Cardiovascular Health Lecture 1.3 : Role of leptin in cardiorenal function

Question 1

What releases leptin?

Answer 1

Adipocytes.

Question 2

What happens to leptin secretion in obese subjects?

Answer 2

Increases.

Question 3

What is the main effect of leptin?

Answer 3

Decreases hunger and increases satiety.

Question 4

If obese people have a 2-3 fold increase n leptin, why do they still become hungry?

Answer 4

Obese people have leptin resistance, so don’t have reduced hunger or increased satiety.

Question 5

What is the receptor of leptin?

Answer 5

OBRb.

Question 6

Which neurons are OBRb receptors found, and what effect do they have?

Answer 6

POMC neuron - decreased food intake

NPY neuron - increased food intake

Question 7

What happens with an imbalance of POMC and NPY neuron activation?

Answer 7

Weight gain or loss.

Question 8

What happens when leptin binds to OBRb?

Answer 8

Jak2 phosphorylates, and activates STAT3, which dimerises. Both STATs phosphorylate, localise to the nucleus and induce gene activation.

Question 9

What pathways does OBRb activate (name 3)?

Answer 9

JAK/STAT pathway
MAPK pathway
PI3K pathway

Question 10

What effect does leptin have on blood pressure?

Answer 10

Increases it.

Question 11

What happens to leptin levels in obese subjects on a low fat diet?

Answer 11

Decreases.

Question 12

What happens to knockouts of leptin or the OBRb receptor? Why? What happens if on a high fat diet?

Answer 12

Develop obesity soon after birth.
No normal leptin signalling, and nothing to regulate hunger causes this.
A high fat diet increases obesity further.

Question 13

What happens to heart rate in a knockout of leptin or OBRb receptor? Why?

Answer 13

No increase in heart rate.

Hypertension associated with obesity isn’t present if leptin pathway isn’t functioning normally.

Question 14

What happens to blood pressure if leptin is supplemented to leptin knockouts?

Answer 14

Hypertension returns.

Question 15

What happens to blood pressure if leptin or OBRb receptors are inhibited/blocked?

Answer 15

Blood pressure returns to normal.

Question 16

Does the glomerulus discriminate by size alone? Explain.

Answer 16

No, not always. Generally under 70kDa is filtered through, but not all.

Question 17

What is megalin?

Answer 17

Scavenger receptor in the proximal tubule of kidneys.

Question 18

Does megalin bind to leptin?

Answer 18

Yes, amongst many other proteins.

Question 19

What does megalin do to proteins it binds to?

Answer 19

Degrades them or takes them in via transcytosis.

Question 20

What is the rate limiting step in degredation or transcytosis of proteins by megalin?

Answer 20

Amount of megalin on the membrane.

Question 21

What does megalin do if cleaved?

Answer 21

Can localise to the nucleus to induce genes.

Question 22

Does leptin get filtered? What happens after?

Answer 22

Yes it does, gets taken up by megalin.

Question 23

Do obese people secrete leptin?

Answer 23

No.

Question 24

What happens to the glomerulus with high levels of leptin, and what effect does this have?

Answer 24

Fibrotic, reducing filtering capacity.

More proteins filter through.

Question 25

How does the glomerulus become fibrotic (with leptin increase)?

Answer 25

Increases TGF-beta 1 levels, which increases collagen, and glomerulus hypertrophy increases.

Question 26

What does AMPK do?

Answer 26

Regulates cellular energy homeostasis.

Question 27

Name 2 adipokines.

Answer 27

Adiponectin and leptin.

Question 28

What do adipokines do to AMPK?

Answer 28

Activate it.

Question 29

What effect does AMPK have on inflammation?

Answer 29

Reduces it.

Question 30

What happens to AMPK levels in obese people? Which other disease is this present in?

Answer 30

Reduced activation, so an increase in inflammation. Also found in diabetes mellitus.

Question 31

How does leptin signal in the kidney, and what effect does this have?

Answer 31

Via megalin binding, and decreases metabolic activity.

Question 32

What happens when the glomerulus is exposed to leptin?

Answer 32

Fibrotic pathways activated via TGF-beta 1 by increasing its export from cells.

Question 33

What effect does leptin have on AMPK?

Answer 33

Activates AMPK.

Question 34

What effect does AMPK have on TGF-beta 1?

Answer 34

Inhibits it.

Question 35

What effect does TGF-beta 1 have on megalin and fibrosis?

Answer 35

Normally inhibits megalin and increases fibrosis.

Question 36

What happens with reduced megalin?

Answer 36

Less megalin to process albumin and leptin.

Question 37

What is a hallmark of obesity in their urine?

Answer 37

Albumin in urine.