section 22.9
Metabolic Homeostasis during Exercise
517
pathway, eventually leading to stimulation of food intake.
Neuropeptide Y contains 36 amino acid residues and has
tyrosine at both the N and C termini (hence the des-
ignation Y). The actions of neuropeptide Y result in
the stimulation of food intake followed by the restora-
tion of depleted adipose stores and inhibition of sym-
pathetic nervous system outflow with a consequent de-
crease in energy expenditure. When leptin levels are
high, food intake decreases; this is mediated by the
pro-opiomelanocortin (POMC)-a-melanocyte stimulat-
ing hormone and melanocortin-4 receptor pathway. In-
hibition of the melanocortin-4 receptor signal transduc-
tion system by the agouti protein leads to obesity in
mice. Agouti protein (AGRP) is normally synthesized in
hair follicles and antagonizes the action of a-melanocyte-
stimulating hormone in eumelanin synthesis (Chapter 17)
by binding to melanocortin-4 receptor. In autosomal-
dominant mice that overexpress agouti protein in skin and
hypothalamus, the phenotype is obese, yellow mice.
In humans, the pathways of regulation of appetite
and food consumption have been verified by identifying
mutations in genes that participate in regulation of body
weight (Figure 22-27). The regulators of conversion of
preadipocytes to adipocytes also determine the adipose
tissue mass. One of the regulators is a transcription factor
known as peroxisome proliferator-activated receptor-y
2
(PPAR-j/2). Troglitazone, a hypoglycemic agent (previ-
ously discussed) that increases insulin sensitivity, is a syn-
thetic ligand for PPAR-/2. However, contrary to studies
in rodents, administration of troglitazone in humans does
not cause significant weight gain as compared to other oral
antidiabetic drugs. Phosphorylation of PPAR-y2 at serl 14
makes the receptor less active in converting preadipocytes
to adipocytes. A mutation converting proline to glutamine
at position 115 blocks phosphorylation at the serine site,
maintains the protein in the active state, and leads to
obesity.
Leptin therapy has corrected obesity in a child with con-
genital leptin deficiency. In obese individuals, the presence
of circulating high levels of leptin has been attributed to
resistance or some other defect in the leptin receptors. This
apparent paradox of high leptin levels associated with obe-
sity is analogous to insulin resistance seen in type
2
dia-
betes mellitus. In general, in the vast majority of obese
patients, the molecular defects remain unknown. Diet and
exercise are the mainstays in the management of obesity.
22.9 Metabolic Homeostasis during Exercise
At rest, skeletal muscle utilizes the catabolism of fatty
acids and branched-chain amino acids to maintain cellular
integrity. In exercise, oxygen utilization by muscle may in-
crease 30-fold, and additional energy can arise from anaer-
obic glycolysis. The substrates used depend on the inten-
sity of exercise and on training. High-intensity exercise can
start almost instantaneously (e.g., the
1 0 0
-m dash or the
clean-and-jerk in weight lifting), but increase of oxygen
utilization is limited by the rates of blood flow, respira-
tion, and oxygen delivery to the tissue. After the onset of
high-intensity exercise, the body and muscle are initially
in oxygen deficit until a new steady-state, increased rate of
oxygen uptake can be achieved. When the exercise ends,
this oxygen debt is repaid during the recovery phase. The
availability of oxygen determines the metabolic fuels uti-
lized. Skeletal muscle has fewer mitochondria per unit
weight than heart or liver. A major adaptation induced by
endurance exercise training is an increase in the potential
for delivery and utilization of oxygen: the heart hyper-
trophies; total blood volume increases; muscle capillarity
increases; and skeletal muscle mitochondrial size, number,
and capacity increase (see Chapter 21).
Exercise Generating Maximum Power
The substrates for muscular activity are intracellular ATP,
phosphocreatine, glycogen, plasma glucose, fatty acids,
ketone bodies, triacylglycerols, and dietary branched-
chain amino acids. In exercise that generates maximum
power, the primary sources are ATP and phosphocreatine.
The total amount of ATP, and of ATP generated by the
adenylate kinase reaction (2ADP —>■
ATP + AMP), is
sufficient for only a fraction of a second. The immediate
reserve is ATP produced by the creatine kinase reaction
(phosphocreatine + ADP —►
ATP + creatine). Maximum-
power-output exercise rapidly depletes phosphocreatine,
can be sustained for short periods (15-20 seconds) and
ends as phosphocreatine is depleted. Some anaerobic gly-
colysis from glycogen may occur during such a period
but would reach a maximum rate only after the work had
stopped. Maximum-power-output work exceeds the ca-
pacity of muscle to generate energy oxidatively even if
this could be initiated rapidly.
High-Intensity Endurance Exercise
This exercise is typified by an individual working in the
range of 60-80% of maximum capacity of oxygen uptake
(e.g., running distances of 5 km up to a marathon). The
exercise is terminated by exhaustion. Phosphocreatine is
the initial energy source; glycogenolysis ensues, anaero-
bically at first, with lactate production, but with increasing
aerobic oxidation as oxygen availability increases. Glyco-
gen utilization is the major fuel for the first 15 minutes, but
