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NEUR30002 > Lecture 31: Neurocircuitry of Metabolism 3 > Flashcards

Lecture 31: Neurocircuitry of Metabolism 3 Flashcards

1
Q

What happens when a db/db mouse is connected to an ob/ob mouse?

A

the satiety factor in db/db mice acts on the factor receptor in the ob/ob mice causing them to lose weight and starve

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2
Q

What is the difference between db/db mice and ob/ob mice?

A

db/db mice do not produce the satiety factor’s receptor and are obese but they do produce the satiety factor
ob/ob mice do not produce the satiety factor but do produce the receptor

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3
Q

What is leptin?

A

a cytokine that is secreted from adipocytes and is encoded by the ob gene

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4
Q

What is the amount of leptin in the blood proportional to?

A

the amount of fat in the body

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5
Q

How does leptin regulate adiposity?

A

by communicating levels of adiposity to the brain

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6
Q

What is the leptin receptor encoded by? Which classes of isoforms are expressed?

A

the db gene

long, short and secretory

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7
Q

Where is the long, fully active isoform of LepR expressed?

A

mainly in the hypothalamus

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8
Q

What happens when leptin binds to the LepR?

A

this activates the Signal Transducer and Activator of Transcription 3 (STAT3) intracellular signalling pathway

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9
Q

What does leptin signalling result in?

A

the phosphorylation of STAT3 (pSTAT3), which is then translocated to the nucleus where it can regulate gene transcription

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10
Q

How does leptin influence AgRP and POMC neurons?

A

leptin inhibits AgRP neurons and activates POMC neurons

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11
Q

Where are leptin receptors expressed?

A

in AgRP and POMC neurons of the ARC as well as in neurons of the VMH

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12
Q

What does conditional deletion of LepR in AgRP neurons result in?

A

increased BW and adiposity

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13
Q

What does conditional deletion of LepR in POMC neurons result in?

A

increased BW and adiposity

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14
Q

What is insulin?

A

a peptide hormone secreted from beta-cells

in the pancreas in response to food intake

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15
Q

What does insulin signal muscle and fat to do?

A

to uptake glucose from the blood

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16
Q

What does insulin signal the liver to do?

A

to stop endogenous glucose production

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17
Q

Which receptor does insulin act on?

A

the insulin receptor (IR) encoded by the Insr gene

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18
Q

Which receptor family is the insulin receptor a member of?

A

the ligand-activated receptor and tyrosine kinase family of transmembrane receptors

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19
Q

What is the structure of the insulin receptor?

A

the single transmembrane polypeptide crosses the cell membrane once
the intracellular part of the receptor contains a tyrosine kinase domain

20
Q

What happens when the insulin receptor is activated?

A

becomes phosphorylated and signals via the protein kinase B (Akt) pathway to modulate gene transcription and neuronal excitability

21
Q

Where are insulin receptors expressed?

A

in AgRP and POMC neurons of the ARC as well as in neurons of the VMH

22
Q

What does conditional deletion of the insulin receptor in AgRP / POMC neurons have profound effects upon?

A

body weight, ad`iposity and glucose homeostasis

23
Q

What does exogenous insulin almost exclusively signal to?

A

AgRP and POMC neurons of the ARC

24
Q

What is endogenous insulin?

A

the insulin after a meal which activates AgRP neurons

25
Q

What is ghrelin?

A

a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract

26
Q

What is ghrelin encoded by and what is it produced from?

A

encoded by the Ghrl gene and is produced from the cleavage of the prepropeptide ghrelin

27
Q

When is ghrelin secreted?

A

when the stomach is empty

when the stomach is stretched, secretion stops

28
Q

How does ghrelin act on the brain?

A

travels via the blood where it crosses the BBB to interacts with neurons in the hypothalamus

29
Q

Which receptor does ghrelin act upon and what is this receptor encoded by?

A

the ghrelin receptor (GPCR) which is encoded by the Ghs-r1 gene

30
Q

Where is the ghrelin receptor expressed?

A

in AgRP neurons of the ARC (activates AgRP neurons in the ARC)

31
Q

What does genetic deletion of ghrelin receptor in the brain result in?

A

weight loss and hypophagia

32
Q

Deletion of the ____ receptor results in weight loss, whereas deletion of the ____ receptor results in weight gain.

A

ghrelin, insulin

33
Q

What are circumventricular organs?

A

structures in the brain characterized by their extensive and highly permeable microvasculature, unlike those in the rest of the brain where there exists a blood brain barrier (BBB)

34
Q

What do circumventricular organs allow for?

A

the linkage between the central nervous system and peripheral blood

35
Q

Where is the median eminence located?

A

in the inferior portion of the hypothalamus and is ventral to the third ventricle

36
Q

What is the role of the median eminence?

A

is rich in fenestrated capillaries and, therefore, allows the passage of factors (hormones, micronutrients) from the blood

37
Q

What is the major cell type that makes up the median eminence?

A

specialised cells known as tanycytes

38
Q

What do tanycytes exhibit when interacting with BBB vessles?

A

a diffuse pattern of tight junction complexes

39
Q

What pattern do tanycytes display when interacting with fenestrated vessels?

A

a honeycomb pattern

40
Q

How is ghrelin able to cross the BBB?

A

requires diffusion across the BBB to enter the ARC whereas leptin and insulin are less restrained

41
Q

What is fasting-induced blood-ARC interface reorganisation associated with?

A

expansion of the ‘brain window’ so that it is accessible to bloodborne molecules

42
Q

How does fasting influence the blood-ARC interface plasticity?

A

fasting induces the increase of VEGF expression in tanycytes and induces fenestration of microvessels

43
Q

What is blood-ARC interface plasticity based on?

A

cell-cell communication

44
Q

What is the purpose of glucose sensing in tanycytes?

A

closes the “brain window” (as this evokes a Ca2+ wave in the tanycyte layer)

45
Q

What is the level of hormonal input into the ARC coordinated by?

A

nutritional status

46
Q

You have just discovered a novel ghrelin receptor antagonist to treat obesity. What time of day would you recommend it to be administered for it to be most effective?

A

1h before meals

NEUR30002 (36 decks)

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