Transcript Overview of Fasting

Overview of Fasting
• Fasting may result from an inability to obtain
food, from the desire to lose weight rapidly, or
in clinical situations in which an individual
cannot eat, for example, because of trauma,
surgery, neoplasms, or burns.
• In the absence of food, plasma levels of
glucose, amino acids, and TAG fall, triggering a
decline in insulin secretion and an increase in
glucagon release.
4/8/2016
2
• The decreased insulin to glucagon ratio, and
the decreased availability of circulating
substrates, makes the period of nutrient
deprivation a catabolic period characterized
by degradation of TAG, glycogen, and protein.
4/8/2016
3
• This sets into motion an exchange of substrates
between liver, adipose tissue, muscle, and brain
that is guided by two priorities:
• 1) the need to maintain adequate plasma levels
of glucose to sustain energy metabolism of the
brain, red blood cells, and other glucose-requiring
tissues, and
• 2) the need to mobilize fatty acids from adipose
tissue, and the synthesis and release of ketone
bodies from the liver, to supply energy to all
other tissues.
4/8/2016
4
Fuel stores
• Enormous caloric stores available in the form
of TAG compared followed by glycogen.
4/8/2016
5
Enzymic changes in fasting
• In fasting the flow of intermediates through
the pathways of energy metabolism is
controlled by four mechanisms:
• 1) the availability of substrates,
• 2) allosteric regulation of enzymes
• , 3) covalent modification of enzymes, and
• 4) induction-repression of enzyme synthesis.
4/8/2016
6
Liver in Fasting
Carbohydrate metabolism
• The liver first uses glycogen degradation and
then gluconeogenesis to maintain blood
glucose levels to sustain energy metabolism of
the brain and other glucose-requiring tissues.
• The presence of glucose 6-phosphatase in the
liver allows the production of free glucose
both from glycogenolysis and from
gluconeogenesis.
4/8/2016
8
Increased glycogen degradation
• During the brief absorptive
period, glucose from the diet is
the major source of blood
glucose.
• Several hours after the meal,
blood glucose levels have
declined sufficiently to cause
increased secretion of glucagon
and decreased release of insulin.
• The increased glucagon to insulin
ratio causes a rapid mobilization
of liver glycogen stores (which
contain about 80 g of glycogen in
the well-fed state).
• Hepatic glycogenolysis is a
transient response to early
fasting.
4/8/2016
9
Increased gluconeogenesis
• The synthesis of glucose
and its subsequent
release into the
circulation are vital
hepatic functions during
fasting ②.
4/8/2016
10
Increased gluconeogenesis
• Gluconeogenesis,
favored by activation of
fructose 1,6bisphosphatase (due to
a drop in its inhibitor,
fructose 2,6bisphosphate) and
• by induction of
phosphoenolpyruvate
(PEP) carboxykinase by
glucagon.
4/8/2016
11
Gluconeogenesis
• Gluconeogenesis plays an essential role in
maintaining blood glucose during both
overnight and prolonged fasting.
4/8/2016
12
Fat metabolism
Increased fatty acid oxidation:
• The oxidation of fatty acids
derived from adipose tissue is the
major source of energy in hepatic
tissue in the postabsorptive state
③.
• The fall in malonyl CoA due to
phosphorylation (inactivation) of
acetyl CoA carboxylase by
activated protein kinase (AMPK)
removes the brake on carnitine
palmitoyl transferase-1 (CPT-1),
allowing β-oxidation to occur.
• Fatty acid oxidation provides the
NADH and the adenosine
triphosphate (ATP) required by
the liver for gluconeogenesis.
4/8/2016
14
Increased synthesis of ketone bodies
• The liver is unique in
being able to synthesize
and release ketone bodies
(primarily 3hydroxybutyrate,
(formerly called βhydroxybutyrate) for use
as fuels by peripheral
tissues (see p. 195).
• Note: The liver cannot
use ketone bodies as a
fuel (lacks thiophorase).
4/8/2016
15
Increased synthesis of ketone bodies
•
•
•
•
4/8/2016
Ketogenesis is favored when the
concentration of acetyl CoA,
produced from fatty acid metabolism,
exceeds the oxidative capacity of the
TCA cycle.
Significant ketogenesis starts during
the first days of fasting .
The availability of circulating ketone
bodies is important in fasting because
they can be used for fuel by most
tissues, including brain tissue, once
their level in the blood is sufficiently
high.
This reduces the need for
gluconeogenesis from amino acid
carbon skeletons, thus preserving
essential protein.
16
Adipose Tissue in Fasting
Carbohydrate metabolism
• Glucose transport into
the adipocyte and its
subsequent metabolism
are depressed due to
low levels of circulating
insulin. This leads to a
decrease in fatty acid
and TAG synthesis
4/8/2016
18
Fat metabolism
• The activation of hormonesensitive lipase and
subsequent hydrolysis of
stored TAG are enhanced by
the elevated catecholamines
epinephrine and, particularly,
norepinephrine.
• These compounds, which are
released from the sympathetic
nerve endings in adipose
tissue, are physiologically
important activators of
hormone-sensitive lipase ①.
• Glucagon also activates the
lipase.
4/8/2016
19
Increased release of fatty acids
• Fatty acids obtained from
hydrolysis of stored TAG are
released into the blood ②.
• Bound to albumin, they are
transported to a variety of
tissues for use as fuel.
• The glycerol produced
following TAG degradation is
used as a gluconeogenic
precursor by the liver.
• Fatty acids are also converted
to acetyl CoA, which can enter
the TCA cycle, thus producing
energy for the adipocyte
4/8/2016
20
Decreased uptake of fatty acids
• In fasting, lipoprotein
lipase activity of
adipose tissue is low.
• Consequently,
circulating TAG of
lipoproteins is not
available for TAG
synthesis in adipose
tissue
4/8/2016
21