Department of Internal Medicine and Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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The effects of obesity and weight
loss on lipoprotein kinetics were evaluated in six lean women [body
mass index (BMI): 21 ± 1 kg/m2] and seven women with
abdominal obesity (BMI: 36 ± 1 kg/m2). Stable isotope
tracer techniques, in conjunction with compartmental modeling, were
used to determine VLDL-triglyceride (TG) and apolipoprotein B-100
(apoB-100) secretion rates in lean women and in obese women before and
after 10% weight loss. VLDL-TG and VLDL-apoB-100 secretion rates were
similar in lean and obese women. Weight loss decreased the rate of
VLDL-TG secretion by ~40% (from 0.41 ± 0.05 to 0.23 ± 0.03 µmol · kg fat-free
mass1 · min
1;
P < 0.05). The relative decline in VLDL-TG produced
from nonsystemic fatty acids, derived from intraperitoneal and
intrahepatic TG, was greater (61 ± 7%) than the decline in
VLDL-TG produced from systemic fatty acids, predominantly derived from
subcutaneous TG (25 ± 8%; P < 0.05). Weight
loss did not affect VLDL-apoB-100 secretion rate. We conclude that
weight loss decreases the rate of VLDL-TG secretion in women with
abdominal obesity, primarily by decreasing the availability of
nonsystemic fatty acids. There is a dissociation in the effect of
weight loss on VLDL-TG and apoB-100 metabolic pathways that may affect
VLDL particle size.
lipoprotein; fatty acids; lipolysis
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INTRODUCTION |
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OBESE PERSONS, particularly those with abdominal (upper-body) obesity, have an increased prevalence of dyslipidemia, manifested by increased fasting plasma triglyceride (TG) and decreased plasma HDL-cholesterol concentrations (12, 26). These alterations in the plasma lipids are associated with an increased risk of coronary heart disease (2, 8, 9, 12, 26). The increase in plasma TG concentration is presumably related to increased hepatic secretion of VLDL, which is the major carrier of TG in plasma during postabsorptive conditions. VLDL-TG secretion is largely regulated by the availability of fatty acids derived from lipolysis of subcutaneous, intraperitoneal, and intrahepatic TG (4, 28, 41). Therefore, the increase in endogenous TG stores and lipolytic rates that is associated with obesity may be responsible for increased VLDL-TG secretion.
Modest weight loss (5-10% of body wt) decreases plasma TG concentrations in obese persons (53). However, the mechanisms that are responsible for the alterations in plasma TG concentrations are not well understood. Moreover, results from several studies suggest that there may be sex differences in the response of lipoprotein kinetics to weight loss. We have recently found that both sex and obesity independently affect basal VLDL-TG metabolism (37). Studies conducted in hypertriglyceridemic (16) and obese (49) men found that weight loss decreased VLDL-TG (16) and VLDL-apolipoprotein B-100 (apoB-100) (16, 49) secretion rates. In contrast, a study conducted in obese women found that weight loss did not affect VLDL-TG secretion (20). However, the failure to show an effect of weight loss on VLDL-TG metabolism in obese women might have been confounded by negative energy balance and the methods used to assess VLDL kinetics, which did not account for tracer recycling or the conversion of tracer to other lipid components that can cause errors in calculating VLDL-TG secretion rate (44, 54). The effect of weight loss on VLDL-apoB-100 kinetics has not been studied in women.
The purpose of the present study was to evaluate the effect of modest weight loss (10% of initial body wt) on 1) VLDL-TG kinetics; 2) VLDL-, intermediate-density lipoprotein (IDL)-, and LDL-apoB-100 kinetics; 3) the relationship between VLDL-TG and VLDL-apoB-100 secretion rates; and 4) the contribution of systemic plasma fatty acids (derived from lipolysis of subcutaneous adipose tissue triglycerides) and nonsystemic fatty acids (derived from lipolysis of intraperitoneal and intrahepatic triglycerides) to VLDL-TG secretion in abdominally obese women. We hypothesized that weight loss will 1) decrease the rate of VLDL-TG secretion; 2) decrease the rate of VLDL-, IDL-, and LDL-apoB-100 secretion; 3) cause a greater decrease in VLDL-TG than in VLDL-apoB-100 secretion rate; and 4) decrease the relative contribution of nonsystemic plasma fatty acids to VLDL-TG. Lipoprotein kinetics and the contribution of fatty acids from different sources to VLDL-TG were determined by using stable isotope tracer techniques in conjunction with compartmental modeling (44).
