Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance
Ndubueze C. Okereke,1
Larraine Huston-Presley,1
Saeid B. Amini,1
Satish Kalhan,2,3 and
Patrick M. Catalano1,3
Departments of 1Reproductive Biology and 2Pediatrics and 3The Schwartz Center for Metabolism and Nutrition, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio 44109
Submitted 31 December 2003
; accepted in final form 22 April 2004
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ABSTRACT
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Our primary objective was to evaluate changes in energy expenditure and body composition in women with normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM). A secondary objective was to examine the relationship between maternal leptin and nutrient metabolism. Fifteen obese women, eight with NGT and seven with GDM, were evaluated before conception (P), at 1214 wk (E), and at 3436 wk (L). Energy expenditure and glucose and fat metabolism were measured using indirect calorimetry. Basal hepatic glucose production was measured using [6,6-2H2]glucose and insulin sensitivity by euglycemic clamp. There was a significant increase (6.6 kg, P = 0.0001) in fat mass from P to L. There was a 30% (P = 0.0001) increase in basal O2 consumprion (
O2, ml/min). There were no significant changes in carbohydrate oxidation during fasting or storage from P to L. There was, however, a significant (P = 0.0001) 150% increase in basal fat oxidation (mg/min) from P to L. Under hyperinsulinemic conditions, there were similar 25% increases in
O2 (P = 0.0001) from P to L in both groups. Because of the significant increases in insulin resistance from P to L, there was a significant (P = 0.0001) decrease in carbohydrate oxidation and storage. There was a net change from lipogenesis to lipolysis, i.e., fat oxidation (3040 mg/min, P = 0.0001) from P to L. Serum leptin concentrations had a significant positive correlation with fat oxidation at E (r = 0.76, P = 0.005) and L (r = 0.72, P = 0.009). Pregnancy in obese women is associated with significant increases in fat mass and basal metabolic rate and an increased reliance on lipids both in the basal state and during the clamp. These modifications are similar in women with NGT and GDM. The increased reliance on fat metabolism is accompanied by a concomitant decrease in carbohydrate metabolism during hyperinsulinemia. The increase in fat oxidation may be related to increased maternal serum leptin.
gestational diabetes; pregnancy; leptin
THE ENERGY COST OF PREGNANCY and amount of fat accretion during gestation vary considerably among published studies. Estimates of the energy cost of pregnancy range from a cost of 80,000 kcal (13) to a net savings of 10,000 kcal (16). Similarly, the increase in adipose tissue during gestation has a wide variation. Forsum et al. (8) reported a mean increase of >5 kg of adipose tissue in Swedish women, whereas Lawrence et al. (16) found no increase in adipose tissue stores in women from the Gambia with their usual nutritional intake. As a result, the recommendations for nutritional intake in pregnancy are diverse and depend on the study population. Furthermore, on the basis of data from Goldberg et al. (11), recommendations for nutritional intake in individuals within a population may be more diverse than previously believed on the basis of wide estimates of energy expenditure and fat accretion among individuals, making general nutritional guidelines difficult.
We (3) have previously reported on the longitudinal changes in energy expenditure and fat accretion in lean women (body fat <25%)with normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM) relative to the alterations in carbohydrate metabolism during gestation. However, similar data in obese women have not been reported.
Moreover, the prevalence of obesity [body mass index (BMI)
30 kg/m2] in the United States in adolescents (22) and adults (19) approaches 20%. Given the strong association of obesity with decreased insulin sensitivity, we prospectively evaluated the longitudinal changes in energy expenditure and fat accretion in a cohort of women with NGT and GDM relative to the alterations in insulin sensitivity during gestation. We hypothesized that women with decreased pregravid insulin sensitivity, i.e., the GDM subjects, have a decrease in energy expenditure and fat accretion compared with a matched NGT group. Additionally, because the role of the increased maternal serum leptin concentrations in pregnancy has not yet been fully explained, we elected to examine the relationship of maternal serum leptin to changes in nutrient metabolism.
