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2
*
Department of Pediatrics, Division of Endocrinology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7220 and
Department of Woman and Child Health, Pediatric Endocrinology Unit Q2:08, Karolinska Institutet, S-171 76 Stockholm, Sweden
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • fasting • cholesterol • apolipoprotein B • insulin-like growth factor-I • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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showed that
cholesterol stored in the lipid droplet of the adipose tissue cell is
released into the plasma and is the chief source of cholesterol during
food deprivation in rabbits. In humans, conflicting data have been
published concerning the effect of fasting on plasma concentrations of
triacylglycerol and cholesterol (Ende 1962
, Samra et al. 1996
, Swaner and Connor 1975
,
Vaisman et al. 1990
). The contradictory reports may be
explained by sex and/or age differences (Samra et al. 1996
, Swaner and Connor 1975
, Vaisman et al. 1990
), presence of obesity (Vaisman et al. 1990
), hyperlipidemia (Ende 1962
), different
health states (Ende 1962
), medications, and different
diets (partial or total starvation) and physical activity during
fasting (Samra et al. 1996
, Swaner and Connor 1975
, Vaisman et al. 1990
). In humans, acute
starvation decreases serum insulin-like growth factor-I
(IGF-I)3
(Oscarsson et al. 1995
), whereas treatment of normal men
with recombinant IGF-I decreases serum cholesterol
(Oscarsson et al. 1995
). This study was designed to
investigate changes in serum levels of lipid components and IGF-I
during 7 d of starvation (no energy) in healthy young adults of
both sexes and of normal weight, who were allowed a supervised 30-min
walk twice a day. |
SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This study is an adjunct to another endocrine study whose details were
reported previously (Sävendahl and Underwood 1997
). Healthy, nonsmoking volunteers between 21 and 38 y
of age, weighing 93–124% of ideal body weight participated in this
study, which was approved by the Institutional Committee for the
Protection of the Rights of Human Subjects at the University of North
Carolina at Chapel Hill. After informed consent was obtained, 14
subjects (8 women and 6 men) were admitted to the General Clinical
Research Center (GCRC) at the University of North Carolina and served
an evening snack (d 0). From 2300 h on d 0, through d 8, oral
intake was limited to mineral water (minimum 2 L daily) and one daily
multivitamin with minerals tablet (Theragran M, Apothecon, Princeton,
NJ). The subjects were allowed a supervised 30-min walk twice a day. On
d 1, 2, 4, 6 and 8, venous blood samples were collected between 0800
and 0845 h; serum was prepared and frozen at -70°C until
biochemical testing was performed.
Laboratory methods.
Serum concentrations of triacylglycerol and cholesterol were measured
by a Hitachi 717 Analyzer (BMC/Roche, Indianapolis, IN) using reagents
from Boehringer Mannheim Diagnostics (Treyburn, NC). HDL cholesterol
was determined by a Fara/Cobas Analyzer (BMC/Roche) using the Dextran
Sulfate (MW 50,000) method (Weisweiler et al. 1979
). LDL
cholesterol was calculated from serum concentrations of
triacylglycerol, cholesterol and HDL cholesterol using the Friedewald
formula. The serum concentration of apolipoprotein B (apo B) was
determined by immunoprecipitation using a specific antibody (Smith
Kline Beecham Laboratories, Atlanta, GA) (Kottke et al. 1986
). The rate of increase in the intensity of light scattered
by the antigen-antibody complex was measured by a nephelometer
(Array 360 System, Beckman/Coulter, Brea, CA). The apo B concentration
was compared with a pooled reference serum in which the concentration
of apo B is known. Immunoreactive IGF-I was measured by a highly
specific nonequilibrium RIA (Copeland et al. 1980
) after
removal of IGF-binding proteins by C18 cartridge
chromatography (Sep-Pak, Waters Associates, Milford, MA)
(Davenport et al. 1990
). The intra-assay CV were
1.9% for cholesterol, 2.0% for triacylglycerol, 3.1% for HDL, 6.0%
for apo B and 6.8% for IGF-I.
Statistical analysis.
