31 - Integration of Metabolism

Question 1

PFK activity is stimulated/inhibited by?

Answer 1

Stimulated AMP or ADP

Inhibited ATP and citrate

PFK is also regulated by F-2,6-bisP, which is governed by epinephrine and glucagon levels through cAMP.

Question 2

How do the following tissues respond to cAMP?

Liver
Heart
Skeletal muscle

Answer 2

F-2,6-bisP allosterically stimulates PFK (and therefore glucose breakdown/glycolysis)

Liver
- Decrease in F-2,6-bisP

Heart
- Increase in F-2,6-bisP

Skeletal muscle
- F-2,6-bisP does not respond to cAMP

Question 3

What does gluconeogenesis need to bypass irreversible steps of glycolysis?

Answer 3

F-1,6-bisPase and G-6-Pase

Reciprocal regulation of gluconeogenesis and glycolysis determines rate and direction.

Question 4

How is glycogen synthesized and mobilized?

Answer 4

1. Glycogen is stored mostly in liver and muscle
2. Mobilization to G-6-P is catalysed by glycogen phosphorylase and the
   reverse reaction by glycogen synthase
3. Reciprocal regulation by phosphorylation/dephosphorylation cycles of the phosphorylase and synthase that are stimulated by insulin, glucagon
   and epinephrine through cAMP
4. Glucagon:insulin ratio determines whether glycogen is synthesized or
   degraded

Question 5

How are fatty acids synthesized and oxidized (mobilized)?

Synthesis is regulated by ___?

What inhibits synthesis?

Answer 5

1. Level of beta-oxidation is determined by fatty acid concentration
2. Fatty acids are mobilized by tissue TG lipases, usually stimulated by
   epinephrine/glucagon and phosphorylation status via cAMP
3. Synthesis is regulated by ACC and level of citrate, insulin-dependent
   dephosphorylation
4. Inhibition of synthesis by palmitoyl-CoA
5. Glucagon:insulin ratio determines the direction

Question 6

What happens when the citric acid cycle uses acetyl-CoA without pyruvate?

Answer 6

Consumption of cycle intermediates

Enzymes of cycle are regulated by substrate availability, NADH and ATP levels.

Question 7

What happens when the citric acid cycle uses acetyl-CoA without pyruvate?

Answer 7

Consumption of cycle intermediates

Enzymes of cycle are regulated by substrate availability, NADH and ATP levels.

Question 8

What does amino acid synthesis and degradation do for TCA cycle, glycolysis and gluconeogenesis?

Answer 8

Provides aKG for citric acid cycle, glycolysis and gluconeogenesis.

Some common amino acids are only able to produce ketones, not glucose.

Question 9

Why does the brain consume so much oxygen?

Answer 9

To maintain membrane potential via Na/K ATPase

GLucose is the normal fuel, but ketone bodies are used if prolonged fasting occurs.

No storage of glycogen.

Question 10

TG hydrolyzes stored TG in response to?

Answer 10

• Glucagon
• Epinephrine

Inhibited by insulin

Question 11

What are the four possible fates of G-6-P in the liver?

Answer 11

Depends on metabolic requirements.

(i) converted to glucose when blood glucose levels are low
(ii) converted to glycogen when blood glucose is adequate
(iii) oxidized to acetyl-CoA (used for energy or lipid biosynthesis) (iv) converted to NADPH for biosynthetic processes

Question 12

What are the three possible fates of fatty acids in the liver?

Answer 12

(i) can be converted to ketones for use as metabolic fuel

(ii) used to synthesize TG when demand for energy is low
(transported to and stored in adipose tissue)

(iii) compartmentalization of fatty acids prevents futile cycling
(malonyl CoA prevents uptake of FA into mitochondria)

Question 13

What are the main sources of energy for the liver?

Answer 13

Fatty acids and amino acids

NOT glucose or ketones

Question 14

What are the main sources of energy for the liver?

Answer 14

Fatty acids and amino acids

NOT glucose or ketones

Question 15

How can muscle protein be broken down for energy?

Answer 15

Amino acids released from muscle proteins can be converted to pyruvate then alanine and transported back to the liver for gluconeogenesis in the alanine-glucose cycle.

Question 16

How can muscle protein be broken down for energy?

Answer 16

Amino acids released from muscle proteins can be converted to pyruvate then alanine and transported back to the liver for gluconeogenesis in the alanine-glucose cycle.

Question 17

Muscle responds to ___ to regulate glycogen synthesis and breakdown

Answer 17

epinephrine but not glucagon (no receptors)

Question 18

What does increase in cAMP in heart tissue do?

Answer 18

Stimulates glycogen breakdown and glycolysis for glucose consumption. This is in contrast to the liver, in which glucagon acts via cAMP to regulate blood glucose levels.

Question 19

What happens if glycolysis runs out of oxygen supply?

Answer 19

Glycolysis will be anaerobic and generate lactate.

The cori cycle converts lactate to glucose in the liver.

Question 20

What type of fuel do heart muscles rely on?

Answer 20

Heart muscle relies entirely on aerobic metabolism, and uses fatty acids primarily but can use any fuel source if required

Question 21

Absence of the hypothalamus will lead to obesity how?

Answer 21

The lipostate will be gone.

Leptin produced by adipocytes suppresses appetite by acting on hypothalamic receptors.

Leptin deficiency can cause obesity in humans, but is rare. Rather target tissues have developed leptin resistance.

Question 22

What does leptin do?

Answer 22

Stimulates fatty acid oxidation and inhibits the accumulation of TG in non-adipose tissues by inactivating ACC.

This reduces malonyl-CoA and increases FA transport into mitochondria.

Insulin also seems to be a component of the lipostat mechanism as it also acts in the hypothalamus to decrease food intake.

Question 23

What is ghrelin?

Answer 23

peptide secreted by empty stomach to stimulate appetite.

Injection leads to increase in adipose tissue in rodents. In humans, plasma levels are low in the fed state and increase in the fasted state.

Question 24

What is adaptive thermogenesis?

Answer 24

Occurs in response to cold temperature and involves the increased expression of “uncoupling proteins” which discharges the H+ gradient in the mitochondrion such that energy if dissipated as heat

Especially important in brown adipose tissue

Question 25

What is adaptive thermogenesis?

Answer 25

Occurs in response to cold temperature and involves the increased expression of “uncoupling proteins” which discharges the H+ gradient in the mitochondrion such that energy if dissipated as heat

Especially important in brown adipose tissue

Question 26

Why can fatty acids not be used to synthesize glucose?

Answer 26

Because the pyruvate or oxaloacetate required for gluconeogenesis cannot be synthesized from acetyl-CoA

Oxaloacetate IS made from acetyl-CoA, but is consumed as fast as it is synthesized in the TCA cycle

Question 27

What happens to glucose synthesis during starvation?

What is survival dependent on?

How is starvation similar to diabetes mellitus?

Answer 27

During starvation, glucose is synthesized in the liver from glycerol (from TG breakdown) and a-ketoacids (from amino acids of muscle proteins).

After several days, ability to metabolize acetyl-CoA is almost zero

Instead the acetyl-CoA is converted to ketones muscle breakdown will stop

Survival during prolonged starvation is dependent on the size of the fat storage pool

diabetes mellitus = starvation due to inability of cells to access available glucose