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MATERIALS AND METHODS
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This prospective study was conducted in the General Clinical Research Center (GCRC) at MetroHealth Medical Center, Case Western Reserve University. The study protocol was approved by the hospital Institutional Review Board and by the Scientific Review Committee of the GCRC. Written informed consent was obtained from each subject before evaluation. Subjects were recruited by advertisements in the local newspaper and given a small stipend for their participation. We (2) previously reported the longitudinal changes in insulin response to infused glucose, basal hepatic glucose production and suppression during insulin infusion and peripheral insulin sensitivity with the hyperglycemic euglycemic clamp in these study subjects. A detailed description of the methods is included in the original report of these studies (2).
Study subjects.
Fifteen healthy obese women (defined as pregravid percent body fat >25%) were recruited before a planned pregnancy to participate in this study. Although BMI is an appropriate estimate of obesity for large population studies, we elected to use body composition to classify our study subjects as obese. None of the subjects was breast feeding or using hormonal contraception, tobacco, or other medications that might affect carbohydrate metabolism or energy expenditure. None of the study subjects had diabetes mellitus before conception, based on the results of a 75-g oral glucose tolerance test (20). Seven of the women were at high risk of developing GDM, based on a history of GDM in a previous pregnancy (n = 4), a strong family history of type 2 diabetes in a first-degree relative (n = 2), or an impaired glucose tolerance test before conception plus a first-degree relative with type 2 diabetes (n = 1). Other than GDM, the pregnancies were uncomplicated. Eight other women were recruited, none of whom had a history of abnormal glucose tolerance either before or during a previous pregnancy, i.e., the NGT group. All subjects were planning to conceive as soon as the baseline pregravid studies were completed.
Each subject was evaluated before conception (pregravid, P), in early gestation (E, 1214 wk), and again in late gestation (L, 3436 wk). Twelve of the 15 subjects were evaluated in the follicular phase of the menstrual cycle, and three were evaluated in the luteal phase. Each subject was instructed in a standard dietary regimen 2 wk before each study period. The dietary regimen was designed to standardize nutritional intake for each subject, maintain weight before conception, and allow appropriate increase in weight during pregnancy. The regimen was identical to the diet employed in the treatment of gestational diabetes at our institution. Physical activity was encouraged throughout gestation and was estimated by means of the Minnesota Leisure Time Physical Activity Questionnaire (25).
Study protocol.
Percentage of body fat was calculated according to the equations of Keys and Brozek (14) to estimate fat-free mass (FFM) at times P and E. At time L, body fat was calculated according to equations of Catalano et al. (4), adjusting the density of FFM because of the increased total body water in late pregnancy. In addition, skinfold measures were obtained at seven sites: triceps, biceps, subscapular, subcostal, suprailiac, and mid- and lower thigh with a Harpenden (British Indicators, Sussex, UK) skinfold caliper. All measurements were obtained on the left side by one examiner (P. M. Catalano).
Euglycemic clamp.
Basal endogenous glucose production (primarily hepatic) was estimated after an 11-h overnight fast by use of a primed constant infusion of labeled glucose, [6,6-2H2]glucose. Basal glucose turnover was estimated according to the steady-state equations of Steele (23). Insulin sensitivity was estimated as the glucose infusion rate required to maintain euglycemia during the clamp plus any residual endogenous glucose production during insulin infusion. The 2-h hyperinsulinemic euglycemic clamp was performed after estimating basal endogenous glucose production as described by DeFronzo et al. (6) to estimate peripheral insulin sensitivity. Residual endogenous glucose production during insulin infusion was estimated by maintaining the constant infusion of labeled glucose and by adding additional isotope to the 20% glucose infusion as described by Tserng and Kalhan (26). Plasma enrichment was determined with a gas chromatograph-mass spectrometer (model 5985B; Hewlett-Packard, Palo Alto, CA). The insulin sensitivity index was calculated by dividing the insulin sensitivity by the mean insulin concentration achieved during the clamp.
Indirect calorimetry.
