Lipid Metabolism During Lipid Metabolism During ExerciseExercise

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

Insert Fig 10.8Insert Fig 10.8

http://www.kumc.edu/research/medicine/biochemistry/bioc800/lip01fra.htm

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

Intramuscular TG utilization is also fiber type dependent– FOG>SO>FG

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