Metabolism 101R. Low, 02/10/14

Need to fix text a la part-1

Definitions Absorptive phase of digestion:

Have just eaten a meal Postabsorptive phase of digestion:

Several hours after eating a meal

Adapted fast:Changes in brain energy use and overall metabolism that extend the ability to fast out to weeks. Begins within a few days.

Glycogen

Trigylceride

Protein

Body Energy Stores

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

R + NH2

NH3

+Urea

TriglyceridesAmino Acids

Ketoacids

The “Full Monty” Cell (which does not exist)

Ketoacids Fatty Acids

Acetyl CoA

7

Glucose

Glycogen

Glycolysis

Pyruvate

Krebs Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

R + NH2

NH3

+Urea

Amino Acids

Glucose

Ketoacids Triglycerides Fatty Acids

Glucose-6-P

Acetyl CoA

8

Ketoacids

Glucose

Glycogen

Glycolysis

Pyruvate

Krebs Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

R + NH2

NH3

+Urea

Amino Acids

Glucose - Fat

Ketoacids Triglycerides Fatty Acids

Glucose-6-P

Acetyl CoA

9

Ketoacids

Glucose

Glycogen

Glycolysis

Pyruvate

Krebs Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

R + NH2

NH3

+Urea

Amino Acids

Glucose - Protein

Ketoacids Triglycerides Fatty Acids

Glucose-6-P

Acetyl CoA

10

Ketoacids

Glucose

Glycogen

Glycolysis

Pyruvate

Krebs Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

R + NH2

NH3

+Urea

Amino Acids

Ketoacids

Ketoacids

Ketoacids Triglycerides Fatty Acids

Glucose-6-P

Acetyl CoA

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12

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

ATP

O2 H2O

Brain

Glucose-6-P

Acetyl CoA

Ketoacids

Ketoacids

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

TriglyceridesAmino Acids

Ketoacids

Muscle

Ketoacids Fatty Acids

Acetyl CoA

13

Lactate

Lactate

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Triglycerides

Adipose TissueFatty Acids

Glucose-6-P

Acetyl CoA

14

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

TriglyceridesAmino Acids

LiverFatty Acids

Glucose-6-P

Acetyl CoA

15

Ketoacids

Ketoacids

R + NH2

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Ketoacids

KidneyKetoacids Fatty Acids

Acetyl CoA

16

Triglycerides

NH3

+Urea

R + NH2

Amino Acids

Amino AcidsAmino Acids

17

Hormones and Energy Metabolism

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HOW DOES ONE DO IT?D

aily

Liv

ing

Emer

genc

y

REDUNDANCY -- COMPLEMENTARITY

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EFFECTS OF INSULIN

PRINCIPAL TARGETS: Liver, Adipose, Muscle

CARBOHYDRATE:- Increased Glucose Uptake: Muscle and Adipose

- Increased Glycogenesis; decreased glycogenolysis

- Decreased Gluconeogenesis

FAT:- Increased Triglyceride Synthesis for Storage- Decreased Breakdown of Triglyceride Stores

PROTEIN:- Increased Synthesis

- Decreased Breakdown

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Major Insulin Actions: Tissue by Tissue

Liver: INcreased glycogen deposition DEcreased glycogenolysis INcreased glucose use DEcreased gluconeogenesis

Muscle: INcreased Glucose transport / use INcreased Protein synthesis DEcreased protein degradation

Adipose: INcreased Triglyceride synthesis / storage DEcreased triglyceride breakdown / release

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

TriglyceridesAmino Acids

Ketoacids

Insulin - Muscle

Ketoacids Fatty Acids

Acetyl CoA

22

Lactate

Lactate

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Triglycerides

Insulin- Adipose TissueFatty Acids

Glucose-6-P

Acetyl CoA

23

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

TriglyceridesAmino Acids

Insulin - LiverFatty Acids

Glucose-6-P

Acetyl CoA

24

Ketoacids

Ketoacids

R + NH2

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Major Glucagon Actions: Tissue by Tissue

Liver: DEcreased glycogen deposition INcreased glycogenolysis DEcreased glucose use INcreased gluconeogenesis INcreased Fatty Acid Oxidation

