Signaling pathways for energy balance

Question 1

What are the two opposing classes of neurons acting on metabolism in the arcuate nucleus of the hypothalamus?

Answer 1

• POMC neurons which are ANOREXIGENIC (appetite suppressing)

- NPY neurons which are OREXIGENIC (appetite stimulating)

Question 2

What do POMC neurons release?

Answer 2

melanocyte-stimulating hormone (a-MSH)

Question 3

What is the receptor for a-MSH?

Answer 3

MC4

Question 4

What do NPY neurons release?

Answer 4

NPY and other neurotransmitters

Question 5

What is the gist of the new discoveries about central regulation of energy balance?

Answer 5

Some of the same metabolic pathways used in controlling fuel utilization in peripheral tissues are used to neuronal signaling.

Question 6

How does the arcuate nucleus of the hypothalamus receive input?

Answer 6

Via hormones (insulin, leptin, ghrelin, others)

Question 7

What are the two ways that NPY neurons stimulate appetite?

Answer 7

1) inhibit the downstream neurons that POMC neurons activate

2) inhibit POMC neurons directly

Question 8

Most likely activator of POMC neurons?

Answer 8

glucose

Question 9

Most likely activator of NPY neurons?

Answer 9

fatty acids

Question 10

Explain how POMC neurons use part of the beta-cell insulin-release pathway in their signaling

Answer 10

pancreatic beta-cells generate ATP via glycolysis and CAC and that ATP inhibits a plasma membrane potassium channel, causing membrane depolarization. This activates a voltage sensitive calcium channel, allowing calcium to enter the cell. Calcium entry triggers insulin release from vesicles. POMC uses the ATP/calcium channel pathway but the action potential generated is simply the neuronal action potential.

Question 11

How does FA influence NPY neuronal activity?

Answer 11

via CAT-1

• Low CAT-1 activity is anorexigenic (decreases appetite and increases energy utilization) by decreasing NPY activity
• High CAT-1 activity is orexigenic (increases appetite and decreases energy utilization) by increasing NPY activity

Question 12

What effect do these brain treatments have on neuronal CAT-1 activity and appetite:

• ACC inhibitors?
• CAT-1 inhibitors?
• AMPK activators?

Answer 12

• ACC inhibitors? - Increase both
• CAT-1 inhibitors? - decrease both
• AMPK activators? - increase both

Question 13

What is a PPAR protein?

Answer 13

• stands for Peroxisome proliferator - activated receptor
• transcription factor
• fatty compounds bind to it

Question 14

What are the two PPAR isoforms?

Answer 14

alpha and gamma

Question 15

Where can you find PPAR-alpha?

Answer 15

liver, heart, skeletal muscle (tissues that burn fat well)

Question 16

Where can you find PPAR-gamma?

Answer 16

adipose tissue

Question 17

What is the action of PPAR-alpha?

Answer 17

• activates FA oxidation by increasing transcription of proteins involved in b-oxidation and FA import to mitochondrial matrix (CAT-1, CAT-2)

Question 18

What is the action of PPAR-gamma?

Answer 18

• activates adipogenesis

- activates increased uptake of FA into adipocyte

Question 19

What drugs are used to target PPAR-alpha and why?

Answer 19

• fibrate family of synthetic ligands

- used therapeutically to increase FA utilization and decrease lipid levels

Question 20

What drugs are used to target PPAR-gamma and why?

Answer 20

• thiazolidinedione (TZD) family of synthetic ligands
• TZDs used as insulin sensitizers
• can have side effects such as weight gain, cardiovascular problems, osteoporosis