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American Journal of Clinical Nutrition, Vol. 79, No. 1, 22-30, January 2004
© 2004 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATIONS

Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women1,2,3

Mirja Tiikkainen, Robert Bergholm, Aila Rissanen, Antti Aro, Irma Salminen, Marjo Tamminen, Kari Teramo and Hannele Yki-Järvinen

1 From the Division of Diabetes, Department of Medicine (MT, RB, MT, and HY-J), the Obesity Research Unit (AR), and the Department of Obstetrics and Gynecology (KT), University of Helsinki, Finland; the Department of Health and Functional Capacity, National Health Institute, Helsinki (AA and IS); and the Minerva Research Insitute, Helsinki (RB).

2 Supported by a research grants from the Academy of Finland (to HY-J), the Medical Society of Finland (to RB), and Hoffmann-La Roche.

3 Address reprint requests to H Yki-Järvinen, Department of Medicine, University of Helsinki, P.O. Box 340, FIN–00029 HUCH, Helsinki, Finland. E-mail: ykijarvi{at}helsinki.fi.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Dietary fat has been reported to influence insulin sensitivity.

Objective: The objective of the study was to determine how identical weight loss (target: loss of 8% of body weight over 3–6 mo) in women taking orlistat or placebo combined with a hypocaloric diet influences body composition and insulin sensitivity.

Design: Forty-seven obese women [body mass index (in kg/m2): 32.1 ± 0.4] were randomly assigned to receive either orlistat (120 mg 3 times daily; n = 23) or placebo (n = 24) with a hypocaloric diet. Whole-body insulin sensitivity (insulin clamp technique), serum fatty acids, and body composition (magnetic resonance imaging) were measured before and after weight loss.

Results: The groups did not differ significantly at baseline with respect to age, body weight, intraabdominal and subcutaneous fat volumes, or insulin sensitivity. Weight loss did not differ significantly between the orlistat (7.3 ± 0.2 kg, or 8.3 ± 0.1%) and placebo (7.4 ± 0.2 kg, or 8.2 ± 0.1%) groups. Insulin sensitivity improved significantly (P < 0.001) and similarly after weight loss in the orlistat (from 4.0 ± 0.3 to 5.1 ± 0.3 mg · kg fat-free mass-1 · min-1) and placebo (from 4.4 ± 0.4 to 5.4 ± 0.4 mg · kg fat-free mass-1 · min-1) groups. Intraabdominal fat and subcutaneous fat decreased significantly in both groups, but the ratio of the 2 decreased significantly only in the orlistat group. The proportion of dihomo-{gamma}-linolenic acid (20:3n-6) in serum phospholipids was inversely related to insulin sensitivity both before (r = -0.48, P < 0.001) and after (r = -0.46, P < 0.001) weight loss, but it did not change significantly in either group.

Conclusions: Weight loss rather than inhibition of fat absorption enhances insulin sensitivity. A decrease in fat absorption by orlistat appears to favorably influence the ratio between intraabdominal and subcutaneous fat, which suggests that exogenous fat or its composition influences fat distribution.

Key Words: Fat intake • fatty acids • visceral fat • diet • nutrition


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Data from animal studies convincingly documented that the composition of diet influences insulin sensitivity independent of body weight (1). Diets that are very high in fat content impair insulin sensitivity more than do high-carbohydrate, low-fat diets. Similarly in humans, extreme changes in the ratio of fat to carbohydrate modulate insulin sensitivity, whereas smaller changes, which are more feasible in daily life, appear to have no effect on insulin sensitivity (2). More promising results regarding the possibility of enhancing insulin action via changes in diet were achieved by altering the composition of dietary fat. In animals, diets containing saturated fat impair insulin action more than do isocaloric diets enriched with monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs, respectively; 1). In humans, decreasing the proportion of saturated fatty acids (SFAs) and increasing that of MUFAs improves insulin sensitivity (3). The mechanism underlying these changes is unclear. One possibility is that incorporation of SFAs into membrane phospholipids of insulin-sensitive tissues such as skeletal muscle impairs insulin action (4). Alternatively, dietary fat content may influence intramyocellular triacylglycerol content (5), which has been inversely correlated with insulin action in several human studies, independent of other factors (6-11).