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RESEARCH DESIGN AND METHODS |
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Subjects
Six lean women (age 27 ± 3 yr) and seven women with class II abdominal obesity (age 40 ± 2 yr; waist circumference >90 cm) participated in this study (Table 1). Subjects were considered to be in good health, except for obesity, after completion of a comprehensive medical evaluation, which included a history and physical examination, an electrocardiogram, standard blood and urine tests, and a 2-h oral glucose tolerance test. Persons with increased fasting plasma glucose concentration (>110 mg/dl), impaired oral glucose tolerance, hypertriglyceridemia (>200 mg/dl), and those taking medications regularly or who smoked tobacco were excluded. All subjects had been weight stable for
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Written informed consent was obtained from all subjects before their participation in the study, which was approved by the Human Studies Committee and the General Clinical Research Center (GCRC) Scientific Advisory Committee of Washington University School of Medicine in St. Louis, MO.
Experimental Protocol
Body composition analyses. Fat mass (FM) and fat-free mass (FFM) were determined by dual-energy X-ray absorptiometry (Hologic QDR 1,000/w, Waltham, MA). Abdominal fat mass was determined by magnetic resonance imaging (Siemens, Iselin, NJ); a five-slice image at the L2-L4 interspace was analyzed to determine average subcutaneous and intra-abdominal adipose tissue mass.
Isotope infusion study.
Subjects were admitted to the inpatient unit of the GCRC at Washington
University School of Medicine the day before the isotope infusion
study. At 1900, subjects consumed a standard meal, containing 12 kcal/kg body weight for lean subjects and 12 kcal/kg adjusted body
weight for obese subjects. Adjusted body weight was calculated as ideal
body weight [the midpoint of the medium frame of the Metropolitan Life
Insurance Table (35)] + 0.25 × (actual body weight ideal body weight). An adjusted body weight was used in
obese subjects to help match relative energy intake with energy requirements in lean and obese groups. The meal consisted of 55% of
total energy as carbohydrates, 30% as fat, and 15% as protein. At
2000, the subjects ingested a liquid formula (Ensure; Ross Laboratories, Columbus, OH) containing 250 kcal (40 g carbohydrates, 6.1 g fat, and 8.8 g protein) and then fasted until the
completion of the isotope infusion and blood sampling protocol the next day.
Sample Collection
Blood samples were collected in chilled tubes containing EDTA to determine substrate concentrations and TTRs, and in chilled tubes containing EDTA and aprotinin (Trasylol) to determine insulin concentrations. Samples were placed in an ice bath, and plasma was separated by centrifugation within 30 min of collection. Aliquots of plasma (2 ml) were refrigerated at 4°C for subsequent isolation of lipoproteins. The remaining plasma samples were stored atIsolation of Lipoproteins
Lipoprotein fractions (VLDL, IDL, and LDL) were isolated by sequential ultracentrifugation (11) within 12 h of blood collection. Briefly, 2 ml of plasma were transferred into Opti Seal tubes (Beckman Instruments, Palo Alto, CA), overlaid with a NaCl-EDTA solution (1.006 kg/l), and centrifuged in a 50.4 Ti rotor (Beckman Instruments) at 100,000 g for 16 h at 8°C. The top layer, containing VLDL, was removed by tube slicing (Beckman Instruments). The density of the remaining sample was adjusted to 1.019 kg/l by use of a NaCl-KBr solution (1.3115 kg/l), and the sample was recentrifuged for the isolation of IDL. To separate LDL, the density of the remaining sample was adjusted to 1.063 kg/l and recentrifuged, and the top layer that contained LDL was collected. The exact amounts of the fractions containing VLDL, IDL, and LDL recovered by tube slicing (~1.3 ml) were recorded to calculate TG and apoB-100 concentrations. The isolated lipoprotein fractions of each sample were stored atSample Analyses
Plasma insulin concentration was measured by radioimmunoassay (18). Total plasma TG and VLDL-TG concentrations were measured by using spectrophotometric analysis and a commercially available enzymatic kit (Sigma Chemical, St. Louis, MO). Plasma fatty acid concentrations were quantified by gas chromatography (Hewlett-Packard 5890-II, Palo Alto, CA) after addition of heptadecanoic acid to plasma as an internal standard (33, 45). Total plasma and VLDL-, IDL-, and LDL-apoB-100 concentrations were measured by using a commercially available immunoturbidimetric kit (Wako Chemicals, Richmond, VA) and spectrophotometric analysis. We used a model-predicted (54) relative mass distribution of plasma VLDL-, IDL-, and LDL-apoB-100, in conjunction with total plasma apoB-100 concentration measurements, to calculate plasma VLDL-apoB-100 concentration, to avoid the confounding effect of incomplete recovery of VLDL-, IDL-, and LDL-apoB-100 (15).All isotopic enrichments were measured by electron impact ionization gas chromatography-mass spectrometry (GC-MS; MSD 5973 system with capillary column; Hewlett-Packard). Plasma glycerol, palmitate, and leucine TTRs were determined as previously described (19, 42, 43, 45). Plasma proteins were precipitated with ice-cold acetone, and hexane was used to extract plasma lipids. Free fatty acids (FFA) were isolated by use of solid-phase extraction columns and converted to their methyl esters with iodomethane. Ions at mass-to-charge ratio (m/z) 270 and 272 were monitored to determine palmitate TTR. The aqueous phase, containing glycerol, was dried by centrifugation under vacuum (Savant Instruments, Farmingdale, NY). Heptafluorobutyric (HFB) anhydride was used to form an HFB derivative of glycerol, and ions at m/z 253 and 257 were monitored to determine glycerol TTR. To determine plasma free leucine TTR, plasma proteins were precipitated with ice-cold acetone, lipids were extracted with hexane, and the aqueous fraction was dried under vacuum (Savant Instruments); the t-butyldimethylsilyl (t-BDMS) derivative was prepared for analysis, and ions at m/z 200 and 203 were monitored.
