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PERIODICAL
FASTING AND CALORIC RESTRICTION FOR LIFE EXTENSION,
DISEASE TREATMENT AND CREATIVITY.
(clinical and experimental data)
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FASTING AND CALORIC RESTRICTION PRODUCE VARIOUS BIOLOGICAL
EFFECTS |
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PROTEIN
METABOLISM AND PROTEIN QUALITY |
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2000
VA Palo Alto Health Care System,
Palo Alto, CA, USA; University of Massachusetts, Amherst,
MA, USA.
The effects of prolonged caloric
restriction on protein kinetics in lean subjects has
not been previously investigated. PURPOSE: To test
the hypotheses that 21 days of caloric restriction
(CR) in lean subjects would a) result in significant
losses of lean mass despite a suppression in leucine
turnover and oxidation, and b) negatively impact exercise
performance. METHODS: Nine young, normal weight men
(23+/-5 y, 78.6+/-5.7 kg, VO2peak: 45.2+/-7.3 ml(.)kg(-1)(.)min(-1),mean+/-SD)
were underfed by 40% of the calories required to maintain
body weight (BW) for 21 days and lost 3.8+/-0.3 kg
BW and 2.0+/-0.4 kg lean mass. Protein intake was
kept at 1.2 g(.)kg(-1)(.)day(-1). Leucine kinetics
were measured using KIC reciprocal pool model in the
post-absorptive state during rest and 50 minutes of
exercise (EX) at 50% of VO2peak. Body composition,
basal metabolic rate (BMR) and exercise performance
were measured throughout the intervention. RESULTS:
At rest, leucine flux (~131 micromol(.)kg(-1)(.)hr(-1))
and oxidation (Rox; ~19 micromol(.)kg(-1)(.)hr(-1))
did not differ pre- and post- CR. During EX, leucine
flux (129+/-6 vs. 121+/-6) and Rox (54+/-6 vs. 46+/-8)were
lower following CR than pre-CR. Nitrogen balance was
negative throughout the intervention (~3.0gN(.)d(-1))
and BMR declined from 1898+/-262 kcal(.)d(-1) to 1670+/-203.
Aerobic performance (VO2peak, endurance cycling) was
not impacted by CR, but arm flexion endurance decreased
by 20%. CONCLUSIONS: Three weeks of caloric restriction
reduced leucine flux and oxidation during exercise
in normal weight young men. However, despite negative
nitrogen balance and loss of lean mass, whole body
exercise performance was well maintained in response
to CR.
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Department of Biochemistry, College
of Medicine, Dongguk University, Kyungju, Kyungpook
780-714, Korea.
Calorie restriction (CR) has
been shown to improve peripheral insulin resistance
and type 2 diabetes in animal models. However, the
exact mechanism of CR on GLUT4 expression and translocation
in insulin-sensitive tissues has not been well elucidated.
In the present study, we examine the effect of CR
on the expression of glucose transporter 4 (GLUT4),
GLUT4 translocation, and glucose transport activity
in adipose tissue from Otsuka Long-Evans Tokushima
Fatty (OLETF) rat and control (LETO) rats. CR (70%
of satiated group) ameliorated hyperglycemia and improved
impaired glucose tolerance (IGT) in OLETF rats. In
skeletal muscle, the expression levels of GLUT4 and
GLUT1 were not significantly different between LETO
and OLETF rats, and were not affected by CR. By contrast,
the expression level of GLUT4 was markedly decreased
in the adipose tissue of OLETF rats, but was dramatically
increased by CR. The GLUT4 recruitment stimulated
by insulin was also improved in OLETF rat adipocytes
by CR. The insulin-stimulated 2-deoxyglucose (2DG)
uptake was significantly increased in adipocytes from
the CR OLETF rats, as compared with the satiated OLETF
rats. Taken together, these results suggest that CR
improves whole body glucose disposal and insulin resistance
in OLETF rats, and that these effects may associate
with the increased adipocyte-specific GLUT4 expression.
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2000
Department of Pharmacology, University
of North Texas Health Science Center at Fort Worth,
76107, USA.
