6 - Metabolic stress in Cancer, Starvation, Exercise Flashcards
Postabsorptive Phase 1
- Glucose Maintained
- Insulin Decreased
-
Liver:
- Glycogenolysis
- Glycogen -> Glucose
- Gluconeogenesis
- Glycogenolysis
- Glucose Oxidation for ATP Generation
Fasting Phase 2
- Decreased Glucose & Insulin
- Increase in KETOACIDS
-
Stored TG’s -> FA’s
- after depletion of hepatic glycogen
- Reliance on LIPID oxidation for ATP generation
Starvation Phase 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
- Protein -> AA’s -> Glucose
Ketogenic Diet
- 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
- Body will liberate TG’s first from adipocytes
- Since there is a low Glycogen supply, Body thinkgs it is “Starving”
Normal Ghrelin Function Pathway
- 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
-
-> Medulla oblongata = Reticular Formation
- -> Hypothalmus NPY signals HUNGER
When feeding Ghrelin is?
- SUPPRESSED
- Leptin from adipocytes -> Hypothalmus
- inhibits NPY gene expression in Arcuate Nucleus
- also reduces AgRP
- increases POMC
- Tells You it’s Full = SATIETY
Ghrelin in STARVATION
- Starvation & Weight loss:
-
INCREASES GHRELIN LEVELS
- then return to normal upon feeding
-
INCREASES GHRELIN LEVELS
Ghrelin levels are ____ in bulimia nervosa patients
HIGHER
Body is telling you you should eat
Ghrelin levels are ____ in OBESE individuals
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
Autophagy
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
- Autophagosome + Lysosome = Autophagolysosome
ATG
Autophagy Related Genes
Used to regulate Autophagy through:
AMPK + Nutrient Availability
Inhibited by mTOR
Autophagosome
Double Membrane Vescicle that captures cytoplasmic cargo
ATG Proteins + Membrane
Autophagolysosome
Provides Hydrolases to degrade cargo in Autophagy
Autophagosome + Lysosome
Recycles AA’s / Nucleosides / FA’s / Sugars for:
Metabolism / Redox / Energy / Biomass
Autophagy Pathway in Nutrient RICH conditions:
- AA’s -> Activate mTORC1
- P6K + 4EBP1
- -> protein translation + Cell Growth
-
DAP1
- INHIBITS AUTOPHAGY
- P6K + 4EBP1
Autophagy in Starvation Conditions
-
LKB1 senses low energy
- activates AMPK
- -> inactivates mTORC1 through TSC
- *rapamycin also inhibits mTORC1
-
DAP1 is no longer inhibiting autophagy
- AUTOPHAGY OCCURS
- -> inactivates mTORC1 through TSC
- activates AMPK
How does AUTOPHAGY help starvation?
-
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
Fatty Acid Uptake in STARVATION
- Fasting causes:
- INCREASES in FATTY ACID UPTAKE TRANSPORTERS in the Muscle
- Decreases the FA transporters in the Liver & Adipose
- INCREASES in FATTY ACID UPTAKE TRANSPORTERS in the Muscle
- Uptake of FFAs in muscle helps maintain FFA in circulation
Agouti-Related Peptide
AgRP
- AgRP neurons in the Hypothalmic Arcuate Nucleus
- focal point for nutritional & metabolic cues
- remember Leptin material
- focal point for nutritional & metabolic cues
- Autophagy is key for regulating food intake through AgRP hypothalmic expression
FFA are _____ in Starvation and leads to?
- FFA INCREASES in starvation
- -> Hypothalmic FFA Uptake
- -> Promotes AUTOPHAGY
- -> Hypothalmic FFA Uptake
Reduction of Autophagy in hypothalmus causes?
-
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
AgRP Neurons are STIMULATED by what?
Active AgRP –> Increase food intake
- Ghrelin
- Fatty Acids
- Glucose
-
Starvation/ Autophagy
-
-> Increase in FFA
- -> Become TG’s
- -> Lipid Droplets -> Autophagy
- -> Become TG’s
-
-> Increase in FFA
AgRP is downregulated by which hormones?
Decrease in AgRP -> Satiety / less food intake
LEPTIN
AgRP remembers leptin material
How does the LIVER work with Exercise?
- 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
- FFA supply energy to liver
- Increased OXIDATION of FFA from adipose
-
Liver is out of glycogen -> glucose
Exercise leads to an INCREASED need for?
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
How does EC change with exercise?
-
Liver’s (Hepatic) Energy charge DECREASES
- –> in turn activates AMPK in liver
- Muscle EC does not change
AMPK changes with exercise
-
Hepatic EC decreases
- Increase in hepatic p-AMPK
-
In other organs outside of liver there is:
- Increase in FA Oxidation
- Increase in Gluconeogenic Drive
High Energy Charge does what to Catabolic pathways?
- High EC
- -> Inhibits Catabolic Pathways (generate energy)
- Inhibits AMPK
- -> Inhibits Catabolic Pathways (generate energy)
High Energy Charge does what to Anabolic pathways?
-
low EC:
- -> Increase in Anabolic Pathways (energy utilizing)
Exercise Increases Gluconeogenesis in which Organs?
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
How does exercise affect GLUCAGON?
- Exercise -> Increased Glucagon secretion & effectiveness
- __tells liver to create more Glucose
-
to feed the muscle
- __to prevent HYPERglycemia
-
to feed the muscle
- __tells liver to create more Glucose
- Prolonged Exercise -> Decreased Insulin
How does exercise INCREASE Insulin sensistivity?
- 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
-
More GLUT4 receptors
- Decreased muscle glycogen concentration
Women’s Differences in metabolism
- Women have more:
- % body fat
- subcutaneous fat (SC)
-
Women have less:
- Viceral Fat
- muscle mass
- oxidize less lipid substrate
Exercise role with T2DM
- Can DELAY or PREVENT T2DM
- Improve:
- Blood Glucose
- Body Weight
- Lipids
- Blood Pressure
