Transcript Lipid Metabolism

Lipid Metabolism During
Exercise
Plasma Free Fatty Acid
Metabolism

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 Mobilization
FFA mobilization is dependent upon
i) Rate of lypolysis in the adipocyte
ii) plasma transport capacity of FFA
iii) rate of reesterification of FFA
Conversion back to triglyceride
Lipolysis

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
Lipogenesis

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 3P 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 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 Regulation

Two most important hormonal regulators
are catecholamines and insulin
 Catecholamines typically stimulate lipolysis
 Insulin stimulates lipogenesis and inhibits
lipolysis
Hormonal Regulation During
Exercise
-adrenergic activity is inhibitory
 -adrenergic activity is stimulatory
 At rest -adrenergic activity inhibits
activation of lipolysis
 During exercise -adrenergic activity
stimulates lipolysis

How do we know?

Phentolamine (-adrenergic blocker)
doubled glycerol concentration in resting
humans
– Increased lipolysis

Propanolol (-adrenergic blocker) did not
alter glycerol concentration
During Exercise

Propanolol reduces the exercise induced
elevation of glycerol by 65%
– Also impairs endurance performance

Phentolamine has no effect
Insulin

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 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 10.8

http://www.kumc.edu/research/medicine/biochemistry/bioc800/lip01fra.htm
A 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 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 lipolysis

Lactate reduces NET lipid mobilization
 Increases reesterification, but doesn’t affect
lipolysis
– Implications for training??
FFA Permeation Across
Membranes

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
Mechanism

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?

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?

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
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 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
Paradox

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 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 Plateau

FFA 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-I

CPT-carnitine palmitoyltransferase I
 Transport 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
Contradiction

In 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 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