ApoB-100 was isolated from the lipoprotein fractions (24) and hydrolyzed with HCl (6 M). The N-heptafluorobutyryl n-propyl ester of leucine was formed for analysis by GC-MS, and ions at m/z 282 and 285 were monitored to determine leucine TTR. VLDL-TGs were isolated by thin-layer chromatography, and the methyl ester and HFB derivative of palmitate and glycerol in VLDL-TG were prepared as previously described (44-46); ions at m/z 270 and 272 (methyl-palmitate) and 467 and 472 (HFB-glycerol) were monitored to determine palmitate and glycerol TTR in VLDL-TG.
Calculations
Basal palmitate rate of appearance (Ra) in plasma was calculated by using the Steele equation for steady-state kinetics (i.e., dividing the palmitate tracer infusion rate by the average plasma palmitate TTR value from 60 to 180 min) (52). FFA Ra was calculated by dividing the palmitate Ra by the proportional contribution of palmitate to total fatty acid concentration in plasma (19, 36).The fractional catabolic rate (FCR) of VLDL-TG (in pools/h), which
represents the fraction of the VLDL-TG pool that leaves the pool per
unit of time, was calculated by fitting the glycerol TTR in plasma and
in VLDL-TG to a multicompartmental model, as previously described
(44). During steady-state conditions, the VLDL-TG FCR is
equal to the VLDL-TG fractional secretion rate. The absolute rate of
VLDL-TG secretion (equal to the absolute rate of VLDL-TG catabolism)
was calculated as 1) total secretion rate, which represents
the total amount of VLDL-TG produced by the liver, normalized to FFM;
and 2) secretion per unit of plasma, which represents the
rate of release of VLDL-TG from the liver into the bloodstream, as
follows
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(1) |
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(2) |
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The relative contribution of systemic plasma FFA to VLDL-TG-bound fatty
acids was calculated by fitting the palmitate TTR in plasma and VLDL-TG
to a multicompartmental model (44) to determine the
fraction of VLDL-TG-bound palmitate that is derived from systemic
plasma palmitate. The contributions of systemic plasma fatty acids
(VLDL-TGPFA) and nonsystemic plasma fatty acids (VLDL-TGNPFA) to VLDL-TG secretion were calculated as
follows
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(3) |
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(4) |
The fractional turnover rates (in pools/h) of apoB-100 in the VLDL,
IDL, and LDL fractions were assessed as previously described (14,
27) by using a compartment model developed by Zech et al.
(54) and the TTR of plasma free leucine and leucine bound to VLDL and IDL (from 0 to 48 h) and the TTR of leucine bound to
LDL (from 0 to 72 h). The total rate of VLDL-apoB-100 secretion (in mg · dl
plasma1 · h
1) was
calculated by multiplying plasma VLDL-apoB-100 concentration, determined by the fraction of total plasma apoB-100 in VLDL, and the
VLDL-apoB-100 fractional turnover rate.
VLDL-TG clearance from plasma (ml/min) was calculated by dividing the rate of VLDL-TG disappearance from plasma (VLDL-TG catabolic rate in µmol/min) by the plasma VLDL-TG concentration (in µmol/ml).
Statistical Analyses
A Student's t-test for independent samples was used to test for significant differences in lipoprotein kinetics between lean and obese subjects before weight loss. A Student's t-test for paired samples was used to evaluate the significance of the effect of weight loss on lipoprotein kinetics in obese subjects. A P value ![]() |
RESULTS |
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Body Composition
Body composition of lean and obese subjects is shown in Table 1. Total body, intra-abdominal, and abdominal subcutaneous fat masses were much greater in obese than in lean women. Obese subjects lost 10 ± 1% of their body weight after completing the weight loss program. Most of the weight loss was due to a decrease in body fat (17 ± 2% of initial fat mass), with only a small decrease in FFM (3 ± 1% of initial FFM).Plasma Insulin and Lipid Concentrations
Baseline plasma insulin concentration was twice as high in obese as in lean women, and it decreased by 25 ± 6% after weight loss (Table 2). Baseline plasma TG and LDL-cholesterol concentrations were higher in obese than in lean subjects, and they decreased by 18 ± 7 and 10 ± 6%, respectively, after weight loss (Table 2). Baseline plasma apoB-100 concentrations were higher in obese than in lean women (P < 0.05) and did not change with weight loss. The proportional contribution of apoB-100 concentration of each lipoprotein subfraction was similar in lean (6 ± 1% VLDL, 6 ± 1% IDL, 88 ± 2% LDL) and obese (7 ± 1% VLDL, 5 ± 1% IDL, 88 ± 1% LDL) subjects and was not affected by weight loss.
