Summary of Metabolic Pathways

Metabolic Profile: Brain

Fuel(s) - glucose is prime fuel uses ~120g/dayFuel use(s) - active transport (Na+, K+ ), biosynthesisGlucose uptake - transporter half-saturated at 1.6 mM normal blood glucose level ~5 mM (90mg%) hexokinase saturated at 0.5 mM hypoglycemic danger level 2.2 mM (40mg%)Main metabolic pathways - totally aerobic metabolism

glycolysis, citric acid cycle, ETS

Metabolic Profile: Skeletal Muscle

Fuel(s) - Resting muscle - fatty acidsHighly-active muscle - glucose from glycogen

produces lactateFuel use(s) - contraction, active transport (Ca2+)Main metabolic pathways - Resting muscle (aerobic)

fatty acid oxidation, citric acid cycle, ETSHighly-active muscle (anaerobic)

glycogenolysis, glycolysis

Metabolic Profile: Heart Muscle

Fuel(s) - main fuel fatty acids Fuel use(s) - contraction, active transport (Ca2+)Main metabolic pathways - totally aerobic metabolism

fatty acid oxidation, citric acid cycle, ETS

Metabolic Profile: Adipose Tissue

Fuel(s) - major fuels glucose, fatty acids

Fuel use(s) - biosynthesis of triacylglycerols, fatty acid synthesis (high blood glucose)

Main metabolic pathways - glycolysis, fatty acid oxidation, citric acid cycle, ETS, fatty acid synthesis, triacylglycerol synthesis, lipolysis

Metabolic Profile: Kidney

Fuel(s) - major fuels glucose, fatty acids

Fuel use(s) - active transport, biosynthesis (glucose)

Main metabolic pathways - Normal conditions - glycolysis, fatty acid oxidation, citric acid cycle, ETS During starvation - gluconeogenesis

Metabolic Profile: LiverFuel(s) - major fuel fatty acids

Fuel use(s) - biosynthesis of glucose, fatty acids, glycogen, triacylglycerols, cholesterol, bile salts, proteins, urea

Main metabolic pathways - metabolic hubCarbohydrate - incoming - glycolysis, glycogenesis, lipogenesis, citric acid cycle, ETS Low blood glucose - glycogenolysis, gluconeogenesis

Lipid - incoming - fatty acid oxidation, citric acid cycle, ETS, cholesterol synthesis, ketone body synthesis Surplus fuel - fatty acid and triacylglycerol synthesisAmino acids - protein synthesis Synthesis of nitrogenous compounds, glucose, urea

Tissue Interrelationships: Liver as Fuel Provider for Other Tissues

Glucose provider - glycogenolysis, gluconeogenesis

Fatty acid provider Excess fuel converted to triacylglycerols then VLDLs Provide fatty acids to other tissues or for storage in adipose tissue

Ketone body provider Soluble form of fatty acid fuel Produced when blood glucose level low

CoriCycle

Tissue Interrelationships: Liver and Skeletal Muscle

Alanine-Glucose Cycle

Tissue Interrelationships: Liver and Skeletal Muscle

Mechanism of Hormone Action: Glucagon and Epinephrine

receptor

hormoneadenylyl cyclase

ATPcyclicAMP

proteinkinasephosphorylated

proteins

hormone binds to receptor andstimulates adenylyl cyclase

adenylyl cyclase catalyzessynthesis of secondarymessenger (cAMP)

cAMP stimulates protein kinase to catalyze phophorylation of key proteins

Glucagon (liver)

Stimulates glycogen phosphorylase glycogenolysis (+)Inhibits glycogen synthase glycogenesis (–)

Stimulates fructose 1,6-phosphatase gluconeogenesis (+)

Inhibits phosphofructokinase glycolysis (–)

Epinephrine (liver)

Stimulates fructose 1,6-phosphatase gluconeogenesis (+)

Stimulates glycogen phosphorylase glycogenolysis (+)Inhibits glycogen synthase glycogenesis (–)

Inhibits phosphofructokinase glycolysis (–)

Epinephrine (skeletal muscle)

Stimulates glycogen phosphorylase glycogenolysis (+)Inhibits glycogen synthase glycogenesis (–)

Stimulates phosphofructokinase glycolysis (+)

Glucagon and Epinephrine (adipose tissue)

Stimulates lipase lipolysis (+)

Mechanism of Hormone Action: Insulin

Insulin binds to receptor Stimulates synthesis of secondary messenger (inositol

triphosphate, IP3 )IP3 activates protein kinase that in turn catalyzes

phosphorylation of key enzymesProcesses and enzymes affected (take in and use fuel)

Stimulates glycogen synthase (liver and muscle) glycogenesis (+)

Inhibits glycogen phosphorylase (liver and muscle) glycogenolysis (–)

Stimulates glucose uptake (liver, muscle, adipose tissue)

Stimulates fatty acid synthesis (liver) lipogenesis (+)

Stimulates phosphofructokinase glycolysis (+)Inhibits fructose 1,6-bisphophatase (liver) gluconeogenesis (–)

Inhibits hormone-sensitive lipase (adipose cells) lipolysis (–)

Combined Effects of Insulin: The well-fed state

Combined Effects of Glucagon: The fasting state

Interplay betweeninsulin and glucagon

Normal Daily Cycle for Glycogen

75 g

100 g

Starvation: First Week

Glucose Production by Liver and KidneyDuring First 10 Days of Fasting

Starvation: Six Weeks

Fuel Metabolism in Starvation

Fuel exchanges and consumption

Amount formed or consumedin 24 hours (grams)

3rd day 40th day

Fuel use by the brain

Fuel output of the liver

Fuel mobilization

Muscle-protein degradation 75

180

40

100Ketone bodies 50

All other use of glucose 50

Glucose 100 40

Adipose-tissue lipolysis 180

20

150

Glucose 120

Ketone bodies 150

40

Fuel output of the kidney 30 40

Metabolic Adjustment by the Liver During Prolonged Fasting or in Uncontrolled Diabetes