Download glucose, amino acids, and fatty acids

CARBOHYDRATE
METABOLIC SOURCES OF ENERGY
Energy is extracted from food via oxidation, resulting in the end products carbon
dioxide and water. This process occurs in 4 stages, shown below .
 In stage l, metabolic fuels are hydrolyzed in the gastrointestinal tract to a
diverse set of monomeric building blocks (glucose, amino acids, and fatty
acids) and absorbed.
 In stage 2, the building blocks are degraded by various pathways in tissues
to a common metabolic intermediate, acetyl-CoA. Most of the energy
contained in metabolic fuels is conserved in the chemical bonds (electrons)
of acetyl-CoA. A smaller portion is conserved in reducing nicotinamide
adenine dinucleotide (NAD) to NADH or flavin adenine dinucleotide (FAD)
to FADH2. Reduction indicates the addition of electrons that may be free,
part of a hydrogen atom (H), or a hydride ion (H-) .
 In stage 3, the citric acid (Krebs, or tricarboxylic acid [TCA] ) cycle
oxidizes acetyl- CoA to C02. The energy released in this process is primarily
conserved by reducing NAD to NADH or FAD to FADH2.
 The final stage is oxidative phosphorylation, in which the energy of NADH
and FADH2 is released via the electron transport chain (ETC) and used by
an ATP synthase to produce ATP. This process requires 02.
METABOLIC ENERGY STORAG
ATP is a form of circulating energy currency in cells. It is formed in catabolic
pathways by phosphorylation of ADP and may provide energy for biosynthesis
(anabolic pathways) . There is a limited amount of ATP in circulation. Most of the
excess energy from the diet is stored as
acetyl CoA) and
fatty acids
(a reduced polymer of
glycogen (a polymer of glucose). Although proteins can be
mobilized for energy in a prolonged fast, they are normally more important for
other functions (contractile elements in muscle, enzymes, intracellular matrix,
etc.) .
REGULATION OF FUEL METABOLISM
The pathways that are operational in fuel metabolism depend on the nutritional
status of the organism. Shifts between storage and mobilization of a particular
fuel, as well as shifts among the types of fuel being used, are very pronounced
in going from the well-fed state to an overnight fast, and finally to a prolonged
state of starvation. The shifting metabolic patterns are regulated mainly by the
insulin/ glucagon ratio. Insulin is an anabolic hormone that promotes fuel
storage. Its action is opposed by a number of hormones, including glucagon,
epinephrine, cortisol, and growth hormone. The major function of glucagon
is to respond rapidly to decreased blood glucose levels by promoting the
synthesis and release of glucose into the circulation.
Anabolic and catabolic pathways are controlled at three important levels:
 Allosteric inhibitors and activators of rate-limiting enzymes
 Control of gene expression by insulin and glucagon
 Phosphorylation (glucagon) and dephosphorylation (insulin) of
rate limiting enzymes
Well-Fed (Absorptive) State
Immediately after a meal, the blood glucose level rises and stimulates the
release of insulin. The three major target tissues for insulin are liver, muscle, and
adipose tissue. Insulin promotes glycogen synthesis in liver and muscle. After the
glycogen stores are filled, the liver converts excess glucose to fatty acids and
triglycerides. Insulin promotes triglyceride synthesis in adipose tissue and protein
synthesis in muscle, as well as glucose entry into both tissues. After a meal,
most of the energy needs of the liver are met by the oxidation of excess amino
acids.
Two tissues,
brain and red blood cells are insensitive to insulin (are insulin
independent). The brain and other nerves derive energy from oxidizing glucose to
C02 and water in both the well-fed and normal fasting states. Only in prolonged
fasting does this situation change. Under all conditions, red blood cells use
glucose
anaerobically for all their energy needs.
Post absorptive State
Glucagon and epinephrine levels rise during an overnight fast. These
hormones exert their effects on skeletal muscle, adipose tissue, and liver. In
liver, glycogen degradation and the release of glucose into the blood are
stimulated . Hepatic gluconeogenesis is also stimulated by glucagon, but the
response is slower than that of glycogenolysis. The release of amino acids from
skeletal muscle and fatty acids from adipose tissue are both stimulated by the
decrease in insulin and by an increase in epinephrine. The amino acids and fatty
acids are taken up by the liver, where the amino acids provide the carbon
skeletons and the oxidation of fatty acids provides the ATP necessary for
gluconeogenesis.
Prolonged Fast (Starvation)
Levels of glucagon and epinephrine are markedly elevated during starvation.
Lipolysis is rapid, resulting in excess acetyl-CoA that is used for ketone
synthesis. Levels of both lipids and ketones are therefore increased in the blood.
Muscle uses fatty acids as the major fuel, and the brain adapts to using ketones
for some of its energy. After several weeks of fasting, the brain derives
approximately two thirds of its energy from ketones and one third from glucose.
The shift from glucose to ketones as the major fuel diminishes the amount of
protein that must be degraded to support gluconeogenesis. There is no "energystorage form" for protein because each protein has a specific function in the cell.
Therefore, the shift from using glucose to ketones during starvation spares
protein, which is essential for these other functions. Red blood cells (and renal
medullary cells) that have few, if any, mitochondria continue to be dependent on
glucose for their energy.