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Fatty Acid and VLDL-TG Kinetics
Total FFA Ra was significantly higher in obese than in lean women. Weight loss reduced FFA Ra by ~10% (Table 3).
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The FCR of VLDL-TG was higher in lean than in obese women before weight
loss. Weight loss reduced the FCR of VLDL-TG in obese women by ~30%.
The rates of total VLDL-TG secretion and VLDL-TG secretion into plasma
were not different between lean and obese women before weight loss.
Weight loss caused a 40% decrease in the rate of VLDL-TG secretion
(Table 3 and Fig. 1).
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The relative contributions of systemic plasma fatty acids (derived from
lipolysis of subcutaneous adipose tissue TGs) and nonsystemic fatty
acids (derived from lipolysis of intraperitoneal adipose tissue and
intrahepatic TGs) to VLDL-TG were not different between lean women and
obese women before weight loss (Table 3). Weight loss reduced the
secretion rate of VLDL-TG derived from both systemic and nonsystemic
fatty acids. However, the relative decrease in VLDL-TG secretion
from nonsystemic fatty acids was greater than that from systemic plasma
fatty acids (Fig. 2), so the proportional
contribution of systemic plasma fatty acids that were incorporated into
VLDL-TG decreased by 20%, and the relative contribution of nonsystemic
fatty acids decreased by 40% (Table 3).
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The clearance rate of VLDL-TG from plasma was greater in lean women than in obese women before weight loss. Weight loss tended to decrease the clearance rate of VLDL-TG, but the differences between the clearance rate before and after weight loss were not statistically significant (P < 0.07) (Table 3).
ApoB-100 Kinetics
The FCR of apoB-100 in the VLDL, IDL, and LDL fractions was greater in lean than in obese women. However, the absolute rate of VLDL-apoB-100 secretion was similar in lean and obese women (Fig. 3). Weight loss did not affect apoB-100 FCR in the lipoprotein fractions (Table 4) or the absolute rate of VLDL-apoB-100 secretion (Fig. 3).
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Relationship Between VLDL-TG and VLDL-apoB-100 Secretion
The ratio between the rate of secretion of VLDL-TG to VLDL-apoB-100 tended to be higher in obese than in lean women, but the differences between groups were not statistically significant. Weight loss reduced the rate of VLDL-TG secretion relative to the rate of VLDL-apoB-100 secretion (Fig. 4).
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DISCUSSION |
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In the present study, we investigated the effect of modest, diet-induced weight loss on lipoprotein kinetics in women with abdominal obesity. Our data demonstrate that a 10% loss in body weight causes a 40% decrease in the basal rate of VLDL-TG secretion by decreasing the contribution of both systemic fatty acids (predominantly derived from lipolysis of subcutaneous adipose tissue TGs) and nonsystemic fatty acids (presumably derived predominantly from lipolysis of intraperitoneal and intrahepatic TGs) to hepatic VLDL-TG formation. Two-thirds of the decrease in VLDL-TG secretion was caused by a decrease in the supply of nonsystemic fatty acids, suggesting that altering lipolytic activity within intrahepatic and intraperitoneal TGs can have considerable metabolic implications. Weight loss did not affect VLDL-apoB-100 secretion, demonstrating a dissociation in the regulation of VLDL-TG and apoB-100 metabolic pathways.
Hepatic fatty acid availability is a major regulator of VLDL-TG secretion (28). Therefore, it is likely that a decrease in fatty acid release from subcutaneous adipose tissue, intraperitoneal adipose tissue, and intrahepatic TGs was, at least in part, responsible for the decrease in VLDL-TG secretion in our obese subjects after weight loss. We found that weight loss in our obese women resulted in a decrease in whole body FFA Ra, which would reduce the delivery of systemic fatty acids to the liver. In fact, there was a direct relationship between the decrease in FFA Ra and the decrease in VLDL-TG secretion derived from systemic plasma fatty acids (R2 = 0.39; P < 0.05). These results suggest that alterations in subcutaneous adipose tissue lipolytic activity and FFA release may be involved in the weight loss-induced decrease in VLDL-TG secretion. In addition, a weight loss-induced decrease in lipolysis is likely to contribute to the normalization of hepatic glucose production (5, 38) and muscle glucose uptake (6, 21-23) that was observed in other studies. The decrease in the contribution of nonsystemic fatty acids to VLDL-TG secretion suggests that weight loss also decreased lipolysis of intraperitoneal and/or intrahepatic TGs. Several factors that occur with weight loss may be responsible for the decrease in lipolytic rates, including a decrease in adipocyte hormone-sensitive lipase activity (25, 48), a decrease in adipocyte size (32), a decrease in intrahepatic (51), subcutaneous (17, 39, 50), and visceral (17, 39, 50) fat masses, and increased insulin sensitivity (17, 21). Although alterations in the rate of de novo lipogenesis could also have contributed to the reduction of VLDL-TG secretion from nonsystemic fatty acid sources in response to weight loss, it is unlikely to have had a major effect, because fatty acids synthesized de novo contribute <5% to total hepatic VLDL-TG secretion in the basal postabsorptive state in lean and overweight subjects (1, 31).
