Integration of Metabolism FOCUS

Fates of glucose 6P

• exported as glucose to replenish blood glucose

• used to synth glycogen or FA

• enter CAC to produce ATP

• enter pentose phosphate, produce NADPH

Fates of amino acids

• used to synth liver, plasma proteins

• enter blood to pass to other organs

• used as biosynth precursor for proteins, nucleotides, hormones

• converted to pyruvate, ammonia —>urea

Fates of pyruvate and acetyl coA from AA

pyruvate: converted to glucose, glycogen (gluconeogenesis)

• acetyl coA

Acetyl coA: CAC to produce ATP

• conversion to lipids for storage

Fates of fatty acids

• convert to liver lipids

• B oxidation to yield acetyl CoA, NADH

  • oxidation in CAC, convert to ketone bodies, synth steroids

• Convert to phospholipids, TAGs

• bind to albumin in blood for transport to heart, skeletal

After a fast: describe how insulin and glucagon secretion change, and how glucagon acts on the liver and adipose tissue

Pancreas secretes more glucagon, less insulin —need to inc glucose

In liver: inc glycogen breakdown, inc gluconeogenesis, dec glycolysis

Adipose: mobilize FA from TAG

Explain how the liver maintains blood glucose, and what fuel the liver itself uses.

• Breaks down glycogen to glucose 6P →glucose for export

• makes glucose from gluconeogenesis

• For own energy: oxidizes FA

What is the main fuel used by the brain

glucose

• if starved, uses ketone bodies (β-hydroxybutyrate)

What is the main fuel used by skeletal tissue

fatty acids

What is the main fuel used by the heart

FA with some glucose, lactate, ketone bodies

What is the main fuel used by RBC—why?

Glucose

• have no mitochondria, so can’t oxidize FA or ketone bodies

• depend entirely on glycolysis

Explain how fatty acids released from adipose tissue travel to other tissues

FA are insoluble in water

• are transported with albumin in plasma, carries to heart, skeletal muscle, liver

explain why glycogen cannot sustain blood glucose for long, and why fat is the main reserve.

Glycogen =small reserve

TAG = main reserve

Once liver glycogen is depleted, describe the sources of carbon for gluconeogenesis, including the role of alanine from muscle

1. Use FA → glycerol, lactate, or use proteins

Can break down muscle proteins —> AA, transaminate w pyruvate → alanine

• alanine → pyruvate for gluconeogenesis

• ammonium → urea, urine

Explain why ketone bodies rise after 2 to 4 days of fasting, and how the brain’s switch to β-hydroxybutyrate spares muscle protein

During fast, low insulin, high glucagon

• Release large amounts of FA → acetyl coA, can synth ketone bodies

Neurons can use B hydroxybutyrate as fuel —since can’t use use lipid/FA, spares muscle

• brain running on body fat

Explain why skeletal muscle shifts to mainly fatty acids during prolonged fasting, and how this benefits the brain

Shift to FA, using fewer ketone bodies

• benefits brain since more ketone bodies as fuel, which can’t use FA directly

Slow- twitch vs. fast-twitch muscle

Slow-twitch (red): rich in mitochondria, makes ATP w OxPhos, resist fatigue

Fast-twitch (white): less mitochondria, develops greater tension, use ATP faster than can replace, rely on glycolysis, fatigue quickly

Describe the fuels a sprinter’s leg muscle uses in the first seconds of a sprint and during the rest of a 30-second sprint, including the role of phosphocreatine.

First few sec: phosphocreatine to phosphorylate ADP, produce ATP

• During rest of sprint, fast-twitch muscle breaks down own glycogen

  • glucose →glycolysis faster than oxygen supplied, pyruvate reduced to lactate (anaerobic) to regen NAD+

Explain Cori cycle

In muscle:

glycogen → lactate

• goes to liver, blood lactate

Lactate → glucose (gluconeogenesis)

• goes to muscle to replenish glycogen stores

Why the heart can benefit from lactate during exercise

Heart highly oxidative, can convert lactate → pyruvate, oxidize it

Contrast fuel use in a sprint with fuel use during a long, moderate- intensity run, and explain the role of epinephrine

Sprint: short bursts of energy — phosphocreatine → ATP or glycogen→lactate

Long run: relies mainly on slow-twitch and OxPhos

• use glucose, FA, ketone bodies

Epinephrine supports both since increases blood glucose

• stimulates glycogen breakdown, FA release

Explain how epinephrine prepares the body for action, including its effects on liver, skeletal muscle, adipose tissue, and the heart.

Epinephrine (adrenal medulla): acts within seconds

• Liver: glycogen breakdown, release glucose to blood

• Skeletal muscle: provides glu6p for glycolysis

• Adiapose tissue: breaks down FA, inc glucagon, dec insulin

• Heart: inc heart rate and output, delivers more fuel, oxygen to muscle

Contrast epinephrine with cortisol in source, chemical type, receptor, and speed of action

Epinephrine: from adrenal medulla, acts in seconds, water sol

• binds adrenergic receptors, increase cAMP

Cortisol: lipid sol, made in adrenal cortex, acts hours-days

• binds receptor that changes gene exp

Explain how cortisol raises blood glucose if the stress continues for hours, and why

it is described as counterbalancing insulin

Inc FA release from adiapose, muscle breakdown for AA to liver → gluconeogenesis

• Raise blood glucose, oppose insulin’s actions of glucose uptake, storage

Explain why the brain’s fuel during acute stress depends on whether the hiker was fed or had been fasting for several days.

If fed: brain uses glucose

If starve: can’t directly use FA or lipids, will use ketone bodies (β-hydroxybutyrate)

List the possible fates of glucose 6-phosphate in the liver, and explain which fate dominates during fasting and why.

• convert to glucose to be released, or glucose → glycogen

• use in glycolysis to produce pyruvate which can enter gluconeogen/ acetyl coA

• Acetyl coA → make FA, enter CAC for OxPhos

• or enter pentose phosphate pathway, make NADPH

During fasting, glucagon blocks glycolysis, most glucose exported

Describe the fates of acetyl-CoA from fatty acids in the liver, and explain why the liver exports ketone bodies instead of oxidizing all of its acetyl-CoA

Acetyl coA → synth ketone bodies/ enter CAC to produce ATP/ make cholesterol

• During fasting, OAA drawn off from gluconeogenesis, B ox has high [NAD+]/[NADH] ratio, so CAC can’t handle all the acetyl CoA

• Excess acetyl coA converted to ketone bodies, fuel for heart, brain, muscles

Explain how amino acids from muscle protein are handled by the liver, including the fate of their nitrogen.

AA from muscles arrive mostly as alanine

• liver removes amino group, use pyruvate for gluconeogenesis

• ammonia → urine

Explain how the liver can supply glucose to other tissues while using fatty acids for its own energy

Liver oxidizes FA for ATP it needs, including ATP, GTP used in gluconeogenesis

• Glycogen breakdown → glu6p → glucose for other organs

liver=supplier of glucose, ketone bodies