Muscle: Not much

Adipose: Not much

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

TriglyceridesAmino Acids

Ketoacids

Glucagon - Muscle

Ketoacids Fatty Acids

Acetyl CoA

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Lactate

Lactate

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Triglycerides

Glucagon - Adipose TissueFatty Acids

Glucose-6-P

Acetyl CoA

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Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

TriglyceridesAmino Acids

Glucagon - LiverFatty Acids

Glucose-6-P

Acetyl CoA

28

Ketoacids

Ketoacids

R + NH2

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GROWTH HORMONE AND CARBOHYDRATE

Reduced Glucose Uptake by Muscle

Reduced intracellular Glucose Processing

Gluconeogenesis: do not believe so?- Glycerol from triglyceride

breakdown CAME from glucose- Increased utilization of amino acids

for protein synthesis means fewer available for true gluconeogensis.

Insulin ANTAGONISM: - Carbohydrate and Fat

Growth Promoter Fat Mobilizer Glucose Sparer

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GROWTH HORMONE AND FAT

Adipose tissue: Triglyceride Mobilization Reduced fat (triglyceride) Synthesis Central role of fat products in the blood as a regulator of Glucose uptake and utilization

They BLOCK Insulin Action: Insulin ANTAGONISM

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GROWTH HORMONE AND PROTEIN

INCREASED SYNTHESIS*DECREASED DEGRADATION

Insulin AGONISM

*Mostly due to increased numbers of ribosomes, i. e. capacity

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

TriglyceridesAmino Acids

Ketoacids

Growth Hormone - MuscleKetoacids Fatty Acids

Acetyl CoA

32

Lactate

Lactate

( )

( )Indirect

( )Indirect

( )Indirect

( )Indirect

( )

( )

( ) = Indirect

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Triglycerides

Growth Hormone - Adipose TissueFatty Acids

Glucose-6-P

Acetyl CoA

33

( )

( ) = Indirect

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

TriglyceridesAmino Acids

Growth Hormone - Liver

Fatty Acids

Glucose-6-P

Acetyl CoA

34

Ketoacids

Ketoacids

R + NH2

( )Indirect

( )Indirect

( )Indirect

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Cortisol and Foodstuff Metabolism

Increased Appetite: ObesityInsulin Resistance (fatty acids)

Carbohydrate: Gluconeogenesis:

- Muscle protein breakdown- Increased liver gluconeogenic enzymes- Glycogen deposition- Hyperglycemia

Fat: - Increased adipose tissue (appetite)- Selective deposition: trunk / visceral fat

Protein:- Profound muscle protein breakdown

Cortisol and MetabolismOrgan by Organ

Muscle Increased Protein Breakdown

Adipose Increased Triglyceride deposition – trunk

Liver Increased gluconeogenesis Increased glycogen deposition Increased glucose export

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Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

TriglyceridesAmino Acids

Ketoacids

Cortisol- Muscle

Ketoacids Fatty Acids

Acetyl CoA

37

Lactate

Lactate

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Triglycerides

Cortisol - Adipose TissueFatty Acids

Glucose-6-P

Acetyl CoA

38

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

GlycerolAmino Acids

ATP

O2 H2O

NH3

+Urea

TriglyceridesAmino Acids

Cortisol - Liver

Fatty Acids

Glucose-6-P

Acetyl CoA

39

Ketoacids

Ketoacids

R + NH2 ( )Indirect

( )Indirect

40

Epinephrine: Effects on Metabolism

Carbohydrate: - Glycogen Breakdown: Liver and Muscle - Gluconeogenesis: Liver (works with cortisol)

Fat: - Increased Lipolysis: Mobilization

Protein: - Little or no effect

KEY PHRASES EMERGENCY / STRESS ENERGY PROVIDER

Epinephrine and MetabolismOrgan by Organ

Muscle Little effect

Adipose Increased Triglyceride breakdown / lipolysis

Liver Increased glycogenolysis Increased gluconeogenesis Increased glucose export

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Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