We are aware of three previous studies, conducted in overweight or
obese subjects, that investigated the effect of weight loss on VLDL-TG
secretion rate (16, 20, 40). The results from these
studies suggest that there may be gender-specific differences in the
effect of weight loss on VLDL-TG kinetics. In two studies conducted
primarily in men, 5-11% weight loss decreased the rate of VLDL-TG
secretion (16, 40), whereas in one study that was conducted in women (20), a 6-10% weight loss did not
affect VLDL-TG secretion. However, conclusions regarding gender effects on VLDL-TG kinetics from these studies are confounded because the men
had greater dyslipidemia than women, and men were studied when they
were weight stable, whereas women were studied when they were actively
losing weight. In addition, the methods used to measure VLDL-TG
kinetics in these studies were not able to fully account for tracer
recycling, which can have a considerable effect on VLDL-TG turnover and
secretion rate measurements (44, 54). In the present
study, we measured VLDL-TG kinetics by a combination of stable isotope
tracer and compartmental modeling techniques that account for tracer
recycling (44). In addition, we studied each subject
before and after a predetermined 10% weight loss and after 4 wk of
weight stability, to eliminate the confounding effects of differences
in individual weight loss and negative energy balance on VLDL-TG
metabolism. Our results demonstrate that modest weight loss in women
who have abdominal obesity and plasma TG concentrations within the
upper range of normal causes a considerable decrease in VLDL-TG
secretion rate and plasma TG concentrations, similar to what has been
observed in men with hypertriglyceridemia.
The contribution of systemic plasma fatty acids to total VLDL-TG secretion tended to be higher, and the contribution of nonsystemic fatty acids tended to be lower, in our obese than in our lean women, but the differences between groups were not statistically significant (P = 0.11). It is possible that our inability to detect a difference in the sources of fatty acids used for VLDL-TG secretion was caused by a type II statistical error because of the small number of subjects in our study. However, we believe that a type II error is unlikely, because we failed to find a relationship between body mass index (BMI) and the relative contribution of systemic and nonsystemic fatty acids to total VLDL-TG secretion in a study of 26 lean, overweight, and obese women (Mittendorfer B and Klein S, unpublished observation). Therefore, the results of the present study and our unpublished observations suggest that, in women, intrahepatic trafficking of systemic and nonsystemic fatty acids into VLDL-TG is not determined by total adiposity. In contrast, Barter and Nestel (4) found that the relative contribution of systemic plasma fatty acids to total VLDL-TG secretion was less in obese than in lean subjects. However, their results may have been confounded by the inclusion of both men and women, and of subjects with hypertriglyceridemia, because gender independently affects basal VLDL-TG kinetics (37), and hypertriglyceridemia is associated with a decrease in the relative contribution of plasma fatty acids to VLDL-TG secretion (41).
Weight loss in our obese women did not affect total VLDL-apoB-100 secretion rate or VLDL-, IDL-, and LDL-apoB-100 FCR. Our findings differ from data reported in two previous studies that were conducted in men, which found that weight loss decreased the rate of VLDL-apoB-100 secretion (16, 49). Initial BMI and percent weight loss in these men (16, 49) were similar to those of the women in our study. Therefore, these results suggest the presence of sexual dimorphism in the response of apoB-100 kinetics to weight loss. We have also found gender differences in baseline VLDL-apoB-100 secretion. The VLDL-apoB-100 secretion rate is similar in lean and obese women, which is consistent with a previous study conducted in women (29) but different from observations made in men, in which VLDL-apoB-100 secretion rates were greater in obese than in lean men (10).
