Lecture 31: Neurocircuitry of Metabolism 3

Question 1

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

Answer 1

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

Question 2

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

Answer 2

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

Question 3

What is leptin?

Answer 3

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

Question 4

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

Answer 4

the amount of fat in the body

Question 5

How does leptin regulate adiposity?

Answer 5

by communicating levels of adiposity to the brain

Question 6

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

Answer 6

the db gene

long, short and secretory

Question 7

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

Answer 7

mainly in the hypothalamus

Question 8

What happens when leptin binds to the LepR?

Answer 8

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

Question 9

What does leptin signalling result in?

Answer 9

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

Question 10

How does leptin influence AgRP and POMC neurons?

Answer 10

leptin inhibits AgRP neurons and activates POMC neurons

Question 11

Where are leptin receptors expressed?

Answer 11

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

Question 12

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

Answer 12

increased BW and adiposity

Question 13

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

Answer 13

increased BW and adiposity

Question 14

What is insulin?

Answer 14

a peptide hormone secreted from beta-cells

in the pancreas in response to food intake

Question 15

What does insulin signal muscle and fat to do?

Answer 15

to uptake glucose from the blood

Question 16

What does insulin signal the liver to do?

Answer 16

to stop endogenous glucose production

Question 17

Which receptor does insulin act on?

Answer 17

the insulin receptor (IR) encoded by the Insr gene

Question 18

Which receptor family is the insulin receptor a member of?

Answer 18

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

Question 19

What is the structure of the insulin receptor?

Answer 19

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

Question 20

What happens when the insulin receptor is activated?

Answer 20

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

Question 21

Where are insulin receptors expressed?

Answer 21

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

Question 22

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

Answer 22

body weight, ad`iposity and glucose homeostasis

Question 23

What does exogenous insulin almost exclusively signal to?

Answer 23

AgRP and POMC neurons of the ARC

Question 24

What is endogenous insulin?

Answer 24

the insulin after a meal which activates AgRP neurons

Question 25

What is ghrelin?

Answer 25

a peptide hormone produced by ghrelinergic cells in the gastrointestinal tract

Question 26

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

Answer 26

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

Question 27

When is ghrelin secreted?

Answer 27

when the stomach is empty | when the stomach is stretched, secretion stops

Question 28

How does ghrelin act on the brain?

Answer 28

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

Question 29

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

Answer 29

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

Question 30

Where is the ghrelin receptor expressed?

Answer 30

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

Question 31

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

Answer 31

weight loss and hypophagia

Question 32

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

Answer 32

ghrelin, insulin

Question 33

What are circumventricular organs?

Answer 33

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)

Question 34

What do circumventricular organs allow for?

Answer 34

the linkage between the central nervous system and peripheral blood

Question 35

Where is the median eminence located?

Answer 35

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

Question 36

What is the role of the median eminence?

Answer 36

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

Question 37

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

Answer 37

specialised cells known as tanycytes

Question 38

What do tanycytes exhibit when interacting with BBB vessles?

Answer 38

a diffuse pattern of tight junction complexes

Question 39

What pattern do tanycytes display when interacting with fenestrated vessels?

Answer 39

a honeycomb pattern

Question 40

How is ghrelin able to cross the BBB?

Answer 40

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

Question 41

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

Answer 41

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

Question 42

How does fasting influence the blood-ARC interface plasticity?

Answer 42

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

Question 43

What is blood-ARC interface plasticity based on?

Answer 43

cell-cell communication

Question 44

What is the purpose of glucose sensing in tanycytes?

Answer 44

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

Question 45

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

Answer 45

nutritional status

Question 46

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?

Answer 46

1h before meals