lipid metabolism during exercise. plasma free fatty acid metabolism plasma ffa during exercise...
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Plasma Free Fatty Acid Plasma Free Fatty Acid MetabolismMetabolism
Plasma FFA during exercise result primarily from mobilized lipid stores in adipose tissue
Adipose tissue is the most important store of energy in mammals– % body fat typically 10 – 25 %
FFA MobilizationFFA Mobilization
FFA mobilization is dependent upon
i) Rate of lypolysis in the adipocyte
ii) plasma transport capacity of FFA
iii) rate of reesterification of FFAConversion back to triglyceride
LipolysisLipolysis
Estimated by measuring glycerol in the plasma
Glycerol appears in the plasma only as a result of lipolysis
Cannot be reused by the adipocyte once liberated (glycerol kinase)
A Quick Note About A Quick Note About LipogenesisLipogenesis
Glycerol 3-P is used as the triacycl glycerol backbone (Houston fig 10.6)
Glycerol 3-P derived from dihydroxyacetone phosphate (from glycolysis)
Glycerol cannot be converted to glycerol 3-P in the adipocyte
Can also use appearance of FFA as estimate of lipolysis
This is balance between lypolysis and reesterification (TG formation)– FFA can be used by adipocyte to form TG
Gives the NET lipolytic rate
Acute ExerciseAcute Exercise
In general lipolysis is increased with exercise
In isolated gluteal adipocytes– Following 30 min of cycling, catecholamine –
stimulated glycerol release was ^ 35-50 % compared to pre-exercise
Using microdialysis probe (in vivo measurement) during 30 min cycling– Glycerol release from abdominal adipocytes
was increased
Typically, in animals and humans, glycerol release increases 4-5 fold in prolonged moderate intensity exercise (3 – 4 hr)
Hormonal RegulationHormonal Regulation
Two most important hormonal regulators are catecholamines and insulin
Catecholamines typically stimulate lipolysisInsulin stimulates lipogenesis and inhibits
lipolysis
Hormonal Regulation During Hormonal Regulation During ExerciseExercise
-adrenergic activity is inhibitory -adrenergic activity is stimulatoryAt rest -adrenergic activity inhibits
activation of lipolysisDuring exercise -adrenergic activity
stimulates lipolysis
How do we know?How do we know?
Phentolamine (-adrenergic blocker) doubled glycerol concentration in resting humans– Increased lipolysis
Propanolol (-adrenergic blocker) did not alter glycerol concentration
During ExerciseDuring Exercise
Propanolol reduces the exercise induced elevation of glycerol by 65%– Also impairs endurance performance
Phentolamine has no effect
InsulinInsulin
Insulin levels are decreased during exercise– Directly related to work intensity– Mediated by -adrenergic inhibition
Fasting, fat-feeding and insulin deprivation in diabetics result in elevated FFA and glycerol in plasma
Hormone Sensitive LipaseHormone Sensitive Lipase
Hormones regulate lipolysis via their effects on hormone sensitive lipase (HSL)– HSL hydrolyzes FFA from glycerol backbone
HSL is regulated by its phosphorylation state
Phosphoylation of the regulatory site activates lipolysis
A note about FFA mobilizationA note about FFA mobilization
As exercise duration increases, FFA mobilization increases,… depending
FFA must be carried in the blood by albumin– FFA/albumin ratio can increase 20 fold during
prolonged exercise– The increased FFA/albumin ratio favors
reesterification
Perfusion to adipose tissuePerfusion to adipose tissue
Increased perfusion to adipose tissue increases FFA mobilization
During prolonged exercise, perfusion to adipose tissue can increase 3-4 fold
This can compensate for the FFA/albumin ratio– Implications for endurance training??
Lactate and lipolysisLactate and lipolysis
Lactate reduces NET lipid mobilizationIncreases reesterification, but doesn’t affect
lipolysis– Implications for training??