Our data demonstrate that weight loss in obese women has different effects on VLDL-TG and VLDL-apoB-100 metabolism. The dissociation between VLDL-TG and VLDL-apoB-100 responses is consistent with the results of several previous studies that evaluated VLDL metabolism during other physiological interventions. Lewis et al. (30) found that increasing plasma fatty acid availability, by infusing Intralipid and heparin, caused a much greater increase in VLDL-TG than in VLDL-apoB-100 secretion rate, and that artificially maintaining normal plasma fatty acid concentration during an insulin infusion increased VLDL-TG, but not VLDL-apoB-100, secretion. In addition, Melish et al. (34) found that a high-carbohydrate diet increased VLDL-TG, but not VLDL-apoB-100, secretion rate. The composite of these data suggests that VLDL-TG metabolism and apoB-100 metabolism are regulated differently and that alterations in the factors that affect VLDL-TG secretion do not necessarily cause a concomitant change in VLDL-apoB-100 metabolism.
In summary, the results of the present study demonstrate that modest weight loss decreases VLDL-TG secretion in obese women, primarily by decreasing the rate of VLDL-TG secretion from nonsystemic fatty acids derived from lipolysis of intrahepatic and/or intraperitoneal TG. In contrast, weight loss did not affect the rate of VLDL-apoB-100 secretion. Changes in the rate of VLDL-TG secretion without concomitant changes in VLDL-apoB-100 kinetics suggest that weight loss in women does not change the number of VLDL particles produced by the liver but alters the average TG content of VLDL or increases the secretion of small VLDL particles. More studies are needed to evaluate the clinical implications of these findings.
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ACKNOWLEDGEMENTS |
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We thank Renata J. Braudy and Jennifer C. McCrea for assistance in subject recruitment; the nursing staff of the General Clinical Research Center for their help in performing the studies; Junyoung Kwon, Sarah Rupe, and Freida Custodio for their technical assistance; and the study subjects for their participation.
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FOOTNOTES |
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This study was supported by National Institutes of Health Grants HD-01459, DK-37948, DK-59534, RR-00036 (General Clinical Research Center), and DK-56341 (Clinical Nutrition Research Unit), and a grant from Roche Laboratories.
Address for reprint requests and other correspondence: S. Klein, Washington Univ. School of Medicine, 660 South Euclid Ave.; Campus Box 8031, St. Louis, MO 63110 (E-mail:sklein{at}im.wustl.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published December 10, 2002;10.1152/ajpendo.00379.2002
Received 26 August 2002; accepted in final form 7 November 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Årsland, A,
Chinkes D,
and
Wolfe RR.
Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man.
J Clin Invest
98:
2008-2017,
1996
2.
Austin, MA.
Plasma triglyceride as a risk factor for cardiovascular disease.
Can J Cardiol
14, Suppl B:
14B-17B,
1998[Medline].
3.
Austin, MA,
Hokanson JE,
and
Edwards KL.
Hypertriglyceridemia as cardiovascular risk factor.
Am J Cardiol
81:
7B-12B,
1998[ISI][Medline].
4.
Barter, PJ,
and
Nestel PJ.
Precursors of plasma triglyceride fatty acids in obesity.
Metabolism
22:
779-783,
1973[ISI][Medline].
5.
Bergman, RN,
Van Citters GW,
Mittelman SD,
Dea MK,
Hamilton-Wessler M,
Kim SP,
and
Ellmerer M.
Central role of the adipocyte in the metabolic syndrome.
J Investig Med
49:
119-26,
2001[ISI][Medline].
6.
Boden, G.
Free fatty acids (FFA), a link between obesity and insulin resistance.
Front Biosci
3:
D169-D175,
1998[Medline].
7.
Boer, P.
Estimated lean body mass as an index for normalization of body fluid volumes in humans.
Am J Physiol Renal Fluid Electrolyte Physiol
247:
F632-F636,
1984
8.
Cambien, F,
Jacqueson A,
Richard JL,
Warnet JM,
Ducimetiere P,
and
Claude JR.
Is the level of serum triglyceride a significant predictor of coronary death in "normocholesterolemic" subjects? The Paris Prospective Study.
Am J Epidemiol
124:
624-632,
1986[Abstract].
9.
Castelli, WP.
Cholesterol and lipids in the risk of coronary artery diseasethe Framingham Heart Study.
Can J Cardiol
4, Suppl A:
5A-10A,
1988[Medline].
10.
Chan, DC,
Watts GF,
Redgrave TG,
Mori TA,
and
Barrett PH.
Apolipoprotein B-100 kinetics in visceral obesity: association with plasma apolipoprotein C-III concentration.
Metabolism
51:
1041-1046,
2002[ISI][Medline].
11.
Converse, CA,
and
Skinner ER.
Lipoprotein Analysis: A Practical Approach. New York: Oxford University Press, 1992.
12.
Cullen, P.
Evidence that triglycerides are an independent coronary heart disease risk factor.
Am J Cardiol
86:
943-949,
2000[ISI][Medline].
13.
Egusa, G,
Beltz WF,
Grundy SM,
and
Howard BV.
Influence of obesity on the metabolism of apolipoprotein B in humans.
