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Frontiers In Physiology > Role of leptin in cardiorenal function > Flashcards

Role of leptin in cardiorenal function Flashcards

1
Q

What is leptin?

A

16 kDa protein of the obese gene

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2
Q

What cells secrete leptin?

A

Adipocytes

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

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3
Q

What is the function of leptin?

A

Maintenance of hunger and satiety

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4
Q

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

A

Obrb via POMC neurons decreases food intake.

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

Obrb

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5
Q

What kind of receptor is Obrb?

A

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

It is an extracellular receptor.

Activates downstream signals via conformational changes

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6
Q

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

A

JAK2 (phosphorylation)

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7
Q

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

A

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

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8
Q

What is the pathway that follows leptin binding to Obrb?

A

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

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9
Q

What receptor does leptin bind to in the kidney?

A

Megalin which activates a different signalling cascade

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10
Q

What is the function of the JAK2/STAT3 pathway?

A

cell growth and proliferation

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11
Q

What is the function of the MAPK pathway?

A

Cell growth and proliferation

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12
Q

What is the function of the PI3K pathway?

A

Cell growth, proliferation, and differentiation

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13
Q

What does leptin do to blood pressure?

A

Direct action of leptin causes increase in blood pressure.

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14
Q

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

A

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

Blood pressure followed the same pattern

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15
Q

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

A

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.

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16
Q

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

A

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

17
Q

Which proteins can pass through the glomerulus?

A

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

18
Q

What are the normal filtration and reabsorbtion rates of albumin?

A

0.06% to 3% of plasma albumin is typically filtered

96% of albumin is reabsorbed

19
Q

What is the result of damage to podocytes?

A

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

20
Q

What is Megalin?

A

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.

21
Q

What is the general function of Megalin receptor?

A

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

22
Q

What is transcytosis?

A

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

23
Q

Where is Megalin located?

A

In the proximal tubule

24
Q

What does Megalin do to albumin?

A

Returns it to circulation via transcytosis

25
Q

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

A

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

26
Q

How does megalin carry out its function?

A

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

27
Q

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

A

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

28
Q

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

A

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.

29
Q

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

A

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.

30
Q

What does leptin do in Proximal Tubule Cells?

A

Leptin upregulates AMPK and mTOR in PTCs

31
Q

How was the discovery of Megalin conducted?

A

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.

32
Q

What pathway is activated by Megalin?

A

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

33
Q

What is the PI3k action?

A

PI3K stimulates Akt which in turn activates mTORC1 and AMPK.

PI3k also stimulates mTORC2.

34
Q

What does leptin do in the kidneys?

A

Fibrotic pathways are activated by leptin in kidneys during obesity.

35
Q

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

A

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

36
Q

What is the effect of AMPK on renal hypertrophy?

A

Activation of AMPK prevents renal hypertrophy

37
Q

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

A

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.

38
Q

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

A

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

39
Q

Summary:

A

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

Frontiers In Physiology (35 decks)

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