PATTERNS OF FUEL METABOLISM IN TISSUES
Fats are much more energy-rich than carbohydrates, proteins, or ketones.
Complete combustion of fat results in 9 kcal/g compared with 4 kcal/g derived
from carbohydrate, protein, and ketones. The storage capacity and pathways for
utilization of fuels varies with different organs and with the nutritional status of the
organism as a whole. The organ-specific patterns of fuel utilization in the wellfed and fasting states are summarized below
Liver
Two major roles of liver in fuel metabolism are to maintain a constant level of
blood glucose under a wide range of conditions and to synthesize ketones when
excess fatty acids are being oxidized. After a meal, the glucose concentration in
the portal blood is elevated. The liver extracts excess glucose and uses it to
replenish its glycogen stores. Any glucose remaining in the liver is then converted
to acetyl CoA and used for fatty acid synthesis. The increase in insulin after a
meal stimulates both glycogen synthesis and fatty acid synthesis in liver. The
fatty acids are converted to triglycerides and released into the blood as very low
density lipoproteins (VLDLs) . In the well-fed state, the liver derives most of its
energy from the oxidation of excess amino acids. Between meals and during
prolonged fasts, the liver releases glucose into the blood. The increase in
glucagon
during
fasting
promotes
both
glycogen
degradation
and
gluconeogenesis. Lactate, glycerol, and amino acids provide carbon skeletons
for glucose synthesis.
Adipose Tissue
After a meal, the elevated insulin stimulates glucose uptake by adipose tissue.
Insulin also stimulates fatty acid release from VLDL and chylomicron triglyceride
(triglyceride is also known as triacylglycerol). Lipoprotein lipase, an enzyme
found in the capillary bed of adipose tissue, is induced by insulin. The fatty acids
that are released from lipoproteins are taken up by adipose tissue and reesterified to triglyceride for storage. The glycerol phosphate required for
triglyceride synthesis comes from glucose metabolized in the adipocyte. Insulin is
also very effective in suppressing the release of fatty acids from adipose tissue.
During the fasting state, the decrease in insulin and the increase in epinephrine
activate hormone-sensitive lipase in fat cells, allowing fatty acids to be released
into the circulation.
Skeletal Muscle
Resting muscle
The major fuels of skeletal muscle are glucose and fatty acids. Because of the
enormous bulk, skeletal muscle is the body's major consumer of fuel. After a
meal, under the influence of insulin, skeletal muscle takes up glucose to
replenish glycogen stores and amino acids that are used for protein synthesis.
Both excess glucose and amino acids can also be oxidized for energy. In the
fasting state, resting muscle uses fatty acids derived from free fatty acids in the
blood. Ketones may be used if the fasting state is prolonged.
Active muscle
The primary fuel used to support muscle contraction depends on the magnitude
and duration of exercise as well as the major fibers involved. Skeletal muscle has
stores of both glycogen and some triglycerides. Blood glucose and free fatty
acids also may be used.
Fast-twitch muscle fibers have a high capacity for anaerobic glycolysis but are
quick to fatigue. They are involved primarily in short-term, high-intensity
exercise.
Slow-twitch muscle fibers in arm and leg muscles are well vascularized and
primarily oxidative. They are used during prolonged, low-to-moderate intensity
exercise and resist fatigue. Slow-twitch fibers and the number of their
mitochondria increase dramatically in trained endurance athletes.
Short bursts of high-intensity exercise are supported by anaerobic glycolysis
drawing on stored muscle glycogen. During moderately high, continuous
exercise, oxidation of glucose and fatty acids are both important, but after 1 to 3
hours of continuous exercise at this level, muscle glycogen stores become
depleted, and the intensity of exercise declines to a rate that can be supported
by oxidation of fatty acids.
Cardiac Muscle
During fetal life cardiac muscle primarily uses glucose as an energy source, but
in the postnatal period there is a major switch to β-oxidation of fatty acids.
Thus, ketones are present during prolonged fasting, they are also used. Thus,
not surprisingly, cardiac myocytes most closely parallel the skeletal muscle
during extended periods of exercise.
In patients with cardiac hypertrophy, this situation reverses to some extent. In the
failing heart, glucose oxidation increases, and β-oxidation falls.
Brain
Although the brain represents 2% of total body weight, it obtains 15 % of the
cardiac output, uses 20% of total 02, and consumes 25% of the total glucose.
Therefore, glucose is the primary fuel for the brain. Blood glucose levels are
tightly regulated to maintain the concentration levels that enable sufficient
glucose uptake into the brain via GLUT 1 and GLUT 3 transporters. Because
glycogen levels in the brain are minor, normal function depends upon continuous
glucose supply from the bloodstream. In hypoglycemic conditions ( <70 mg/dL),
centers in the hypothalamus sense a fall in blood glucose level, and the release
of glucagon and epinephrine is triggered. Fatty acids cannot cross the bloodbrain barrier and are therefore not used at all. Between meals, the brain relies on
blood glucose supplied by either hepatic glycogenolysis or gluconeogenesis.
Only in prolonged fasts does the brain gain the capacity to use ketones for
energy, and even then ketones supply only approximately two thirds of the fuel;
the remainder is glucose.