Indirect calorimetry was used to estimate the metabolic rate and route of glucose disposal during the last 45 min of the 2-h estimate of basal endogenous glucose production and the 2-h hyperinsulinemic euglycemic clamp, i.e., at steady state. A ventilated hood system was used for continuous collection and mixing of expired air. The analyzers were calibrated before and after each procedure using standard gases. Expired air was continually withdrawn, dried in a condenser, and delivered to a Magnetopneumatic oxygen analyzer (Magnos 4G; Hartmann & Braun, Frankfurt, Germany) and an infrared carbon dioxide analyzer (Uras 3G, Hartmann & Braun) and delivered to a flowmeter (Interface Associates, Irvine, CA). The total volume of expired air was corrected for standard temperature and pressure conditions. The electrical outputs were interfaced with a desktop computer, and integrated measurements of oxygen consumption (
O2, measured in ml/min) and carbon dioxide production (ml/min), respiratory quotient (RQ), and total resting energy expenditure (REE, expressed as kcal/min) were averaged and recorded every 5 min. All of the studies were conducted at the same time of the day during each period of study. All subjects were in a semirecumbent position on their left side (so as not to impair venous return in late gestation) for
2 h before indirect calorimetry measurements. The variation in measurements of
O2 when repeated within 3 days in the same subject was in the range of 23%. The analyzers and flowmeter were calibrated on a regular basis by burning absolute ethyl alcohol to estimate RQ (=0.66) and using a tissot to calibrate gas flow.
The urinary nitrogen level was determined using a timed urinary sample collected throughout the study to calculate nonprotein RQ. The quantity of urinary urea nitrogen excreted during the study was used as an index of protein oxidation, assuming that 1 g of nitrogen equals 6.25 g of protein. Oxidation rates of carbohydrate and lipid were then calculated according to the tables of Frayn (9). The low and high 5-min measurement of
O2 was not used in the mean estimates of energy expenditure or routes of glucose disposal, i.e., oxidative or nonoxidative glucose disposal. The nonoxidative route of glucose disposal (i.e., glucose storage as glycogen, conversion to 3 carbon fragments, and lipogenesis) was determined in the basal state as the difference between total basal glucose turnover and rate of glucose oxidation as estimated from indirect calorimetry. Nonoxidative glucose disposal during the clamp was estimated as the difference between total glucose disposal during the euglycemic clamp studies and rate of glucose oxidation as estimated from indirect calorimetry. RQ > 1.0 was assumed to represent lipogenesis.
Specific methodologies.
Serum leptin was measured in duplicate by radioimmunoassay (Linco, St. Charles, MO). The intra- and interassay coefficients of variation were 6 and 8%, respectively. This assay measures total (free and bound) and circulating leptin.
Total nonesterified free fatty acid (FFA) concentrations were measured in duplicate by an in vitro enzymatic calorimetric method (Wako, Richmond, VA). The assay is linear from 0 to 2.0 meq/l and sensitive to 0.02 meq/l.
Statistical analysis.
The data are expressed as means ± SD. Statistical analyses were performed using t-tests and analysis of variance with repeated measures for two groups to determine changes over time, differences between groups, and time/group interactions. Linear and nonlinear regression analyses were used to assess the correlation between independent variables. Adjustments for potential confounding variables were made using partial correlation analysis. Statistical analysis was performed with the Statview II (version 5; SAS Institute, Cary, NC) statistical package. Values of P
0.05 were considered significant.
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RESULTS
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All subjects had normal results of routine renal, thyroid, and liver chemistries. The pregravid characteristics of our study subjects are shown in Table 1. Because of the study design, there were no significant differences in any of the demographic characteristics or body composition between the NGT and GDM groups. All subjects were, by definition, obese, with >25% body fat. There were no significant differences in caloric intake in study subjects across time or between groups. In addition, there were no significant differences in percentages of protein, lipids, or carbohydrates in their diets across time or between groups, as demonstrated by a 3-day dietary record. Although physical activity decreased significantly (P = 0.01) with advancing gestation, there was no significant difference between groups (Table 1).
Body composition.
