of over-eating, effect of adipokines, 5 key adipokines and their roles.

Answer 53

image/ drawing p70

Question 54

What is sarcopenia?

Answer 54

the age-related loss of muscle mass, strength, power and performance

Question 55

What is sarcopenia associated with?

Answer 55

age related increase in adiposity

Question 56

What does obesity lead to an accumulation of within skeletal muscle?

Answer 56

triglycerides

Question 57

How does insulin work at the cellular level?

Answer 57

- 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

Question 58

How does obesity/adiposity lead to insulin resistance?

Answer 58

- 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

Question 59

how does adiposity impact glucose levels in blood?

Answer 59

get insulin resistance and blood glucose stays high with increased adiposity

Question 60

impact of skeletal muscle tissue change in age + obesity on GLUT4 expression?

Answer 60

reduces expression

Question 61

obesity + skeletal muscle + insulin resistance... isolated myotubes in obesity are ...

Answer 61

obese myotubes (w adiposity) = intrinsically insulin resistance

Question 62

BMI and central adiposity (WHR) impact on T2DM risk?

Answer 62

increases

Question 63

How does obesity cause skeletal muscle atrophy?

Answer 63

- pro-inflammatory cytokines (adipokines) promote atrophy of myotubes - TNF-a induces muscle E3 ligases MAFbx, MURF1

Question 64

Summarise the issues obesity leads to within skeletal muscle. (image p73)

Answer 64

...

Question 65

what do muscle cells (myoblasts) cultured in OBESE adipose media develop into?

Answer 65

thinner myotubes (muscle fibres)

Question 66

in obesity, the adipokine resistin is INC/DEC?

Answer 66

significantly increased. if BMI >25

Question 67

myoblasts cultured in presence of adipokine resistin exhibit what? 2 specifc things?

Answer 67

impaired myogenesis ... redcued myotube thickness reduced nuclear fusion index

Question 68

what is myogenesis?

Answer 68

formation of skeletal muscular tissue

Question 69

obesity therapeutic: Lorcaserin is a...

Answer 69

selective serotonin 2C receptor agonist

Question 70

obesity therapeutic: Lorcaserin works on...

Answer 70

5-HT2c-R

Question 71

incWhat is the current treatment for obesity?/ adipokine modulation

Answer 71

exercise and low calorie diet

Question 72

benefits of incorporatingcombination of exercise and low calorie diet to manage obesity?

Answer 72

inc good genes e.g. adiponectin and decrease leptin, TNFa etc. :)

Question 73

key risk factor for metabolic syndrome disorders eg CVD T2DM

Answer 73

central adiposity

Question 74

pathological changes to adipose tissue in obese px ->? 2

Answer 74

infiltration of immune cells secretion of pathological cytokines (adipokines)

Question 75

obesity + pathological adipokines are associated with... 2

Answer 75

insulni resistance and T2DM (reduced glucose uptake and obese myotubes)

Question 76

adipokines can drive X and impair Y

Answer 76

drive muscle atrophy impair myogenesis

Question 77

OA link with obesity occurs from...

Answer 77

obese synovial fibroblast inflamm phenotype