FFA Permeation Across FFA Permeation Across MembranesMembranes
Is FFA movement into the cell simple diffusion or carrier mediated?
Traditional thought was simple diffusion, but recent evidence argues for carrier mediation
Support for Carrier Support for Carrier MechanismMechanism
During exercise, FFA flux into the cell is too high to be a result of mass action
Cellular uptake of FFA can be saturated A specific membrane fatty acid binding
protein (FABPpm) has been identified
What’s this mean?What’s this mean?
During exercise in humans, FFA transport is saturated as unbound FFA concentrations increase in the plasma (2-3 hr extensions)
Maximal velocity of palmitate uptake is increased with muscular contraction and reduced with low CHO availability
What’s that mean?What’s that mean?
Increased FFA availability in the plasma does not necessarily translate to increased uptake of FFA in the cell
Fat loading???
What happens once FFA gets What happens once FFA gets inside the cell?inside the cell?
Lipids don’t like water (hydrophobic), so special carrier proteins are necessary in the cytoplasm
FABPc have been isolated from muscle– High levels in SO fibers, intermediate in FOG,
and low in FG
Energy or StorageEnergy or Storage
Once in the cell, the FFA can be oxidized or reesterified to intramuscular TG pool
During exercise, FFA will go predominately toward oxidation for energy generation
The Substrate Utilization The Substrate Utilization ParadoxParadox
As exercise intensity increases, the relative contribution from fat oxidation decreases
During light to moderate exercise though, the increase in oxygen consumption offsets the relative decrease in contribution from fat– Up to ~60 – 70 %– No lactate accumulation
Also, as duration of exercise progresses, relative contribution from fat metabolism increases– Decrease in RER after several hours of light
intensity exercise– Determined by substrate availability and
oxidative capacity
FFA Oxidation RateFFA Oxidation Rate
To a certain extent FFA oxidation is dependent or related to FFA concentration in the plasma
At low intensity (30% VO2max) gradual increases in FFA levels in plasma resulted in increased turnover of radiolabelled oleate
In general, fat oxidation and uptake increase at the onset of exercise
Mobilization from the adipose tissue is not sufficient to meet this increased demand– Transient decrease in FFA levels
As exercise continues, FFA concentrations in plasma rise
FFA Oxidation PlateauFFA Oxidation PlateauFFA concentration in plasma and FFA
oxidation are related except…– When lactate begins to accumulate (> 70 %
VO2max)– When FFA levels are extremely high (plateaus)
With endurance training, the FFA oxidation plateau is eliminated – increased FABPpm??
Regulation of Oxidation by CPT-IRegulation of Oxidation by CPT-I
CPT-carnitine palmitoyltransferase ITransport acyl carnitine across
mitochondrial membrane– Acyl carnitine-FFA attached to carnitine carrier
protein
FFA can’t get into the mitochondria without carnitine
Elevations in glucose activate fatty acid synthesis
Fatty acid synthesis intermediates (malonyl co-A) inhibit CPT-I– In effect inhibits fatty acid entry into
mitochondria
Fasting induced hypoglycemia removes inhibition of CPT-I– Increases oxidation of FFA
ContradictionContradictionIn situ and experimental invivo conditions
show that reduced glucose availability reduces rate of exogenous FFA oxidation
The old “Fat burns in the flame of carbohydrate” maxim
But, Krebs intermediates were maintained– Palmitate supraphysiologic??
Mechanisms for this phenomena not determined
Intramuscular TG UtilizationIntramuscular TG Utilization
Intramuscular triglyceride oxidation is dependent upon exercise intensity and duration
In animals, whole body exercise to exhaustion results in decreases in intramuscular TG content
Lower intensity exercise, results are equivocal
In humans using various modes of exercise, TG content of VL decreased 25-50 %• Exercise prolonged at 55-70 % VO2max
• During intense exercise 5 min in duration, TG decreased 29 %• Significant contribution of oxidative
metabolism at 5 min