The results of the longitudinal changes in weight, body composition, and skinfold measures are shown in Table 2. There was a significant (P = 0.0001) increase in weight and body composition over time in all subjects. There was also a significant (P = 0.001) increase in the sum of the seven skinfold measurements. There were no significant differences in any of the measurements between groups. Total weight gain in all of these women was 12.1 ± 3.9 kg, and 55.5 ± 20% of total weight gain was fat mass. There was a wide range of weight gain (5.1 to 20.5 kg), fat mass gain (2.0 to 13.1 kg) and FFM gain (0 to 10.4 kg) among the study subjects.
Basal energy expenditure and glucose and fat metabolism.
The longitudinal changes in basal energy expenditure (
O2 and REE), basal glucose metabolism, and fat oxidation are shown in Table 3. There was a significant (P = 0.0001) 2735% increase in basal
O2 in pregnancy when expressed in milliliters per minute but no difference between groups. When basal
O2 was expressed as milliliters per kilogram FFM per minute, there was again a significant (P = 0.0001) increase over time. Additionally, there was a significant (P = 0.04) time/group interaction between groups. Where there was only a 14% increase in the NGT group, there was a 22% increase in basal
O2 and milliliters per kilogram FFM per minute in the GDM group, with the greatest increases occurring in the GDM group from times E to L. The increases in basal kilocalories per day were similar, with a significant (P = 0.0001) 2733% increases in both groups but no differences between NGT and GDM. The mean and range of the increase in percent basal energy expenditure (kcal/day) in all subjects from P to E was 7% (range 322%), from E to L was 22% (range 446%), and from P to L was 30% (range 1447%). When the basal energy expenditure was expressed as kilocalories per kilogram FFM per day, there was a significant (P = 0.0001) 1421% increase in both groups. Although there was a 2230% increase in basal carbohydrate oxidation (mg/min) over time, this was not significant (P = 0.14). The data were essentially the same when basal carbohydrate oxidation was expressed as milligrams per kilogram FFM per minute. Of interest, there was a significant (P = 0.0001) increase in basal endogenous glucose production, whether expressed as mg/min endogenous glucose production (30%) or as milligrams per kilogram FFM per minute of endogenous glucose production (16%) over time. Much the same was observed for nonoxidative glucose disposal, although there was a wide variation, particularly in the GDM subjects. Last, there was a significant increase in basal fat oxidation when expressed as milligrams per minute (5281%, P = 0.0001) or milligrams per kilogram FFM per minute (3466%, P = 0.001) over time.
Energy expenditure and glucose and fat metabolism under insulin stimulation.
The longitudinal changes in energy expenditure (
O2 and REE), route of glucose metabolism, and fat oxidation measured during the clamp are shown in Table 4. There was a significant (P = 0.0001) 2132% increase in
O2 in pregnancy when expressed in millilters per minute. However, there was a group/time interaction (P = 0.05), with the GDM subjects showing a much greater increase in
O2 from E to L. When
O2 was expressed as milliliters per kilogram FFM per minute, there was again a significant (P = 0.0001) increase over time and a significant (P = 0.01) time/group interaction between groups. Where there was only an 8% increase in the NGT group, there was a 19% increase in
O2, (ml·kg FFM1·min1) in the GDM group, with the greatest increases occurring in the GDM group from E to L. The increases in energy expenditure were similar with significant (P = 0.0001) 2228% increases in kilocalories per day in both groups. When the energy expenditure was expressed as kilocalories per kilogram FFM per day, there was a significant (P = 0.0001) 916% increase in both groups. There was a significant (P = 0.0001) 50% decrease in insulin sensitivity from P to L in both groups, which was significantly (P = 0.03) less in the GDM group compared with the NGT group. There was a significant (P = 0.01) 910% decrease in carbohydrate oxidation (mg/min) during the clamp from P to L. The data were essentially the same, i.e., an 18% decrease (P = 0.0001), when carbohydrate oxidation was expressed as milligrams per kilogram FFM per day. The same was observed for nonoxidative glucose production. There was a significant (P = 0.0001) 6570% decrease in nonoxidative glucose metabolism when expressed either as milligrams per minute or per kilogram FFM per minute. Because of the decreased insulin sensitivity in the GDM subjects, their nonoxidative glucose metabolism was significantly (P = 0.04) less compared with the NGT group. Last, there was a significant increase in the fat oxidation (3466%) during the clamp when expressed either as milligrams per minute (P = 0,0001) or milligrams per kilogram FFM per minute (P = 0.0001). There was a significant (P = 0.0001) change from net lipogenesis pregravid (nonprotein RQ 1.02) to lipolysis (nonprotein RQ 0.900.93) in late pregnancy (Fig. 1).

