Lecture 30: Neurocircuitry of Metabolism 2

Question 1

What is AgRP synthesised by?

Answer 1

neuropeptide Y (NPY)-containing cell bodies located in the arcuate nucleus in the hypothalamus

Question 2

What does AgRP or NPY promote when administered intracerebroventricularly?

Answer 2

food intake

Question 3

How do the levels of AgRP and NPY in AgRP neurons change throughout the day?

Answer 3

increase during fasting and decrease after refeeding (regulated by metabolic status)

Question 4

How is AgRP mRNA expression change in a fasted state?

Answer 4

elevated

Question 5

What are AgRP neurons activated by?

Answer 5

energy deficit

Question 6

What does neuronal activation lead to?

Answer 6

changes in intracellular calcium levels

Question 7

Why does fasting increase c-Fos expression in AgRP / NPY neurons?

Answer 7

because the gene that codes for c-FOS is among the genes whose activity is altered by calcium levels

Question 8

What are POMC neurons considered as?

Answer 8

the brakes of metabolism

Question 9

What does genetic ablation of POMC neurons result in?

Answer 9

weight gain and hyperphagia

Question 10

What does optogenic or chemogenic (DREADDS) activation of POMC neurons result in?

Answer 10

weight loss and hypophagia

Question 11

What does the POMC gene encode?

Answer 11

the POMC precursor protein, which produces many biologically active peptides via a series of enzymatic steps in a tissue-specific manner

Question 12

What does the POMC precursor protein produce?

Answer 12

melanocyte-stimulating hormones (MSHs), corticotropin (ACTH) and beta-endorphin

Question 13

Where is POMC protein directed?

Answer 13

into secretory granules where post-translational processing yields many peptides by successive, cell-specific, enzymatic modifications

Question 14

Where does cleavage by the pro-peptide convertases PC1 and PC2 occur?

Answer 14

at specific pairs of basic residues and cleaves alpha-MSH, beta-MSH and gamma-MSH

Question 15

What does alpha-MSH, beta-MSH and gamma-MSH have in common?

Answer 15

are all agonists at the Melanocortin 4 receptor (MC4R)

Question 16

What is melanocortin 4 receptor?

Answer 16

a Gs protein-coupled receptor that binds alpha-melanocyte stimulating hormone (alpha-MSH)

Question 17

What are mutations in the MC4R gene associated with?

Answer 17

genome-wide association studies of BMI confirmed that they are associated with obesity

Question 18

What does ICV administration of alpha-MSH result in?

Answer 18

weight loss and hypophagia

Question 19

mice or humans lacking MC4R or alpha-MSH are…

Answer 19

obese and hyperphagic

Question 20

Where are MC4R receptors heavily expressed?

Answer 20

on cell bodies of the PVH and LH

Question 21

Where do neurons of the PVH project to and what do these projections govern?

Answer 21

preganglionic neurons in the spinal cord which in turn govern the innervation to peripheral tissues such as liver and fat to regulate energy stores

Question 22

What do neurons of the LH regulate?

Answer 22

feeding behaviour and motivated behaviours

Question 23

How does alpha-MSH and AgRP act on MC4R receptors?

Answer 23

alpha-MSH is an agonist at MC4R receptors and AgRP is an antagonist at MC4R receptors

Question 24

What does POMC promote?

Answer 24

satiety

Question 25

What happens to POMC in the neuron?

Answer 25

is cleaved producing the neuropeptide, alpha-MSH which is secreted from the neuron and acts as an agonist on MC4R on second order PVH or LH neurons to elicit effects on energy balance

Question 26

What do defects in the melanocortin system underly?

Answer 26

human obesity

Question 27

What is AgRP peptide secreted from?

Answer 27

AgRP / NPY neurons and acts as an antagonist at MC4R

Question 28

What does the melanocortin circuit form?

Answer 28

the basics by which opposing neuronal populations of the ARC can elicit biphasic actions upon energy balance

Question 29

What is the lipostatic hypothesis?

Answer 29

the brain monitors the amount body fat and acts to “defend” this
energy store against perturbations

Question 30

What is parabiosis?

Answer 30

the surgical union of two animals to produce a common blood

supply and allows the investigation of bloodborne circulating factors

Question 31

What happens when a db/db mouse is connected to a lean weight mouse?

Answer 31

db/db overproduces a satiety factor but does not respond to it
lean wt responds to the satiety factor and starves

Question 32

What happens when a ob/ob mouse is connected to a lean weight mouse?

Answer 32

ob/ob mice respond to the satiety factor produced in the lean wt mice
production of a satiety factor in lean wt mice is not sufficient to cause starvation in ob/ob mice