The age-associated increase
in oxidative damage in ad libitum-fed mice is attenuated
in mice fed calorically restricted (CR) diets. The
objective of this study was to determine if this effect
results from a slowing of age-related accumulation
of oxidative damage, or from a reversible decrease
of oxidative damage by caloric restriction. To address
these possibilities, crossover studies were conducted
in C57BL/6 mice aged 15 to 22 months that had been
maintained, after 4 months of age, on ad libitum (AL)
or a 60% of AL caloric regimen. One half of the mice
in these groups were switched to the opposite regimen
of caloric intake for periods up to 6 weeks, and protein
oxidative damage (measured as carbonyl concentration
and loss of sulfhydryl content) was measured in homogenates
of brain and heart. In AL-fed mice, the protein carbonyl
content increased with age, whereas the sulfhydryl
content decreased. Old mice maintained continuously
under CR had reduced levels of protein oxidative damage
when compared with the old mice fed AL. The effects
of chronic CR on the carbonyl content of the whole
brain and the sulfhydryl content of the heart were
fully reversible within 3-6 weeks following reinstatement
of AL feeding. The effect of chronic CR on the sulfhydryl
content of the brain cortex was only partially reversible.
The introduction of CR for 6 weeks in the old mice
resulted in a reduction of protein oxidative damage
(as indicated by whole brain carbonyl content and
cortex sulfhydryl), although this effect was not equivalent
to that of CR from 4 months of age. The introduction
of CR did not affect the sulfhydryl content of the
heart. Overall, the current findings indicate that
changes in the level of caloric intake may reversibly
affect the concentration of oxidized proteins and
sufhydryl content. In addition, chronic restriction
of caloric intake also retards the age-associated
accumulation of oxidative damage. The magnitude of
the reversible and chronic effects appears to be dependent
upon the tissue examined and the nature of the oxidative
alteration.
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1999
Dipartimento di Scienze Mediche,
Universita del Piemonte Orientale, Novara, Italy.
The effect of cycloheximide
(CH) on the fasting-induced changes of rat liver cell
and protein turnover has been investigated. Late starvation
phase (3-4-day-fasting period) was characterised by
a decrease in liver weight and protein and DNA content.
The loss of DNA was not related to liver cell necrosis
but due not only to depression of cell proliferation
as shown by the drop in the labelling index but also
induction of apoptosis. This type of apoptosis was
documented by the increase in the apoptotic index
(cells labelled by TUNEL) and transglutaminase activity
as well as by DNA fragmentation. The liver cells of
fasted rats appeared smaller as shown by the higher
cell density and DNA/protein ratio than in controls.
Females were more resistant to fasting-induced apoptosis
than males. A single dose of CH, a drug primary known
as inhibitor of protein synthesis, induced or enhanced
apoptosis in fed and 2-days fasted male rats, respectively,
without any sign of cell necrosis. On the contrary,
the administration of repeated doses of CH blocked
apoptosis induced by fasting. CH "froze"
protein and DNA content as well as apoptotic process
at the level of 2 days-fasted rats. While fasting-induced
liver protein loss resulted from a marked reduction
in protein synthesis with a slight decrease in degradation,
repeated treatment with CH virtually blocked protein
loss by abolishing protein catabolism. These data
suggest a direct relationship between the catabolic
side of protein turnover and the apoptotic process.
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Clinical Diabetes and Nutrition
Section, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health,
Phoenix AZ 85016, USA.
Uncoupling protein (UCP) 2
and UCP3 are newly discovered proteins that can uncouple
ATP production from mitochondrial respiration, thereby
dissipating energy as heat and affecting energy metabolism
efficiency. In contrast to UCP1, which is only present
in brown adipose tissue, UCP2 has a wide tissue distribution,
whereas UCP3 is expressed predominantly in skeletal
muscle. Some evidence of a role for UCPs in modulating
metabolic rate was provided by linkage and association
studies. Furthermore, UCP3 gene _expression was found
to correlate negatively with body mass index and positively
with sleeping metabolic rate in Pima Indians. Treatment
with thyroid hormone increases _expression of the
UCP2 and UCP3 genes. Other regulators of UCP2 and
UCP3 gene _expression are beta3-adrenergic agonists
and glucocorticoids. Surprisingly, fasting has a stimulatory
effect on UCP2 and UCP3 mRNA levels, possibly explained
by the effects of free fatty acid on UCP2 and UCP3
gene _expression.
