FORM & FUNCTION (Obesity 2: Randle Cycle)

Question 1

Excess nutrient (non-starvation):

Answer 1

-supply and demand determines which metabolic fuel is used
-CHO: 55-75%
-Fat: 15-30%
-Protein: 10-15%

Question 2

Randle-cycle:

Answer 2

-body prioritizes whichever fuel is in abundance: CHO or fat
*reciprocal regulation

Question 3

Reciprocal regulation:

Answer 3

-use of one substrate INHIBITS the use of another
-excess lipid (obesity): blocks glucose metabolism
-excess glucose (high sugar diet): blocks lipid metabolism

Question 4

Excess glucose inhibits FFA usage: mechanism

Answer 4

1. Excess citrate exits the mitochondria and reforms acetyl-CoA in the cytoplasm
2. High glucose leads to insulin release which stimulates malonyl-CoA synthesis
3. Malonyl-CoA inhibits CPT-I, stalling FFA attachement to carnitine

Question 5

Excess glucose inhibits FFA usage: end result

Answer 5

-glucose-derived malonyl-CoA suppresses fatty acid oxidation by inhibiting fatty acid activation via CPT-1

Question 6

Excess FFA inhibits glucose usage: mechanism

Answer 6

1. High FFA beta-oxidation increases mitochondrial levels of acetyl-CoA
2. High levels of acetyl-CoA inhibits pyruvate dehydrogenase (PDH), preventing pyruvate conversion to acetyl-CoA and stalls glycolysis
3. Excess citrate inhibits GLUT-4 to suppress glucose transport

Question 7

Excess FFA inhibits glucose usage: end result

Answer 7

-FFA-derived acetyl-CoA and citrate inhibits PDH and GLUT4 to prevent glucose import and breakdown

Question 8

3 key/shared molecules:

Answer 8

1. Malonyl-CoA
2. Citrate
3. Acetyl-CoA

Question 9

Malonyl Co-A

Answer 9

-inhibits CPT-1
>from glucose: inhibits fat metabolism
>from fat: negative feedback

Question 10

Citrate:

Answer 10

-inhibits GLUT4
>from glucose: negative feedback
>from fat: inhibits glucose metabolism

Question 11

Acetyl-CoA:

Answer 11

-inhibits PDH
>from glucose: negative feedback
>from fat: inhibits glucose metabolism

Question 12

Obesity effects on Randle-cycle:

Answer 12

-obese individuals have elevated circulatory FFA
-increase FFA usage inhibits glucose metabolism via PDH and GLUT4
-impaired skeletal muscle uptake after a meal: hyperglycemia

Question 13

Consequence of hyperglycemia after a meal obese (Randle-cycle)

Answer 13

-body produces more insulin than normal (hyperinsulinemia)
*eventually insulin resistance starts to build, leading to onset of diabetes
*”fatty acid syndrome”

Question 14

Obesity on blood glucose:

Answer 14

1. Animals experience longer periods of hyperglycemia post meal
2. Beta-cells in pancreas works much harder and produces excess insulin (precursor to resistance and diabetes)

Question 15

Why longer periods of hyperglycemia? (obesity)

Answer 15

-more TIME and INSULIN is required to OUTCOMPETE EXCESS FFA to normalize glucose