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Fig. 1. Longitudinal changes in lipogenesis/lipolysis from pregravid through late pregnancy in women with normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM). Ox, oxidation. FFM, fat-free mass. Values are means ± SD.
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There was a significant inverse correlation between insulin sensitivity and fat mass in P (r = 0.68, P = 0.02) and when analyzed at all three time points (r = 058, P = 0.0001; Fig. 2). However, there were no significant correlations between fat mass and insulin sensitivity when the
changes from P to E and from E to L were analyzed.
There were no significant correlations between the changes (
) in basal energy expenditure and basal endogenous glucose production from P to E. However, there was a significant negative correlation (r = 0.65, P = 0.008) between the changes in the increased basal endogenous glucose production and decreased basal fat oxidation from P through E (Fig. 3).
Leptin.
Eleven subjects had basal leptin concentrations obtained during all three time periods. There was a significant (P = 0.005) increase in serum leptin in pregnancy in both groups (Table 5). The increase in serum leptin appeared at E, and there was little further increase from E to L. There was no significant correlation between serum leptin concentrations and measurements of fat oxidation at P (r = 0.37, P = 0.27); however, there was a significant correlation between serum leptin and fat oxidation (mg/min) at E (r = 0.76, P = 0.005) and L (r = 0.72, P = 0.01; Fig. 4). The results were similar when fat oxidation was expressed as milligrams per kilogram FFM per minute or when leptin concentrations and measures of fat oxidation were correlated during the clamp (data not shown). However, when we performed partial correlations between basal leptin and fat oxidation adjusted for maternal fat mass, only the correlation in E remained strong (r = 0.52), whereas the partial correlations at P were negative (r = 0.40) and lost significance in L (r = 0.06). As might be anticipated, there was a significant negative correlation between basal serum leptin and basal glucose oxidation (mg·kg FFM1·min1) at E (r = 0.61, P = 0.04) and L (r = 0.62, P = 0.04).

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Fig. 4. Relationship between basal leptin concentrations and basal fat oxidation A: pregravid; B: early pregnancy; C: late pregnancy.
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Ten subjects had serum FFA concentrations measured during all three time periods. There was no significant change in basal FFA over time or between groups. However, there was a significant (P = 0.002) decrease in the suppression of FFA by insulin in late pregnancy (Table 6).
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DISCUSSION
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Our results do not support our hypothesis that women with GDM have significant decreases in total energy expenditure and fat accretion compared with a matched NGT group. However, there are significant alterations in these metabolic parameters in all of our study subjects over the course of pregnancy. Much the same was observed in a parallel study of lean NGT and GDM subjects (3). We speculate that the metabolic alterations of pregnancy, for example, the 5060% decrease in insulin sensitivity, are uniform across a spectrum of subjects from lean to obese, NGT and GDM. The rationale is that the metabolic alterations of pregnancy are relatively uniform because of the placental production of various hormones, cytokines, and growth factors. Hence, the pregravid metabolic condition of the individual has the greatest impact as to the effect of the pregnancy milieu on maternal metabolism.