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1998
INSERM Unit 317, Louis Bugnard
Institute, Rangueil Hospital, Paul Sabatier University,
Toulouse, France.
Uncoupling protein-2 (UCP2)
is a mitochondrial protein expressed in a wide range
of human tissues. By uncoupling respiration from ATP
synthesis, UCP2 might be involved in the control of
energy expenditure. We have investigated UCP2 gene
_expression in human adipose tissue. In eight subjects,
we found a positive correlation (r = 0.91, P <
0.002) between subcutaneous and visceral fat depots
UCP2 messenger RNA (mRNA) levels, suggesting that
UCP2 mRNA level in subcutaneous adipose tissue is
a good index of UCP2 gene _expression in whole body
adipose tissues. The effect of a 25-day very-low-calorie
diet un UCP2 mRNA level and resting metabolic rate
was investigated in eight obese premenopausal women.
There was no difference in UCP2 mRNA levels before
and during the diet. After 25 days of hypocaloric
diet, a positive correlation was found between adipose
tissue UCP2 mRNA level and resting metabolic rate
adjusted for lean body mass (r = 0.82, P < 0.01).
These results show that very-low-calorie diet, unlike
short-term fasting, is not associated with an induction
in UCP2 mRNA _expression, and that adipose tissue
UCP2 mRNA levels may be related to variations in resting
energy expenditure in humans.
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1997
Institut National de la Sante
et de la Recherche Medicale Unite 317, Institut Louis
Bugnard, Universite Paul Sabatier, Batiment L3, Hopital
Rangueil, 31403 Toulouse Cedex 4, France.
Uncoupling protein-2 and -3
(UCP2 and UCP3) are mitochondrial proteins that show
high sequence homology with the brown adipocyte-specific
UCP1. UCP1 induces heat production by uncoupling respiration
from ATP synthesis. UCP2 is widely expressed in human
tissues, whereas UCP3 _expression seems restricted
to skeletal muscle, an important site of thermogenesis
in humans. We have investigated the regulation of
UCP2 and UCP3 gene _expression in skeletal muscle
and adipose tissue from lean and obese humans. UCP2
and -3 mRNA levels were not correlated with body mass
index (BMI) in skeletal muscle, but a positive correlation
(r = 0.55, P < 0.01, n = 22) was found between
UCP2 mRNA level in adipose tissue and BMI. The effect
of fasting was investigated in eight lean and six
obese subjects maintained on a hypocaloric diet (1,045
kJ/d) for 5 d. Calorie restriction induced a similar
2-2.5-fold increase in UCP2 and -3 mRNA levels in
lean and obese subjects. To study the effect of insulin
on UCP gene _expression, six lean and five obese subjects
underwent a 3-h euglycemic hyperinsulinemic clamp.
Insulin infusion did not modify UCP2 and -3 mRNA levels.
In conclusion, the similar induction of gene _expression
observed during fasting in lean and obese subjects
shows that there is no major alteration of UCP2 and
-3 gene regulation in adipose tissue and skeletal
muscle of obese subjects. The increase in UCP2 and
-3 mRNA levels suggests a role for these proteins
in the metabolic adaptation to fasting.
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1994
Centre d'Ecologie et Physiologie
Energetiques, Centre National de la Recherche Scientifique,
Strasburg, France.
During seasonal cycles in ground
squirrels, as in many other species, there are periods
of spontaneous loss of appetite, very low calorie
intake and a 30% loss in body mass. Measurements of
nitrogen balance during early and later stages of
the mass loss phase of the cycle (-1.2 +/- 6.7 and
+13.1 +/- 8.8 mg/24 h, respectively) showed a total
sparing of protein, indicating a selective use of
fat. However, when no food at all was available, nitrogen
balance was negative (-45 +/- 5 mg/24 h). Provided
that they have access to some food, ground squirrels
are therefore able to compensate for any protein utilization,
while at the same time selectively losing large amounts
of fat. It appears that a factor related to spontaneous
reduction in food intake enables these animals to
achieve the total sparing of protein that eludes dieting
humans on comparably low caloric intakes.
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