Lipid Metabolism During Exercise

Introduction 1.) Energy Density 2.) Polar explorers/sled dogs American Indians (pemican) 3.) Migrating fish and birds 4.) 3 sources plasma FFA from adipocytes (large > 50,000 kcals) intramuscular TG (2,000 -3,000 kcals) plasma TG (very small role during exercise in humans) 5.) Destabilizing effect on membranes High IMTG (obesity, type-II diabetes) linked with insulin resistance in muscle.

Storage and Mobilization of Triglycerides

Adipose Tissue Lipolysis Glycerol release, no Glycerol Kinase in adipocyte or muscle –α, β,Insulin,Lactate re-esterification FFA Passive vs. Carrier-mediated Fatty acid binding protein (FABP) EPI Insulin

B increases cAMP Alpha decreases cAMP Insulin activated PDE thus decreases cAMP

Hormone Sensitive Lipase Phosphorylated by Protein Kinase A –becomes active –catabolic in nature Mechanism: Epinephrine binds to β receptor on adipocyte this causes activation of AC – increase in cAMP cAMP activates Protein Kinase A Insulin counteracts this deactivates Protein Kinase A via activation of PP-1, activates PDE which decreases cAMP

Regulation of Hormone- Sensitive Lipase PKA

C C COH CC O CC OH Dehydration Synthesis C C CCC O CCO Triglyceride C C COH + CC O C OH Glycerol FFA H.S. Lipase

Hormone Sensitive Lipase (cont.) C C COC O CCC Triglyceride HSL (activated by protein kinase A) C C COH HOCCCC O Glycerol FFA +

Hormone Sensitive Lipase

Adrenoceptor Blockade Schematic

FFA/Blood Glycerol at Rest and Exercise Exercise 50% Notice the magnitude of the change in FFA vs. glycerol

FFA Transport to Muscle Cells Fatty Acids from adipose –transported in blood via Albumin – 3 per –brought to muscle cell at fatty acid binding receptor proteins –taken into muscle cell Triglycerides in blood (chylomicrons and VLDL) broken down by lipoprotein lipase in capillary of the muscle before being taken into cell

FFA uptake, activation and trans- location

FA transporters 1.FABPpm 2.FATP 3.FAT/CD36 Higher in ST vs. FT Training has been shown to increase the amount of FA transporters in the PM.

CC O C OH CoAS H H2OH2O ATP AMP CC O CSCoA Acyl - CoA Synthetase Fatty acid (acyl) CoA Carnitine Transferase Mitochondrial Matrix

Fatty Acid Transport Into Mitochondria FA can’t cross mitochondrial membrane Must use carnitine acyl transferase (CAT) system CAT I located in outer wall Binds carnitine to FA, enabling it to pass inner mem. RATE LIMITING STEP IN FAT UTILIZATION! CAT II located in mitochondrial matrix removes carnitine from FA

Fatty Acid Transport Into Mitochondria (cont.) Step 1: FFAFatty Acyl CoA (Acyl CoA synthase – in outer wall) Fatty Acyl CoAFatty Acyl Carnitine CAT I Fatty Acyl Carnitine CAT II Fatty Acyl CoA (inside mitochondrial matrix) Step 2: Step 3: *With training, ↑ number of mitochondria, ↑ CAT I, ∴ ↑ fat use with exercise.

β -Oxidation Cycle *No rate limiting steps in β -Oxidation cycle! Rate limiting step occurs with CAT I.*

OHCCCC O FFA ATP AMP CoAS H H2OH2O Step 1: Acyl CoA Synthase ~SCCC O CoA HH HH Fatty Acyl CoA

Step 2: ~SCCC O CoA HH HH Fatty Acyl CoA FAD FADH 2 Acyl CoA Dehydrogenase ~SCCC O CoA H H Enoyl CoA (trans dehydrogenase rx) **Recall: Fatty Acyl CoA is transported into mitochondria via CAT I & II complex**

~SCCC O CoA H Enoyl CoA Step 3: H 2 O (add to make 2° -OH) Enoyl CoA Hydrase ~SCCC O CoA H H OH L-Hydroxyacyl CoA H H

~SCCC O CoA H H OHOH L-Hydroxyacyl CoA H Step 4: NAD NADH + H L-Hydroxyacyl Dehydrogenase (oxidize 2°-OH to keto) ~SCCC O CoA HO Keto Acyl H (β)(β) ( β Carbon)

Step 5: ~SCCC O CoA HO Keto AcylH (β)(β) CoASH ~SC O CoA Acyl CoA ~SCC O CoA H H Acetyl CoA (on to Krebs cycle) H Ketothiolase β -oxidation? ( β ) carbon oxidized from saturated to keto → NAD & FAD are reduced!

Energy yield of Palmitic Acid (16 C - FS - FA) CCCCCCCCCCCCCCCC 7 FADH 2 x 2 = 14 7 NADH 2 x 3 = 21 8 Acetyl CoA x 12 = 96_ 131 __ ATP Activation with Co ASH ATP → AMP In CAC: 3 NADH 1 FADH 1 ATP

Glycerol C C COH Glycerol Glycerol kinase only in liver ATPADPC C CO~P OHOH OH Glycerol 3-P H NAD NADH 2 (Glycerol P dehydrogenase) C C CO~P O OH DHAP gluconeogenesis glycolysis

Muscle Glycogen vs. FFA Expenditure

Substrates Providing Energy

Plasma Triacylglycerol FABP VLDL Chylomicron - 50% - 85% LDL 1. 10% of fat use 2. Slow twitch Fast twitch 3. LPL activity 1 hr of exercise hr 2x LPL ~ ~

Blood 80% H 2 O FFA - Albumin Tri C |C |C Lipoprotein Lipase FFA In VLDL and chilomicrons

Triglyceride Breakdown for Energy C C COC O CCC Triglyceride HSL C C COH HOCCCC O Glycerol FFA + Step 1:

CHO & Lipid Crossover Concept

G-3-P 1-3 DPG PyruvateLactic Acid NAD NADH 2 NAD MCT Lactic AcidPyruvate NAD NADH 2 NADNADH 2 PDH Acetyl Co-A Krebs (next slide) (Inside mitochondria) (cytoplasm)

Acetyl Co-A Citrate OAA NADH 2 FADH 2 TCA Cycle Yields: -3 NADH 2 -1 FADH 2 -1 ATP

Both muscular contraction and Insulin translocate FAT/CD36 from intracellular sites to plasma membrane. Recent studies have found the effects of insulin and muscular contraction to be additive, suggesting separate ICF pools of FA transporters.

Beta oxidation of FA in the mitochondria increases acetyl-CoA and citrate concentrations.

AMPK prevents formation of malonyl Co-A, which is a allosteric inhibitor of CAT I, thus AMPK increases FFA uptake into mitochondrial matrix

Triglyceride Formation C C COH HOCCCC O Glycerol FFA H2OH2O (Dehydration Synthesis) + C C COC O CCC Triglyceride