6 - Metabolic stress in Cancer, Starvation, Exercise

Question 1

Postabsorptive Phase 1

Answer 1

• Glucose Maintained
• Insulin Decreased
• Liver:
  
  • Glycogenolysis
    
    • Glycogen -> Glucose
  • Gluconeogenesis
• Glucose Oxidation for ATP Generation

Question 2

Fasting Phase 2

Answer 2

• Decreased Glucose & Insulin
• Increase in KETOACIDS
• Stored TG’s -> FA’s
  
  • ​after depletion of hepatic glycogen
• Reliance on LIPID oxidation for ATP generation

Question 3

Starvation Phase 3

Answer 3

• Greatly reduced Glucose + Insulin
• Greatly increased KETOACIDS
• depletion of LIPID storage
• Reliance on LEAN TISSUE & PROTEIN catabolism
  
  • ​Protein -> AA’s -> Glucose
    
    • for ATP generation

Question 4

Ketogenic Diet

Answer 4

• High PROTEIN diet
  
  • low carbohydrate supply
• ​Normally Glycogen > TG’s > Protein
  
  • Since there is a low Glycogen supply, Body thinkgs it is “Starving”
    
    • Body will liberate TG’s first from adipocytes
      
      • ​and produce ketones

Question 5

Normal Ghrelin Function Pathway

Answer 5

• Ghrelin signaled to release from STOMACH
  
  • ​-> Hypothalmus NPY signals HUNGER
    
    • AgRP also increased
    • POMC decreased
      
      • ​-> Medulla oblongata = Reticular Formation
        
        • ​Somatic: Increase Feeding
        • Sympathetic : Reduce Metabolism

Question 6

When feeding Ghrelin is?

Answer 6

• SUPPRESSED
• ​​Leptin from adipocytes -> Hypothalmus
  
  • inhibits NPY gene expression in Arcuate Nucleus
  • also reduces AgRP
  • increases POMC
    
    • ​ Tells You it’s Full = SATIETY

Question 7

Ghrelin in STARVATION

Answer 7

• Starvation & Weight loss:
  
  • INCREASES GHRELIN LEVELS
    
    • then return to normal upon feeding

Question 8

Ghrelin levels are ____ in bulimia nervosa patients

Answer 8

HIGHER

Body is telling you you should eat

Question 9

​Ghrelin levels are ____ in OBESE individuals

Answer 9

Lower

Body is telling you to stop eating

But in obese individuals w/ WEIGHT LOSS:

Ghrelin levels will INCREASE

Telling you should eat more, but you have to try and IGNORE

Question 10

Autophagy

Answer 10

Intracellular LYSOSOMAL degradation & recycling of proteins

• Regulated through ATG (autophagy related genes) by
  
  • mTOR inhibits
  • AMPK & Nutrient availability
• ​ATG protein + Membrane = Autophagosome
  
  • Autophagosome + Lysosome = Autophagolysosome
    
    • provides Hydrolases to degrade cargo

Question 11

ATG

Answer 11

Autophagy Related Genes

Used to regulate Autophagy through:

AMPK + Nutrient Availability

Inhibited by mTOR

Question 12

Autophagosome

Answer 12

Double Membrane Vescicle that captures cytoplasmic cargo

ATG Proteins + Membrane

Question 13

Autophagolysosome

Answer 13

Provides Hydrolases to degrade cargo in Autophagy

Autophagosome + Lysosome

Recycles AA’s / Nucleosides / FA’s / Sugars for:

Metabolism / Redox / Energy / Biomass

Question 14

Autophagy Pathway in Nutrient RICH conditions:

Answer 14

• AA’s -> Activate mTORC1
  
  • ​P6K + 4EBP1
    
    • -> protein translation + Cell Growth
  • DAP1
    
    • ​INHIBITS AUTOPHAGY

Question 15

Autophagy in Starvation Conditions

Answer 15

• LKB1 senses low energy
  
  • ​activates AMPK
    
    • -> inactivates mTORC1 through TSC
      
      • ​*rapamycin also inhibits mTORC1
    • ​​​​DAP1 is no longer inhibiting autophagy
      
      • ​AUTOPHAGY OCCURS

Question 16

How does AUTOPHAGY help starvation?