TriglyceridesAmino Acids

Ketoacids

Epinephrine - Muscle

Ketoacids Fatty Acids

Acetyl CoA

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Lactate

Lactate

( )Indirect

( )Indirect

( )Indirect

( )Indirect

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Triglycerides

Epinephrine - Adipose Tissue

Fatty Acids

Glucose-6-P

Acetyl CoA

43

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

TriglyceridesAmino Acids

Epinephrine - Liver

Fatty Acids

Glucose-6-P

Acetyl CoA

44

Ketoacids

Ketoacids

R + NH2

Glycerol

( )Indirect

( )Indirect ( )Indirect( )Indirect

( )Indirect

( )Indirect

Daily LivingFeeding to Fasting

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Sources of glucose over time following a Meal

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Whole Body Substrate Utilization During Fasting

Feeding to Adapted FastOrgan Integration – Version 1

Metabolism-101 Cartoons

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4949

We are talking about adultsNot Children*

*Low: Protein-Energy Malnutrition Coming up next

We are talking about AdaptationNot starvation / cachexia

Rat

s ≠

Peop

le

Big Picture - FedCarbs:

Refill stores: Glycogen, liver, muscle Burn Remainder (most tissues)

Protein: Refill stores (muscle) Burn Remainder

Fat: Storage Limited use as ongoing energy source

Dominant Ongoing Energy Needs: glucose, amino acids

Big Picture – 24 hr Fast

Carbs: Some glycogen stores used Gluconeogenesis

Protein: Amino acids (muscle) to liver - gluconeogenesis

Fat: Mobilization of triglyceride reserves

Dominant Ongoing Energy Needs: fatty acids(Exceptions: Nerves, Blood Cells – Glucose)

Big Picture – Adapted Fast

Carbs: Some glycogen stores used Gluconeogenesis

Protein: Amino acids (muscle) to liver - gluconeogenesis

Fat: Mobilization of triglyceride reserves

Keto Acids as dominant Energy Source, Incl. Brain(exception: liver uses fatty acids)

Reduced Gluconeogenesis: Kidney takes overReduced BMR

Big Picture – Hormone Profiles

Fed:InsulinGlucagonGrowth Hormone

Thyroid Hormone

24 hr Fast:InsulinGlucagonGrowth Hormone

Thyroid Hormone

Adapted Fast:Insulin

GlucagonGrowth HormoneThyroid Hormone

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Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

ATP

O2 H2O

Brain - FED

Glucose-6-P

Acetyl CoA

FED

55

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

ATP

O2 H2O

Brain – 24 hr FAST

Glucose-6-P

Acetyl CoA

24 hr FAST

56

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

ATP

O2 H2O

Brain - ADAPTED FAST

Glucose-6-P

Acetyl CoA

Ketoacids

Ketoacids

ADAPTEDFAST

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

Amino Acids

Ketoacids

Muscle - FEDKetoacids Fatty Acids

Acetyl CoA

57

Lactate

Lactate

FED

Triglycerides

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

Amino Acids

Ketoacids

Muscle – 24 hr FASTKetoacids Fatty Acids

Acetyl CoA

58

Lactate

Lactate

24 hr. FAST

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

Protein

Amino Acids

ATP

O2 H2O

Amino Acids

Ketoacids

Muscle - ADAPTED FASTKetoacids Fatty Acids

Acetyl CoA

59

Lactate

Lactate Glycerol

AdaptedFast

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Triglycerides

Adipose Tissue - FEDFatty Acids

Glucose-6-P

Acetyl CoA

60

FED

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Adipose Tissue – 24 hr FASTFatty Acids

Glucose-6-P

Acetyl CoA

61

Glycerol

24 hr. FAST

Glucose

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Adipose Tissue - ADAPTED FASTFatty Acids

Glucose-6-P

Acetyl CoA

62

ADAPTEDFAST

Glycerol

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

TriglyceridesAmino Acids

Liver - FEDFatty Acids

Glucose-6-P

Acetyl CoA

63

Ketoacids

Ketoacids

R + NH2

FED

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

GlycerolAmino Acids

Liver- 24 hr FASTFatty Acids

Glucose-6-P

Acetyl CoA

64

Ketoacids

Ketoacids

R + NH2

FAST-24 hr.

