Role of leptin in cardiorenal function

Question 1

What is leptin?

Answer 1

16 kDa protein of the obese gene

Question 2

What cells secrete leptin?

Answer 2

Adipocytes

reflection between adiposity and plasma leptin (BMI = plasma levels)

Question 3

What is the function of leptin?

Answer 3

Maintenance of hunger and satiety

Question 4

What is the receptor for leptin and what is the response?

Answer 4

Obrb via POMC neurons decreases food intake.

Obrb via NPY neurons signals for an increase in food intake.

Obrb

Question 5

What kind of receptor is Obrb?

Answer 5

Obrb is part of a family of 6 isoforms (a - f)

It is an extracellular receptor.

Activates downstream signals via conformational changes

Question 6

What is the first intracellular messenger that is released after leptin binds to Obrb?

Answer 6

JAK2 (phosphorylation)

Question 7

What is the next signal in the leptin pathway after JAK2?

Answer 7

STAT3 (2 of these proteins are phosphorylated and activate proteins within the nucleus)

Question 8

What is the pathway that follows leptin binding to Obrb?

Answer 8

JAK2 gets phosphorylated which activates STAT3 which also gets phosphorylated and unites before going to the nucleus.

Question 9

What receptor does leptin bind to in the kidney?

Answer 9

Megalin which activates a different signalling cascade

Question 10

What is the function of the JAK2/STAT3 pathway?

Answer 10

cell growth and proliferation

Question 11

What is the function of the MAPK pathway?

Answer 11

Cell growth and proliferation

Question 12

What is the function of the PI3K pathway?

Answer 12

Cell growth, proliferation, and differentiation

Question 13

What does leptin do to blood pressure?

Answer 13

Direct action of leptin causes increase in blood pressure.

Question 14

What happens to plasma leptin in rats with high fat diet before and after losing weight? What happens to blood pressure?

Answer 14

Rats fed a high fat have higher plasma leptin and diet causes a reduction in plasma leptin.

Blood pressure followed the same pattern

Question 15

What is the evidence in mice that suggests that leptin causes an increase in heart rate and blood pressure?

Answer 15

Mice that were obese but had leptin knocked out did not experience a higher blood pressure and heart rate. This was seen with both systolic and diastolic pressures. When leptin was reintroduced they had higher blood pressure again.

Question 16

What part of the brain does leptin target that contributes to leptin’s action of increasing the blood pressure?

Answer 16

Leptin targets Dorsomedial nucleus of the hypothalamus in the brain to regulate blood pressure

Question 17

Which proteins can pass through the glomerulus?

Answer 17

Glomerulus filters proteins that are less that 70 kDa. But this is in general and not 100% of these proteins are fltered.

Question 18

What are the normal filtration and reabsorbtion rates of albumin?

Answer 18

0.06% to 3% of plasma albumin is typically filtered

96% of albumin is reabsorbed

Question 19

What is the result of damage to podocytes?

Answer 19

Damage to podocytes could cause more “stuff” to end up in urine

Question 20

What is Megalin?

Answer 20

Megalin is a kind of receptor (scavenger receptor) in the proximal tubule that binds to small ligands like albumin, leptin, and vitamin D binding protein.

Question 21

What is the general function of Megalin receptor?

Answer 21

Involved in degradation/transcytosis of the proteins that bind to it.

Question 22

What is transcytosis?

Answer 22

Process by which a molecule/protein all the way through the cell to the other membrane.

Question 23

Where is Megalin located?

Answer 23

In the proximal tubule

Question 24

What does Megalin do to albumin?

Answer 24

Returns it to circulation via transcytosis

Question 25

Since Megalin binds to both leptin and albumin does that mean they compete?

Answer 25

No, they are present in very different concentrations that there is no real competition.

Question 26

How does megalin carry out its function?

Answer 26

peptidase breaks megalin down into functional part that interacts with nucleus intracellularly.

Question 27

What happens to leptin processing in the kidneys during obesity (5x normal concentration of leptin)?

Answer 27

In obese individuals there is no leptin in urine. This indicates the kidneys are able to process the high leptin concentrations

Question 28

What happens in the glomerulus as a result of high leptin concentrations?

Answer 28

Leptin alters the glomerulus. It upregulates TGF-beta 1 which causes fibrosis to develop on the kidneys (collagen type 4) and hypertrophy of the glomerulus.

Question 29

What does AMPK do in the kidneys in response to leptin and adiponectin?

Answer 29

It regulates cell energy homeostasis. AMPK activation causes a reduction in inflammation. Obesity causes a decrease in AMPK production and as a result an increase in inflammation.

Question 30

What does leptin do in Proximal Tubule Cells?

Answer 30

Leptin upregulates AMPK and mTOR in PTCs

Question 31

How was the discovery of Megalin conducted?

Answer 31

Elevated concentrations of leptin results in PI3K pathway activation. The receptor for this can't be ObR or the other leptin receptors because they don't exist in the proximal tubules. As a result the discovery of Megalin came about.

Question 32

What pathway is activated by Megalin?

Answer 32

The PI3K pathway is indirectly activated. PI3K itself is not activated by leptin.

Question 33

What is the PI3k action?

Answer 33

PI3K stimulates Akt which in turn activates mTORC1 and AMPK. PI3k also stimulates mTORC2.

Question 34

What does leptin do in the kidneys?

Answer 34

Fibrotic pathways are activated by leptin in kidneys during obesity.

Question 35

How is TGF-Beta 1 produced? What does leptin do to this pathway?

Answer 35

TGF-Beta1 gets produced and matured and then then released to signal to surrounding cells. Leptin increases this release

Question 36

What is the effect of AMPK on renal hypertrophy?

Answer 36

Activation of AMPK prevents renal hypertrophy

Question 37

Why do high leptin concentrations cause a drop in albumin in the body?

Answer 37

Leptin upregulates AMPK which activates TGF-Beta 1 and in turn inhibits megalin. Fibrosis increases as a result. Megalin inhibition causes less transocytosis of albumin which in turn results in more albumin excretion.

Question 38

What is the result of acute leptin exposure? How is this result different to long term effects of a high fat diet?

Answer 38

Acute leptin exposure alters signalling mediator expression and proximal tubule size in a different manner to a high fat diet.

Question 39

Summary:

Answer 39

Leptin as multiple actions. It increases blood pressure via direct action on the brain It increases albumin loss through urine via megalin downregulation caused by AMPK activation. In obesity leptin may be a potential therapeutic target in future research