J Clin Invest
76:
596-603,
1985[ISI][Medline].
14.
Elias, N,
Patterson BW,
and
Schonfeld G.
In vivo metabolism of ApoB, ApoA-I, and VLDL triglycerides in a form of hypobetalipoproteinemia not linked to the ApoB gene.
Arterioscler Thromb Vasc Biol
20:
1309-1315,
2000
15.
Gaw, A,
Packard CJ,
Murray EF,
Lindsay GM,
Griffin BA,
Caslake MJ,
Vallance BD,
Lorimer AR,
and
Shepherd J.
Effects of simvastatin on apoB metabolism and LDL subfraction distribution.
Arterioscler Thromb
13:
170-189,
1993[Abstract].
16.
Ginsberg, HN,
Le NA,
and
Gibson JC.
Regulation of the production and catabolism of plasma low density lipoproteins in hypertriglyceridemic subjects. Effect of weight loss.
J Clin Invest
75:
614-623,
1985[ISI][Medline].
17.
Goodpaster, BH,
Kelley DE,
Wing RR,
Meier A,
and
Thaete FL.
Effects of weight loss on regional fat distribution and insulin sensitivity in obesity.
Diabetes
48:
839-847,
1999[Abstract].
18.
Hales, CN,
and
Randle PJ.
Immunoassay of insulin with insulin antibody precipitate.
Biochem J
88:
137-146,
1963[ISI].
19.
Horowitz, JF,
and
Klein S.
Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women.
Am J Physiol Endocrinol Metab
278:
E1144-E1152,
2000
20.
Jourdan, M,
Margen S,
and
Bradfield RB.
The turnover rate of serum glycerides in the lipoproteins of fasting obese women during weight loss.
Am J Clin Nutr
27:
850-858,
1974[ISI][Medline].
21.
Kelley, DE,
Goodpaster B,
Wing RR,
and
Simoneau JA.
Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss.
Am J Physiol Endocrinol Metab
277:
E1130-E1141,
1999
22.
Kelley, DE,
Mokan M,
Simoneau JA,
and
Mandarino LJ.
Interaction between glucose and free fatty acid metabolism in human skeletal muscle.
J Clin Invest
92:
91-98,
1993[ISI][Medline].
23.
Kelley, DE,
Wing R,
Buonocore C,
Sturis J,
Polonsky K,
and
Fitzsimmons M.
Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus.
J Clin Endocrinol Metab
77:
1287-1293,
1993[Abstract].
24.
Klein, RL,
and
Zilversmit DB.
Direct determination of human and rabbit apolipoprotein B selectively precipitated with butanol-isopropyl ether.
J Lipid Res
25:
1380-1386,
1984[Abstract].
25.
Klein, S,
Luu K,
Gasic S,
and
Green A.
Effect of weight loss on whole body and cellular lipid metabolism in severely obese humans.
Am J Physiol Endocrinol Metab
270:
E739-E745,
1996
26.
Lamon-Fava, S,
Wilson PW,
and
Schaefer EJ.
Impact of body mass index on coronary heart disease risk factors in men and women. The Framingham Offspring Study.
Arterioscler Thromb Vasc Biol
16:
1509-1515,
1996
27.
Latour, MA,
Patterson BW,
Pulai J,
Chen Z,
and
Schonfeld G.
Metabolism of apolipoprotein B-100 in a kindred with familial hypobetalipoproteinemia without a truncated form of apoB.
J Lipid Res
38:
592-599,
1997[Abstract].
28.
Lewis, GF.
Fatty acid regulation of very low density lipoprotein production.
Curr Opin Lipidol
8:
146-156,
1997[ISI][Medline].
29.
Lewis, GF,
Uffelman KD,
Szeto LW,
and
Steiner G.
Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals.
Diabetes
42:
833-842,
1993[Abstract].
30.
Lewis, GF,
Uffelman KD,
Szeto LW,
Weller B,
and
Steiner G.
Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.
J Clin Invest
95:
158-166,
1995[ISI][Medline].
31.
Marques-Lopes, I,
Ansorena D,
Astiasaran I,
Forga L,
and
Martinez JA.
Postprandial de novo lipogenesis and metabolic changes induced by a high-carbohydrate, low-fat meal in lean and overweight men.
Am J Clin Nutr
73:
253-261,
2001
32.
Mauriege, P,
Imbeault P,
Langin D,
Lacaille M,
Almeras N,
Tremblay A,
and
Despres JP.
Regional and gender variations in adipose tissue lipolysis in response to weight loss.
J Lipid Res
40:
1559-1571,
1999
33.
McDonald-Gibson, RG,
and
Young M.
The use of an automatic solids injection system for quantitative determination of plasma long-chain nonesterified fatty acids by gas-lipid chromatography.
Clin Chim Acta
53:
117-126,
1974[ISI][Medline].
34.