The results of our study emphasize the wide variation in metabolic measurements in pregnancy reported among and within various populations. Reports of the mean accretion of fat mass in pregnancy have ranged from essentially no increase in fat mass in women from the Gambia (16), whose diets were not supplemented, to 5.8 kg in Swedish women (8). More recently, Goldberg et al. (11) estimated weight gain and accretion of fat mass (using the total body water method) in 12 women in the UK, from the time before conception through 36 wk of gestation. The mean total weight gain was 11.9 ± 4.1 kg, and fat mass was 2.8 ± 3.2 kg (range 2.0 to +8 kg) or a 17% increase in fat mass. This is similar to the mean total weight gain of 12.1 ± 3.9 kg but less than the 6.6 ± 2.9 kg (
30%) increase in fat mass observed in our subjects. The discrepancies in the data may represent differences in methodologies to assess body composition, i.e., total body water vs. hydrodensitometry. Additionally, before conception, the subjects of Goldberg et al. were leaner, with a mean pregravid BMI of 23, whereas our subjects had a mean pregravid BMI of 27 and included women who went on to develop GDM. Although our subjects with GDM had decreased insulin sensitivity and less accretion of fat mass in pregnancy compared with the NGT group, the difference in accretion of adipose tissue did not reach statistical significance (P = 0.69). On the basis of these data, using a power analysis we would need 660 subjects in each group to have an 80% power to demonstrate a significant difference at P < 0.05, the wide variation in fat accretion among study subjects, accounting for the large number of study subjects.
Of particular interest is the relationship between the changes in insulin sensitivity and changes in fat mass. As described by Swinburn et al. (24), in long-term studies of Pima Indians there is an inverse relationship between the decreases in insulin sensitivity and accretion of fat mass; i.e., the increase in insulin resistance is related to an increase in fat mass. In contrast to our studies in lean women (3), we did not observe an inverse correlation between the changes in insulin sensitivity and fat mass in early gestation. There was, however, a significant negative correlation between the decrease in insulin sensitivity and accretion of fat mass from P to L (r = 0.58, P = 0.0001). Part of this explanation may lie in the fact that, for our obese study subjects, there was a net increase in insulin sensitivity from P to E (Table 6). On the basis of Fig. 2, this relationship is curvilinear, with increases in fat mass occurring only when there is a decrease in insulin sensitivity <0.1. The cause and effect mechanisms and mediators by which increases in adiposity are related to decreases in glucose insulin sensitivity in pregnancy are not well understood. However, because these changes occur over a matter of weeks and months in pregnancy, in contrast to years in the nongravid individual, the pregnancy condition offers us a model to better understand these mechanisms. Evidence has accumulated that white adipose tissue acts as an endocrine organ, producing cytokines and hormones. We speculate that the increases in fat accretion with concurrent increase in cytokines such as leptin and TNF-
are related to the decreases in insulin sensitivity (12, 15).
The theoretical increases in total energy expenditure of pregnancy had been estimated to be
80,000 kcal, or
300 kcal/day (13). The additional energy costs include the increases in maternal and fetoplacental tissue (particularly adipose tissue,
10,000 kcal/kg) and the energy costs of pregnancy such as increased maternal cardiac output. However, in the past decade, these estimates have been revised to reflect the great variability in energy costs both among and within various populations. In this study, we elected to evaluate basal metabolic rate, which represents
60% of total energy expenditure for the average person.
There was an
30% increase in basal energy expenditure from P to L, whether expressed as basal
O2, milliliters per minute, or kilocalories per day. After adjustment for FFM, the increase in energy expenditure was
14% in the NGT and 21% in the GDM subjects. These differences did not reach statistical significance (P = 0.3 to 0.5) because of the great interindividual variability. The increase in basal kilocalories per day in our subjects ranged from 14 to 47%, a threefold difference.
There was a significant inverse correlation between the changes in basal endogenous glucose production and fat oxidation from P to E (Fig. 3). Although there was generally an increase in basal endogenous glucose production (
1 mg·kg FFM1·min1), one-half of the subjects had increasing and the other half had decreasing fat oxidation. One would have anticipated an increase in fat oxidation or FFA to be associated with an increase in basal endogenous glucose production, but serum FFA concentrations were unchanged over the same time period. We speculate that the subjects with decreased fat oxidation from P to E had increased FFA reesterification and were accruing fat tissue compared with subjects with increased fat oxidation.