Answer 16

• Autophagy liberates material that can generate energy through the TCA Cycle
  
  • ​​​Studies showed that autophagy is necessary for more energy through TCA
• Autophagy generated nutrients can be EXPORTED
  
  • –> to help OTHER cells.
  • Without Autophagy starvation is MORE severe
    
    • intracellular AA drop
    • block protein synthesis

Question 17

Fatty Acid Uptake in STARVATION

Answer 17

• Fasting causes:
  
  • INCREASES in FATTY ACID UPTAKE TRANSPORTERS in the Muscle
    
    • Decreases the FA transporters in the Liver & Adipose
• ​​​Uptake of FFAs in muscle helps maintain FFA in circulation

Question 18

Agouti-Related Peptide

AgRP

Answer 18

• AgRP neurons in the Hypothalmic Arcuate Nucleus
  
  • focal point for nutritional & metabolic cues
    
    • ​remember Leptin material
• Autophagy is key for regulating food intake through AgRP hypothalmic expression

Question 19

FFA are _____ in Starvation and leads to?

Answer 19

• FFA INCREASES in starvation
  
  • -> Hypothalmic FFA Uptake
    
    • -> Promotes AUTOPHAGY​​

Question 20

Reduction of Autophagy in hypothalmus causes?

Answer 20

• Reduces AgRP
  
  • ​Food Intake
  • Adiposity
• Autophagy is KEY for regulating food intake through AgRP hypothamic expression
  
  • _​_Without Autophagy, AgRP does not stimulate an increase in food intake

Question 21

AgRP Neurons are STIMULATED by what?

Answer 21

Active AgRP –> Increase food intake

• Ghrelin
• Fatty Acids​
• Glucose
• Starvation​/ Autophagy
  
  • ​-> Increase in FFA
    
    • -> Become TG’s
      
      • -> Lipid Droplets -> Autophagy

Question 22

AgRP is downregulated by which hormones?

Answer 22

Decrease in AgRP -> Satiety / less food intake

LEPTIN

AgRP remembers leptin material

Question 23

How does the LIVER work with Exercise?

Answer 23

• Without energy stores in Liver exercise is not possible
  
  • liver meets energy demands of the muscle
• Exercise -> Starvation mode
  
  • Liver is out of glycogen -> glucose
    
    • ​Increased OXIDATION of FFA from adipose
      
      • ​FFA supply energy to liver
        
        • FFA->Acetyl-CoA -> Krebs

Question 24

Exercise leads to an INCREASED need for?

Answer 24

Glucose / Lipids / Glycogen in the muscle__​

Some amino acids

• Glucose comes from the liver, which consumes ATP
  
  • -> Energy Charge decreases (less ATP avail)
  • pushes cell into:
    
    • Gluconeogenesis / Fatty Acid Oxidation
    • Enhanced Activation of AMPK

Question 25

**How does EC change with exercise?**

Answer 25

* ***Liver's (Hepatic) Energy charge DECREASES*** * ***​***--\> in turn activates AMPK in liver * *_Muscle EC does not change_*

Question 26

**AMPK changes with exercise**

Answer 26

* *Hepatic EC decreases* * Increase in **hepatic p-AMPK****​** * _In other organs outside of liver there is:_ * Increase in **FA Oxidation** * Increase in **Gluconeogenic Drive**

Question 27

**High Energy Charge does what to Catabolic pathways?**

Answer 27

* High EC * -\> ***Inhibits Catabolic Pathways*** (generate energy) * *Inhibits **AMPK***

Question 28

**High Energy Charge does what to Anabolic pathways?**

Answer 28

* *low EC:* * *​-\>* **Increase in Anabolic Pathways** (energy utilizing)

Question 29

**Exercise Increases Gluconeogenesis in which Organs?**

Answer 29

​All nutrients go to **_LIVER_** to be converted to **Glucose** **_Exercise also accelerates the_** **_DELIVERY & EXTRACTION of glucose_** * **Gut** * **​AA / Pyruvate + Lactate** * **Muscle** * **​Pyruvate + Lactate** * **Adipose** * **Glycerol**

Question 30

**How does exercise affect GLUCAGON?**

Answer 30

* Exercise -\> **Increased Glucagon secretion & effectiveness** * _​_tells _liver_ to create more **Glucose** * **​**to feed the _muscle_ * _​_to prevent HYPERglycemia * Prolonged Exercise -\> ***Decreased Insulin***

Question 31

**How does exercise INCREASE Insulin sensistivity?**

Answer 31

* Acute Exercise increases effectiveness in: * **Insulin's ability to transport glucose** * **​**​**Increased activity of insulin receptor** * **​**More **GLUT4** receptors * to bring bring glucose into cells * ***Decreased muscle glycogen concentration***

Question 32

**Women's Differences in metabolism**

Answer 32

* Women have _**more**:_ * **_% body fat_** * **_subcutaneous fat (SC)_** * **​**Women have ***less:*** * ***​Viceral Fat*** * ***muscle mass*** * ***oxidize less lipid substrate***

Question 33

**Exercise role with T2DM**

Answer 33

* **Can DELAY or PREVENT T2DM** * Improve: * **Blood Glucose** * **Body Weight** * ***Lipids*** * **Blood Pressure**