Age-Related Decline in Peripheral Metabolic Tissue Homeostasis

Question 1

Name the main metabolic diseases

Answer 1

Obesity
Type 2 diabetes
Metabolic syndrome

Question 2

Define obesity

Answer 2

Excess body fat - resulting from chronic imbalance of energy

Question 3

What is a limitation of BMI as a proxy measure of adiposity?

Answer 3

Ignores types of fat and where fat stored - requires imaging

Question 4

What are the 4 key features of metabolic syndrome?

Answer 4

Central obesity - fat around waist
Dyslipidemia - improperly regulated fat metabolism (increased triglycerides, increased LDL, decreased HDL)
Increased blood pressure
Increased blood glucose - linked to insulin resistance

Question 5

What is the vicious circle with obesity, diabetes, and ageing?

Answer 5

Ageing predisposes to obesity and diabetes

Obesity and diabetes cause damage - accelerates ageing

Question 6

Which hormone controls carbohydrate homeostasis?

Answer 6

Insulin

Question 7

Which hormone controls lipid homeostasis?

Answer 7

Leptin

Question 8

Which cell type detects glucose and what does this cause?

Answer 8

Beta-cells in islets of Langerhans

Secrete insulin into blood

Question 9

What are the metabolic effects of insulin?

Answer 9

CNS - anorexigenic effect - promotes satiety
Liver - prevents gluconeogenesis - decreases liver glucose output
Skeletal muscle - increases glucose uptake and glycogen synthesis
Adipose tissue - decreases lipolysis (fatty acid store breakdown)

Question 10

Which tissue type produces leptin?

Answer 10

Adipose tissue

Question 11

What are the metabolic effects of leptin?

Answer 11

Hypothalamus - decreases appetite and food intake

Skeletal muscle - increases fatty acid B-oxidation

Question 12

Name the 2 types of body fat depots

Answer 12

Visceral

Subcutaneous

Question 13

What are the characteristics of viseral body fat depots?

Answer 13

Within abdominal cavity
Close to organs - can impair function
More harmful

Question 14

What are the characteristics of subcutaneous body fat depots?

Answer 14

Not harmful

Some positive effects

Question 15

Name the 2 types of adipose tissue

Answer 15

White adipose tissue (WAT)

Brown adipose tissue (BAT)

Question 16

What are the characteristics of WAT?

Answer 16

Most space in adipocytes taken up by fat droplet

Question 17

What are the characteristics of BAT?

Answer 17

Many mitochondria, highly vascularised
UCP1 only expressed in BAT mitos - uncouples fatty acid oxidation from ATP production
Energy released as heat - instead of ATP - prevents increased biomass - prevents obesity
Good adipose tissue type
Important for thermogenesis

Question 18

What might explain the age-related decrease in BAT?

Answer 18

Sex hormones maintain BAT - cortisol promotes shrinking of BAT
Young adults - increased sex hormones - most energy stored in BAT
Ageing - decreased sex hormones - most energy stored in WAT
Stress - increased cortisol - decreased BAT - more energy stored in WAT

Question 19

How does fat distribution change with age?

Answer 19

Young - most subcutaneous - small depots
Middle age - more of both depots - larger increase in visceral depots
Old age - less of both depots - larger decrease in subcutaneous - ectopic fat forms in organs (e.g. liver) - mot specialised for fat storage - toxic effect

Question 20

What is the process of adipocyte development?

Answer 20

Mesenchymal progenitor cells - undergo determination - become preadipocytes (stem cells)
Preadipocytes replicate
Preadipocytes differentiate - become developing adipocytes
Developing adipocytes undergo lipid accumulation - become mature adipocytes
Mature adipocytes undergo apoptosis - replaced by preadipocytes

Question 21

How is adipocyte development altered with age?

Answer 21

Same/slightly more preadipocytes
Decreased developing adipocytes - due to transcriptional factor changes
Decreased mature adipocytes - due to decreased maturation potential of developing adipocytes

Question 22

What is the adipose tissue expandability hypothesis?

Answer 22

Adipose tissue has finite capacity for fat storage

Point when capacity reached - fat deposited ectopically - lipotoxicity

Question 23

What is fat stored as in adipose tissue?

Answer 23

Triglycerides

Question 24

What are triglycerides released as into the blood?

Answer 24

Fatty acids

Question 25

What are the steps of insulin receptor signalling?

Answer 25

Insulin binds to receptor Association of IRS (adaptor protein) Recruits p85 (kinase) - phosphorylates PIP2 - forms PIP3 (second messenger) Akt and PDK1 bind PIP3 Akt and PDK1 in close proximity - PDK1 phosphorylates Akt - activates

Question 26

What is Akt?

Answer 26

Master kinase

Question 27

What are the effects of Akt?

Answer 27

Glucose uptake Glycogen synthesis Decreased hepatic glucose output Decreased lipolysis

Question 28

How are fatty acids toxic?

Answer 28

Can be metabolised to other lipid products - e.g. ceramide, diacylglycerol - activate pro-inflammatory signalling kinases

Question 29

How does a feedback loop downregulate insulin signalling?

Answer 29

Akt activates mTORC1 - leads to IRS phosphorylation - marked for proteasomal degradation - physiological Proinflammatory signalling kinases phosphorylate IRS1 - marked for proteasomal degradation - pathological - insulin resistance

Question 30

What are the effects of insulin resistance?

Answer 30

Hyperglycaemia (high blood glucose) - due to decreased glucose uptake by muscle, increased liver glucose output Lipidemia (high blood fatty acid) - due to lipolysis by adipose tissue

Question 31

How does glucose distribution differ between insulin-sensitive and insulin-resistant individuals?

Answer 31

Decreased muscle glycogen content in insulin-resistant Increased liver lipid content in insulin-resistant - glucose stored in liver instead of muscle - due to increased lipogenesis in liver

Question 32

What is non-alcoholic fatty liver disease (NAFLD)?

Answer 32

Accumulation of fat in liver with low/no alcohol consumption

Question 33

Which traits increase the risk of NAFLD?

Answer 33

High BMI Age More metabolic syndrome criteria

Question 34

What is the overall effect of ageing on metabolic syndromes?

Answer 34

Ageing limits adipose tissue expandability - worsens lipotoxicity caused by obesity Excess fat stored in non-adipose tissues - exerts lipotoxic effect Lipotoxicity contributes to insulin resistance in peripheral metabolic tissues Muscle insulin resistance impairs energy storage as glycogen - promotes lipogenesis in liver - NAFLD development