In our obese subjects, there was no change in either basal carbohydrate oxidation or nonoxidative carbohydrate metabolism over time. However, there was a significant 5080% increase in basal fat oxidation. The increase was particularly evident from E to L, when there was increased accretion of adipose tissue and decreasing insulin sensitivity. These data support the hypothesis put forth by Eckel (7), which stated that increased lipid rather than carbohydrate oxidation may represent an adaptive mechanism for the prevention of additional weight (adipose tissue) in situations where there were preexisting obesity and decreasing insulin sensitivity.
The metabolic changes during insulin infusion in late gestation in obese women are similar to what we observed in lean women. There are progressive decreases in glucose and lipid insulin sensitivity, carbohydrate oxidation, and nonoxidative metabolism but a significant fivefold increase in fat oxidation with advancing gestation. As first described by Freinkel (10), these data support the concept that, during fasting, pregnancy is a state of accelerated starvation with increased maternal reliance on lipids rather than carbohydrates for meeting energy needs. Carbohydrates and amino acids are thus made available for fetoplacental energy requirements and growth.
Although the source of leptin is well documented, the role of the increased maternal leptin concentrations during gestation has remained elusive. In addition to maternal adipose tissue (29), the placenta produces leptin, and leptin concentrations fall within 48 h of delivery (17). Although leptin was originally thought to be related only to appetite suppression via central mechanisms, further reports pointed to a role of leptin in the control of energy expenditure (21). In obese subjects, leptin may have a stimulatory effect on fat oxidation by peripheral tissues (27). Minokoshi et al. (18) have recently reported that leptin stimulates fat oxidation in skeletal muscle by activating AMP-activated protein kinase (AMPK) and then AMPK activation allows phosphorylation of acetyl-coenzyme A carboxylase, resulting in potent stimulation of fatty acid oxidation in muscle. Hyperleptinemia downregulates expression of lipogenic enzymes and upregulates enzymes of fatty acid oxidation (5, 28). Hence, increase in maternal leptin, possibly from placental sources, may affect the increases in fat oxidation observed in our obese subjects.
When adjusted for maternal fat mass, the partial correlation between maternal leptin concentration and fat oxidation remained strong (r = 0.52) in early but not late pregnancy (r = 0.06). We speculate that in early pregnancy there is a significant increase in placental leptin production but relatively small increase in maternal fat accretion. Hence, increased leptin of placental origin may account for the strong correlation of leptin and fat oxidation in early pregnancy. In contrast, in late gestation there is little change in maternal leptin concentration but significant increase in maternal fat mass. Therefore, maternal leptin possibly from maternal adipose tissue sources rather than placenta may account for the significant correlation of maternal fat mass and fat oxidation in late gestation (r = 0.86, P = 0.0007) rather than in early gestation (r = 0.65, P = 0.03).
In summary, during pregnancy in obese women, there are significant alterations in body composition and energy expenditure among individuals but no difference between women with NGT and those with GDM. There are significant increases in fat mass and basal metabolic rate and an increased reliance on lipid metabolism both in the basal state and during insulin infusion. The increased reliance on fat metabolism is accompanied by a concomitant decrease in carbohydrate metabolism under conditions of hyperinsulinemia but not in the basal state. Whereas in lean women there is an increase in basal carbohydrate oxidation with advancing gestation, the increases in maternal fat oxidation may be related to increased maternal serum leptin. We speculate that it is the pregravid metabolic status of the individual (and not whether or not the individual develops GDM) that provides the baseline on which the alterations in pregnancy metabolism are mediated through placental hormones, cytokines, and growth factors. The exact sites and mechanisms of these changes require further evaluation.
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GRANTS
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This study was supported by National Institute of Child Health and Human Development (NICHD) Grant HD-11089 (P. M. Catalano), General Clinical Research Center Grant MO1-RR-80, and Women's Reproductive Health Training Grant HD-01273 (N. C. Okereke).
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ACKNOWLEDGMENTS
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We thank the research nurses in the GCRC for expert assistance and, most of all, our study subjects for the time and effort.
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FOOTNOTES
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Address for reprint requests and other correspondence: P. M. Catalano, MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109 (E-mail: pcatalano{at}metrohealth.org).
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.
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