Glucose

Glycogen

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty AcidsAmino Acids

ATP

O2 H2O

NH3

+Urea

GlycerolAmino Acids

Liver – ADAPTED FASTFatty Acids

Glucose-6-P

Acetyl CoA

65

Ketoacids

Ketoacids

R + NH2

24 hr FAST

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Ketoacids

Kidney - FEDKetoacids Fatty Acids

Acetyl CoA

66

FED

Triglycerides

NH3

+Urea

R + NH2

Amino Acids

Amino AcidsAmino Acids

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Ketoacids

Kidney – 24 hr FASTKetoacids Fatty Acids

Acetyl CoA

67

24 hr.FAST

Amino Acids

Amino AcidsAmino Acids

NH3

+Urea

R + NH2

Glucose

Glycogen

Glucose-6-P

Glycolysis

Pyruvate

TCA Cycle

Oxidative Phosphorylation

Triglycerides

Glycerol Fatty Acids

ATP

O2 H2O

Amino Acids

Ketoacids

Kidney - ADAPTED FASTKetoacids Fatty Acids

Acetyl CoA

68

Glycerol

AdaptedFast

Amino Acids

NH3

+Urea

R + NH2

Add KidneyGlycerol replaces Triglycerides-FastAdd Red BarsAdd Slide text including hormone profile

Feeding to FastOrgan Integration – Version 2

(Based on Devlin)

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Glucose

Absorptive – Just Ate

GlucosePyruvateLactate

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Absorptive Phase (Just Ate)

FAT

Glucose Glycogen

AminoAcids ATP

ATP

Glycogen

VLDL

CHO

AminoAcids

FAT

TG

ATP

72

Postabsorptive Phase (No Food Several Hours)

Glucose

Glycogen

ATP

Glycogen

aa

Glucose-6-PLactate /pyruvate

Fatty Acids

Glycerol

ATP

73

CHO

AminoAcids

FAT

Adapted Fast

CHO

AminoAcids

FAT

Glucose

Glycogen

ATP

Glycogen

aa

Glucose-6-PLactate /pyruvate

Fatty Acids

Glycerol

Ketoacids

Ketoacids

Glucose

ATP

74

Feeding to FastOrgan Integration – Version 3

(Based on CMB Lectures - Tracy)

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Glucose

Fats

AminoAcids

Absorptive – Just Ate

ATP

Glycogen

CarbsFatAmino Acids

ATP

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Glucose

Fats

AminoAcids

Post-absorptive – Have not eaten for awhile

Glycogen

ATP

PyruvateLactate

CarbsFatAmino Acids

ATP

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Glucose

Fats

AminoAcids

Post-absorptive – Adapted Fast

Glycogen

ATP

PyruvateLactate

CarbsFatAmino Acids

Ketoacids

ATP

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Hormones and Daily Living

How are all of these things managed?

80

HOW DOES ONE DO IT?D

aily

Liv

ing

Emer

genc

y

81

Managing Daily Living Order of importance

1st: Insulin2nd: Insulin3rd: Insulin4th: Glucagon5th: Growth Hormone

82

EFFECTS OF INSULIN

PRINCIPAL TARGETS: LIVER, ADIPOSE, MUSCLE

Carbohydrate:- Increased Glucose Uptake: Muscle and Adipose

- Increased Glycogenesis; decreased glycogenolysis

- Decreased Gluconeogenesis

Fat:- Increased Triglyceride Synthesis for Storage

- Decreased Breakdown of Triglyceride Stores

Protein:- Increased Synthesis

- Decreased Breakdown

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Lack of Insulin

Muscle Reduced glucose uptake and utilization Mobilization of glycogen Increased muscle protein breakdown

Adipose Tissue Reduced triglyceride uptake and storage Increased triglyceride breakdown and release into the blood

Liver Increased Glycogenolysis Increased gluconeogenesis THE LIVER IS A GLUCOSE EXPORTER

Hormones and Daily Living

858585The End