Melish, J,
Le NA,
Ginsberg H,
Steinberg D,
and
Brown WV.
Dissociation of apoprotein B and triglyceride production in very-low-density lipoproteins.
Am J Physiol Endocrinol Metab
239:
E354-E362,
1980
35.
Metropolitan, LIC
1983 Metropolitan height and weight tables.
Stat Bull Metrop Life Found
64:
3-9,
1983[Medline].
36.
Mittendorfer, B,
Horowitz JF,
and
Klein S.
Effect of gender on lipid kinetics during endurance exercise of moderate intensity in untrained subjects.
Am J Physiol Endocrinol Metab
283:
E58-E65,
2002
37.
Mittendorfer B, Patterson BW, and Klein S. Effect of sex and
obesity on basal very-low density lipoprotein triacylglycerol kinetics.
Am J Clin Nutr. In press.
38.
Muscelli, E,
Camastra S,
Catalano C,
Galvan AQ,
Ciociaro D,
Baldi S,
and
Ferrannini E.
Metabolic and cardiovascular assessment in moderate obesity: effect of weight loss.
J Clin Endocrinol Metab
82:
2937-2943,
1997
39.
Nicklas, BJ,
Rogus EM,
Berman DM,
Dennis KE,
and
Goldberg AP.
Responses of adipose tissue lipoprotein lipase to weight loss affect lipid levels and weight regain in women.
Am J Physiol Endocrinol Metab
279:
E1012-E1019,
2000
40.
Olefsky, J,
Reaven GM,
and
Farquhar JW.
Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects.
J Clin Invest
53:
64-76,
1974[ISI][Medline].
41.
Parks, EJ,
Krauss RM,
Christiansen MP,
Neese RA,
and
Hellerstein MK.
Effects of a low-fat, high-carbohydrate diet on VLDL-triglyceride assembly, production, and clearance.
J Clin Invest
104:
1087-1096,
1999
42.
Patterson, BW,
Carraro F,
and
Wolfe RR.
Measurement of 15N enrichment in multiple amino acids and urea in a single analysis by gas chromatography/mass spectrometry.
Biol Mass Spectrom
22:
518-523,
1993[ISI][Medline].
43.
Patterson, BW,
Horowitz JF,
Wu G,
Watford M,
Coppack SW,
and
Klein S.
Regional muscle and adipose tissue amino acid metabolism in lean and obese women.
Am J Physiol Endocrinol Metab
282:
E931-E936,
2002
44.
Patterson, BW,
Mittendorfer B,
Elias N,
Satyanarayana R,
and
Klein S.
Use of stable isotopically labeled tracers to measure very low density lipoprotein-triglyceride turnover.
J Lipid Res
43:
223-233,
2002
45.
Patterson, BW,
Zhao G,
Elias N,
Hachey DL,
and
Klein S.
Validation of a new procedure to determine plasma fatty acid concentration and isotopic enrichment.
J Lipid Res
40:
2118-2124,
1999
46.
Patterson, BW,
Zhao G,
and
Klein S.
Improved accuracy and precision of gas chromatography/mass spectrometry measurements for metabolic tracers.
Metabolism
47:
706-712,
1998[ISI][Medline].
47.
Reichl, D.
Lipoproteins of human peripheral lymph.
Eur Heart J
11, Suppl E:
230-236,
1990[ISI][Medline].
48.
Reynisdottir, S,
Langin D,
Carlstrom K,
Holm C,
Rossner S,
and
Arner P.
Effects of weight reduction on the regulation of lipolysis in adipocytes of women with upper-body obesity.
Clin Sci (Lond)
89:
421-429,
1995[ISI][Medline].
49.
Riches, FM,
Watts GF,
Hua J,
Stewart GR,
Naoumova RP,
and
Barrett PH.
Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men.
J Clin Endocrinol Metab
84:
2854-2861,
1999
50.
Ross, R,
Dagnone D,
Jones PJ,
Smith H,
Paddags A,
Hudson R,
and
Janssen I.
Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial.
Ann Intern Med
133:
92-103,
2000
51.
Silverman, EM,
Sapala JA,
and
Appelman HD.
Regression of hepatic steatosis in morbidly obese persons after gastric bypass.
Am J Clin Pathol
104:
23-31,
1995[ISI][Medline].
52.
Steele, R.
Influences of glucose loading and of injected insulin on hepatic glucose output.
Ann NY Acad Sci
82:
420-430,
1959[ISI].
53.
Wadden, TA,
Anderson DA,
and
Foster GD.
Two-year changes in lipids and lipoproteins associated with the maintenance of a 5% to 10% reduction in initial weight: some findings and some questions.
Obes Res
7:
170-178,
1999[Abstract].
54.
Zech, LA,
Grundy SM,
Steinberg D,
and
Berman M.
Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.
J Clin Invest
63:
1262-1273,
1979[ISI][Medline].