Final Review Sessions. 3/16 (FRI) 126 Wellman (4-6 6 pm) 3/19 (MON) 1309 Surge 3 (4-6 6 pm) Office Hours

Lecture 20 ormonal regulation of metabolism Spring Break

Regulation of Metabolism at the Organismal Level Role of ormones Role of ormones (Adrenaline, Glucagon, Insulin)

Food Glucose (ketone bodies) Fatty and keto acids Lactate Alanine Fatty acids, ketone bodies, branched amino acids (resting muscle) Fatty acids, glycerol Glucose, fatty acids, ketone bodies Detoxification We BIS103

ormonal Regulation coordination of metabolic activities of different organs circulation in blood (endocrine hormones) binding to specific receptors in target cells (high affinity) amplification cascades to activate enzymes enzyme activation by covalent modification desensitization (resetting of response system) integration of multiple (hormonal) signals

ormone-induced Activation of Adenylate Cyclase Blood inactive γ β α ormone Receptor Cell Membrane Cytosol Adenylate Cyclase GDP GTP G-Protein p. 110

Blood inactive α GTP γ β ormone Receptor Cell Membrane Cytosol Adenylate Cyclase GDP p. 110

Blood active α GTP γ β ormone Receptor Cell Membrane Cytosol Adenylate Cyclase ATP + 2 O 3 :5 -camp + PPi Second Messenger p. 110

Regulation of camp-dependent Protein Kinase A (PKA) -O O P O - O O P O - ATP O O P O O - O O N N 2 O N 2 N N O P O - O - Adenylate cyclase O O -O P O P O - PPi O - O - 2 O x 4 N 2 N N N N O O O P O -O camp (cyclic AMP) -O O P O - O O O Cyclic Nucleotide Phosphodiesterase AMP N N N 2 N N C R R C 2 C + 2 R 4 camp 2 O Inactive PKA Active PKA C R Catalytic subunit Regulatory subunit p. 111

Activation Cascade for Glycogen Phosphorylase Blood Adenylate Cyclase ATP 2 0 α GTP γ β ormone Receptor Cell Membrane Cytosol PPi 3 :5 -camp Cyclic Nucleotide Phosphodiesterase 5 AMP C R R C C C PKA (inactive) PKA (active) camp camp R R camp camp p. 112

C R R C C C PKA (inactive) PKA (active) camp camp R R camp camp ATP ADP ATP ADP Phosphorylase b kinase (inactive) (+) Ca 2+ Phosphorylase b kinase (active) Glycogen synthase (active) Glycogen synthase (inactive) Pi Protein phosphatase 2 0 Pi Protein phosphatase 2 0 ATP ADP ATP ADP Phosphorylase b (inactive) Phosphorylase a (active) Protein phosphatase inhibitor (inactive) Protein phosphatase inhibitor (active) Pi Protein phosphatase 2 0 Pi Protein phosphatase 2 0 Glycogen phosphorolysis p. 112

ormone ( first messenger ) ormone Receptor Adenylate Cyclase Desensitization (Resetting) GTPase activity (G protein) ydrolysis of camp camp ( second messenger ) Protein Kinase A Glycogen phosphorylase kinase Glycogen phosphorylase Glycogen Reserve

Allosteric Control of Glycogen Phosphorylase b PO 3-4 (+) AMP (-) ATP (-) Glc-6-P Glycogen phosphorylase b + Glucose-1-P p. 113

Target Proteins for camp-dependent Protein Kinase A F6P-2-kinase Triacylglycerol lipase (+) (+) F2,6BP-2-phosphatase Pyruvate kinase (-) Protein Kinase A Glycogen synthase Phosphorylase b Protein Phosphatase kinase Inhibitor Protein (-) (+) (+) Phosphorylase b Phosphorylase a p. 113

Adrenaline (Epinephrine): The Fight-or-Flight ormone produced in adrenal medulla derived from tyrosine (see p. 103) prepares periphal organs for bursts of activity

eart beat goes up, blood pressure increases increased oxygen delivery Glucagon secretion (+), Insulin secretion (-)( reinforces adrenaline effect Adrenaline Fatty acid mobilization (+) Glycogen degradation (+) Glycolysis (+) Energy Glycogen degradation (+) Gluconeogenesis (+) Glycolysis (-)(

ormonal Regulation of Mammalian Metabolism Adrenaline Target tissues: Muscle (M), Adipose (A), Liver (L) Metabolic Effect Target Enzyme (+) Glycogen degradation (M, L) (+) Glycogen phosphorylase (-) Glycogen synthase (+) Glycolysis (M) (+) Phosphofructokinase-2 (+) Gluconeogenesis (L) (-) Glycolysis (L) (-) Phosphofructokinase-2 (+) Fatty acid mobilization (A) (+) Triacylglycerol lipase (+) Glucagon secretion (-)) Insulin secretion p. 115