Values are expressed as means ± SEM. The significance of differences between prefasting and postfasting measurements and differences between subgroups of patients was evaluated by two-tailed Student's t test with correction made for unequal variance. The significance of differences over time was evaluated by repeated-measures one-way ANOVA. The probability level for significance was set at P < 0.05. Statistical analyses were performed using SuperAnova software (Abacus Concepts, Berkeley, CA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One week of fasting decreased plasma glucose by 1.52 ± 0.11
mmol/L (P < 0.0001). The serum concentrations of total
cholesterol, LDL cholesterol and apolipoprotein B (apo B) were
increased in each subject in response to 1 wk of fasting (Table 1). A gradual (nonlinear) increase was observed for the mean serum
concentrations of cholesterol, LDL and apo B when assessed on d 1
(prefast), 2, 4 and 8 (postfast) (Fig. 1
). One week of fasting increased serum concentrations of total
cholesterol by 1.83 ± 0.26 mmol/L (37.3 ± 5.0%,
P < 0.0001, one-way ANOVA), LDL cholesterol by
1.95 ± 0.22 mmol/L (66.1 ± 6.6%, P < 0.0001) and apo B by 0.54 ± 0.08 g/L (65.0 ± 9.2%,
P < 0.0001). To determine whether the
fasting-induced increases in serum lipids were associated with sex,
age, body mass index (BMI), body weight and weight loss, the 10
subjects were subgrouped (Fig. 2
). The increases in total cholesterol, LDL cholesterol and apo B were
associated with the amount of weight loss. Total cholesterol increased
by 1.43 ± 0.29 mmol/L in patients losing less weight (4.4–5.5
kg) compared with 2.36 ± 0.32 mmol/L in patients losing more
weight (6.0–6.4 kg) (P < 0.05). There was also a
trend (P = 0.09) toward larger increases in
serum cholesterol in patients with lower body weight (59–67 kg)
compared with patients with higher body weight (71–84 kg) (Fig. 2)
.
There was no obvious effect of sex, age or BMI on serum lipids(Fig. 2)
.
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The mean serum concentration of IGF-I gradually decreased when
measured on d 1, 2, 4, 6 and 8 (Fig. 1)
. One week of fasting decreased
IGF-I from 246 ± 29 to 87 ± 10 µg/L
(38 ± 5% of prefasting values, P < 0.0001,
one-way ANOVA).
|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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showed that 6 d
of subtotal starvation (837 kJ/d) did not affect serum triacylglycerol
and cholesterol in nonobese men and women, whereas triacylglycerol
decreased and cholesterol was unaffected in obese individuals. In a
mixed group of lean, normal and moderately obese men <35 y old,
Ende (1962)
showed a small (13.9%, P = 0.06) increase in serum cholesterol after 3 d of subtotal
starvation (682 kJ/d). On the other hand, Kudchodkar et al. (1977)
reported decreasing serum cholesterol after 9 d of
energy restriction (1260–4200 kJ/d) in obese, hyperlipidemic men.
These contradictory reports may be explained by sex and/or age
differences (Ende 1962
, Kudchodkar et al. 1977
, Samra et al. 1996
, Vaisman et al. 1990
), presence of obesity (Kudchodkar et al. 1977
, Vaisman et al. 1990
), hyperlipidemia
(Ende 1962
, Kudchodkar et al. 1977
),
different health states (Ende 1962
, Kudchodkar et al. 1977
), medications, and different diets and physical
activity during fasting (Ende 1962
, Kudchodkar et al. 1977
, Samra et al. 1996
, Vaisman et al. 1990
). This study was designed to minimize these
confounding factors.
Complete fasting is accompanied by substantial lipolysis (Samra et al. 1996
, Stout et al. 1976
, Vaisman et al. 1990
) and could explain the observed increases in serum
lipids in our subjects. However, a decreased LDL uptake by the liver
could be a second mechanism contributing to increased LDL levels. This
is supported by studies showing that insulin, which is decreased during
energy deprivation (Becker et al. 1971
), increases
hepatic LDL receptor gene expression (Streicher et al. 1996
) and LDL receptor-binding (Salter et al. 1987
).
We observed falling serum IGF-I and increasing LDL levels in
response to 1 wk of fasting. This is in keeping with the inverse
correlation between LDL and IGF-I in nonfasting subjects
(Hoogerbrugge et al. 1989
). In addition, IGF-I
treatment of normal men (Oscarsson et al. 1995
) and
patients with hypopituitarism (Thorén et al. 1994
)
decreases cholesterol concentrations. In sum, the negative correlation
between serum IGF-I and LDL suggests a causal relationship.
