Age-Related Decline in Peripheral Metabolic Tissue Homeostasis Flashcards
Name the main metabolic diseases
Obesity
Type 2 diabetes
Metabolic syndrome
Define obesity
Excess body fat - resulting from chronic imbalance of energy
What is a limitation of BMI as a proxy measure of adiposity?
Ignores types of fat and where fat stored - requires imaging
What are the 4 key features of metabolic syndrome?
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
What is the vicious circle with obesity, diabetes, and ageing?
Ageing predisposes to obesity and diabetes
Obesity and diabetes cause damage - accelerates ageing
Which hormone controls carbohydrate homeostasis?
Insulin
Which hormone controls lipid homeostasis?
Leptin
Which cell type detects glucose and what does this cause?
Beta-cells in islets of Langerhans
Secrete insulin into blood
What are the metabolic effects of insulin?
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)
Which tissue type produces leptin?
Adipose tissue
What are the metabolic effects of leptin?
Hypothalamus - decreases appetite and food intake
Skeletal muscle - increases fatty acid B-oxidation
Name the 2 types of body fat depots
Visceral
Subcutaneous
What are the characteristics of viseral body fat depots?
Within abdominal cavity
Close to organs - can impair function
More harmful
What are the characteristics of subcutaneous body fat depots?
Not harmful
Some positive effects
Name the 2 types of adipose tissue
White adipose tissue (WAT)
Brown adipose tissue (BAT)
What are the characteristics of WAT?
Most space in adipocytes taken up by fat droplet
What are the characteristics of BAT?
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
What might explain the age-related decrease in BAT?
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
How does fat distribution change with age?
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
What is the process of adipocyte development?
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
How is adipocyte development altered with age?
Same/slightly more preadipocytes
Decreased developing adipocytes - due to transcriptional factor changes
Decreased mature adipocytes - due to decreased maturation potential of developing adipocytes
What is the adipose tissue expandability hypothesis?
Adipose tissue has finite capacity for fat storage
Point when capacity reached - fat deposited ectopically - lipotoxicity
What is fat stored as in adipose tissue?
Triglycerides
What are triglycerides released as into the blood?
Fatty acids
What are the steps of insulin receptor signalling?
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
What is Akt?
Master kinase
What are the effects of Akt?
Glucose uptake
Glycogen synthesis
Decreased hepatic glucose output
Decreased lipolysis
How are fatty acids toxic?
Can be metabolised to other lipid products - e.g. ceramide, diacylglycerol - activate pro-inflammatory signalling kinases
How does a feedback loop downregulate insulin signalling?
Akt activates mTORC1 - leads to IRS phosphorylation - marked for proteasomal degradation - physiological
Proinflammatory signalling kinases phosphorylate IRS1 - marked for proteasomal degradation - pathological - insulin resistance
What are the effects of insulin resistance?
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
How does glucose distribution differ between insulin-sensitive and insulin-resistant individuals?
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
What is non-alcoholic fatty liver disease (NAFLD)?
Accumulation of fat in liver with low/no alcohol consumption
Which traits increase the risk of NAFLD?
High BMI
Age
More metabolic syndrome criteria
What is the overall effect of ageing on metabolic syndromes?
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