We BIS103 eart does not store glycogen (very little) or lipids Many mitochondria (50% of cell volume) Completely aerobic at all times (depends on oxygen!) If oxygen delivery is blocked (e.g., blood clots), heart muscles will die (heart attack)

large store of glycogen (75% of total) >50% of oxygen consumption, resting >90% of oxygen consumption, contracting (glucose preferred fuel)

ATP (<5 sec) Anaerobic (45-80 sec) Aerobic (> 2 min) Creatine~P (10-15 15 sec) Peak Consumption

omeostasis of Blood Glucose Levels Glucagon secreted by α islet cells of pancreas peptide hormone (29 amino acid residues) maintains blood glucose levels (increase) Insulin secreted by β islet cells of pancreas peptide hormone (MW ~ 5,800) maintains blood glucose levels (decrease)

very active respiratory metabolism (~ 20% of total oxygen consumed) uses normally only glucose as fuel (~70% of daily intake; no fuel stores) can switch to ketone bodies when necessary (minimizes protein degradation) cannot use fatty acids (blood-brain barrier) 5 mm (blood) ~ 1 mm (brain) Glucose < 2.2 mm (blood) ~ 0.05 mm (brain) = K M of hexokinase Danger Zone

Secreted in response to low blood glucose Glucagon Not muscles Glucose Fatty acid mobilization (+) Glycogen degradation (+) Gluconeogenesis (+) Glycogen synthesis (-)( Glycolysis (-)( Fatty acid synthesis (-)(

ormonal Regulation of Mammalian Metabolism Glucagon Target tissues: Liver (L), Adipose (A) Metabolic Effect Target Enzyme (+) Glycogen degradation (L) (-) Glycogen synthesis (L) (+) Glycogen phosphorylase (-) Glycogen synthase (-)) Glycolysis (L) (+) Fru-2,6 2,6-BP phosphatase (-) Pyruvate kinase (+) Gluconeogenesis (L) (+) Fru-2,6 2,6-BP phosphatase (+) Fatty acid mobilization (A) (+) Triacylglycerol lipase p. 115

Glucose Insulin Secreted in response to high blood glucose TAG synthesis (+) Glucose uptake (+) Glycogen synthesis (+) Glycolysis (+) Acetyl-CoA synthesis (+) Fatty acid synthesis (+) Glycogen degradation (-)( Gluconeogenesis (-) Glucose uptake (+) Glycogen synthesis (+) Glycolysis (+) Acetyl-CoA synthesis (+) Protein synthesis (+) Glycogen degradation (-)(

ormonal Regulation of Mammalian Metabolism Insulin Target tissues: Muscle (M), Adipose (A), Liver (L) Metabolic Effect Target Enzyme (+) Glucose uptake (M, A) (+) Glucose uptake (L) (+) Glycogen synthesis (L, M) (-)) Glycogen degradation (L, M) (+) Glycolysis (L, M) (-) Gluconeogenesis (L) (+) Acetyl-CoA production (L, M) (+) Fatty acid synthesis (L) (+) Triacylglycerol synthesis (A) (+) Glucose transporter (GLUT4) (+) Glucokinase (Transcription) (+) Glycogen synthase (-) Glycogen phosphorylase (+) Phosphofructokinase-2 (+) PD complex (+) Acetyl-CoA carboxylase (+) Lipoprotein lipase p. 115

Glucose regulation of insulin secretion by pancreatic β cells

Isoenzymes of Glucose Transporters (GLUT) V GLUT 4 (muscles, adipocytes) GLUT 1/3 (most tissues) GLUT 2 (liver, pancreatic β cells) 1 5 ~15 Blood Glucose [mm]

Insulin Receptor and Signaling Blood Insulin Receptor PI-3K Insulin Insulin Receptor Receptor P P Insulin Receptor Cytosol PIP 3 PIP 2 PKB P P IRS-1 IRS-1 P GSK3 (inactive) P MAPKKK (Raf-1) GSK3 (active) MAPKK (MEK) MAPK GS (inactive) P GS (active) Transcription Factors p. 114 Glycogen Synthesis Target Genes (e.g., Glucokinase)

Fasting and Starvation Lean (70 kg) Obese (140 kg) Circulating Fuels Glycogen Proteins Body Fat (TAG) 23 g (0.1 kcal) 225 g (0.9 kcal) 6 kg (24 kcal) 15 kg (141 kcal) 25 g (0.11 kcal) 230 g (0.92 kcal) 8 kg (32 kcal) 80 kg (752 kcal) Estimated Survival 3 months 14 months

Overnight fast Liver glycogen depleted maintain blood glucose Blood glucose drops glucagon Mobilization of triacylglycerides liver, muscles Liver: gluconeogenesis (glycerol, glucogenic amino acids urea) Liver: OAA drops ketogenesis brain, heart, skeletal muscles Prolonged Starvation Ketogenesis (mobilization of triacylglycerides ketone bodies) Degradation of nonessential proteins (skeletal muscles) Endphase When body fat depleted, degradation of essential proteins Organ failure

Relative Concentrations in Blood During Fasting/Starvation Glucose Ketone bodies Fatty acids 2 d 4 d 6 d

Spring Break!!!

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