We conclude that acute starvation in healthy, nonobese human subjects increases serum total cholesterol, LDL cholesterol and apo B concentrations. Further studies, which may include measurements of turnover of radiolabeled LDL-particles, are required to investigate the mechanism by which fasting affects lipid metabolism.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: apoB, apolipoprotein B; BMI, body mass index; IGF-I, insulin-like growth factor-I.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1. Becker D. J., Pimstone B. L., Hansen J.D., L & Hendricks S. Insulin secretion in protein-calorie malnutrition. Diabetes 1971;20:542-551[Medline]
2.
Copeland K. C., Underwood L. E., Van Wyk J. J. Induction of immunoreactive somatomedin-C in human serum by growth hormone: dose response relationships and effect on chromatographic profiles. J. Clin. Endocrinol. Metab. 1980;50:690-697
3.
Davenport M. L., D'Ercole A. J., Underwood L. E. Effect of maternal fasting on fetal growth, serum insulin-like growth factors (IGFs), and tissue IGF messenger ribonucleic acids. Endocrinology 1990;126:2062-2067
4. Ende N. Starvation studies with special reference to cholesterol. Am. J. Clin. Nutr. 1962;11:270-280[Abstract]
5.
Hoogerbrugge -v.d., Linden N., Jansen H., Hulsmann W. C., Birkenhager J. C. Relationship between insulin-like growth factor-I and low-density lipoprotein cholesterol levels in primary hypothyroidism in women. J. Endocrinol. 1989;123:341-345
6. Kottke B., Zinsmeister A. R., Holmes D. R., Jr, Kneller R. W., Hallaway B. J., Mao S.J.T. Apolipoproteins and coronary artery disease. Mayo Clin. Proc. 1986;61:313-320[Medline]
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Kudchodkar B. J., Harbhajan S. S., Mason D. T., Borhani M. D. Effects of acute caloric restriction on cholesterol metabolism in man. Am. J. Clin. Nutr. 1977;30:1135-1146
8. Oscarsson J., Lundstam U., Gustafsson B., Wilton P., Edén S., Wiklund O. Recombinant human insulin-like growth factor-I decreases serum lipoprotein (a) concentration in normal adult men. Clin. Endocrinol. 1995;42:673-676[Medline]
9. Salter A. M., Fisher S. C., Brindley D. N. Binding of low-density lipoprotein to monolayer cultures of rat hepatocytes is increased by insulin and decreased by dexamethasone. FEBS Lett 1987;220:159-162[Medline]
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Samra J. S., Clark M. L., Humphreys S. M., MacDonald I. A., Frayn K. N. Regulation of lipid metabolism in adipose tissue during early starvation. Am. J. Physiol. 1996;271:E541-E546
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Sävendahl L., Underwood L. E. Decreased interleukin-2 production from cultured peripheral blood mononuclear cells in human acute starvation. J. Clin. Endocrinol. Metab. 1997;82:1177-1180
12. Stout R. W., Henry R. W., Buchanan K. D. Triglyceride metabolism in acute starvation, the role of secretin and glucagon. Eur. J. Clin. Investig. 1976;6:179-185[Medline]
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Streicher R., Kotzka J., Muller-Wieland D., Siemeister G., Munch M., Auci H., Krone W. SREBP-1 mediates activation of the low density lipoprotein receptor promoter by insulin and insulin-like growth factor-I. J. Biol. Chem. 1996;271:7128-7133
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Swaner J. C., Connor W. E. Hypercholesterolemia of total starvation: its mechanism via tissue mobilization of cholesterol. Am. J. Physiol. 1975;229:365-369
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Thorén M. C., Wivall-Helleryd I. L., Blum W. F., Hall K. E. Effects of repeated subcutaneous administration of recombinant human insulin-like growth factor I in adults with growth hormone deficiency. Eur. J. Endocrinol. 1994;131:33-40
16. Vaisman N., Sklan D., Dayan Y. Effect of moderate semi-starvation on plasma lipids. Int. J. Obes. 1990;14:989-996[Medline]
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