Orlistat (Xenical; Hoffmann-La Roche, Basel, Switzerland) is an inhibitor of gastric and pancreatic lipases, which at a thrice-daily dose of 120 mg reduces fat absorption by {approx}30% (12) and has been proven to be useful in facilitating both weight loss and weight maintenance (13). It was also shown to alter the proportion of fatty acids in serum triacylglycerols, cholesterol esters, and phospholipids (14). Weight loss is accompanied by loss of both subcutaneous and visceral fat and by improved insulin sensitivity (15-20). Inhibition of fat absorption with the use of orlistat has been associated with greater improvement in insulin sensitivity than has the use of placebo (21-23), but it is unclear whether these beneficial metabolic effects are specific to orlistat or are secondary to a hypocaloric diet and weight loss: in studies reporting data on serum insulin concentrations, weight loss has been greater in the orlistat group than in the placebo group (21-23). In a placebo-controlled study including 523 subjects with initially normal glucose tolerance, orlistat decreased serum insulin and glucose concentrations during an oral-glucose-tolerance test, and this treatment effect remained significant even after adjustment for changes in body weight between the orlistat and placebo groups (23). These data thus suggested that orlistat improved insulin sensitivity independent of body weight. In an uncontrolled study involving 6 patients, orlistat was found to improve insulin sensitivity, which was measured with the use of the euglycemic insulin clamp technique, independent of changes in body weight (24). In the present study, we wished to ascertain whether orlistat has weight loss–independent effects on insulin sensitivity or body composition in obese women with a history of gestational diabetes, which increases the risk of developing type 2 diabetes (25). For this purpose, we designed a double-blind, placebo-controlled study in which the aim was to achieve 8% weight loss over a similar period in women taking orlistat and in those taking placebo. Insulin sensitivity was measured by using the euglycemic insulin clamp technique, and body composition was measured by using magnetic resonance imaging. To determine whether orlistat modified fatty acid composition as expected on the basis of previous studies (14, 26), we measured the composition of fatty acids in serum phospholipids by gas chromatography.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and study design
The participants of the study were recruited by using hospital records of women who had been treated during 1987–1999 at the Department of Obstetrics and Gynaecology at Helsinki University Central Hospital because of gestational diabetes mellitus. They had to meet the inclusion criteria of 1) previous gestational diabetes mellitus, 2) current age 20–50 y, 3) body mass index (in kg/m2) after delivery of 28–35, and 4) no known acute or chronic disease according to history, physical examination, and standard laboratory tests (blood counts, serum creatinine, thyroid-stimulating hormone, electrolyte concentrations, liver function tests, and electrocardiogram). A 2-h oral-glucose-tolerance test with 75 g glucose was performed to exclude women with diabetes (27). Other exclusion criteria included treatment with drugs, which may alter glucose tolerance; pregnancy; lack of reliable contraception; postmenopausal status; or clinical or biochemical evidence of any significant disease other than obesity. A total of 57 women who met the inclusion and exclusion criteria were included in the study. In each woman, insulin sensitivity (measured by using the euglycemic hyperinsulinemic clamp technique), intraabdominal and subcutaneous fat (measured by using magnetic resonance imaging), and waist-to-hip ratio were measured before and after weight loss as detailed below.

After baseline measurements, the women participated in a weight-loss program in which the goal was to achieve a loss of 8% of body weight over 3–6 mo. The women were placed on a nutritionally balanced hypocaloric diet, which consisted of 30% of energy as fat (10% SFAs, 10% MUFAs, and 10% PUFAs), 50% of energy as carbohydrate, and 20% of energy as protein. Cholesterol was limited to 300 mg/d. The estimated basal metabolic rate was multiplied by a factor to include physical activity in the estimate of totals daily energy requirement. On the basis of this estimate, a diet inducing a caloric deficit of {approx}600 kcal/d (for patients weighing <100 kg) to 800 kcal/d (for patients weighing >100 kg) was prescribed. During the weight-loss period, the patients met with a dietitian every 2 wk. Women were randomly assigned in a double-blind fashion to receive thrice-daily doses of either orlistat (120 mg) or placebo as an adjunct to the hypocaloric diet. Before the metabolic studies and the weight-loss period, all women were asked to keep a 3-d diary of food intake. During weeks 12–15 of the weight-loss period, the subjects were interviewed by telephone with regard to their dietary intake. Food diaries were analyzed with the use of NUTRICA software (version 3.0; Research Centre of the Social Insurance Institution, Helsinki). When the goal (8% weight loss) was achieved, the patients were placed on a weight-maintaining diet for 2 wk, after which the initial metabolic studies were repeated. Ten of the women did not achieve the required 8% weight loss and were withdrawn from the study.

The nature and potential risks of the study were explained to all subjects before they provided written informed consent. The Ethics Committee of the Helsinki University Central Hospital approved the experimental protocol.

Methods
Whole-body insulin sensitivity
Whole-body insulin sensitivity of glucose metabolism (the M-value) was determined by using the euglycemic insulin clamp technique (28). The study was begun at 0800 after a 12-h fast. Two 18-gauge catheters (Venflon; Viggo-Spectramed, Helsingborg, Sweden) were inserted, one in the left antecubital vein for infusions of insulin and glucose and the other retrogradely in the same arm in a dorsal vein of the hand, which was kept in a heated (60 °C) chamber for withdrawal of arterialized venous blood. Insulin (Actrapid Human; Novo Nordisk, Copenhagen) was infused in a primed continuous manner at a rate of 1 mU · kg-1 · min-1 for 120 min. Normoglycemia was maintained by adjusting the rate of a 20% glucose infusion according to plasma glucose measurements, which were performed every 5 min in arterialized venous blood. Before the insulin infusion, blood samples were taken for measurement of fasting glucose, glycosylated hemoglobin, triacylglycerols, total and LDL cholesterol, free fatty acids, fatty acid composition of serum phospolipids, and serum free insulin concentrations. Blood samples for serum free insulin and free fatty acid concentrations were also drawn every 30 min during the 2-h insulin infusion. The M-value was calculated from the glucose infusion rate after correction for changes in the glucose pool size and expressed per kilogram of fat-free mass (FFM).

Intraabdominal and subcutaneous fat (magnetic resonance imaging)
A series of T1-weighted trans-axial scans for the measurement of intraabdominal and subcutaneous fat were acquired from a region extending from 8 cm above to 8 cm below the 4th and 5th lumbar interspace (16 slices; field of view: 375 x 500 mm2; slice thickness: 10 mm; breath-hold repetition time: 138.9 ms; echo time: 4.1 ms). Intraabdominal and subcutaneous fat areas were measured by using an image analysis program (ALICE, version 3.0; Parexel, Waltham, MA). A histogram of pixel intensity in the intraabdominal region was displayed, and the intensity corresponding to the nadir between the lean and fat peaks was used as a cutoff. Intraabdominal adipose tissue was defined as the area of pixels in the intraabdominal region above this cutoff. For calculation of subcutaneous adipose tissue area, a region of interest was first manually drawn at the demarcation of subcutaneous adipose tissue and intraabdominal adipose tissue as previously described (29). The reproducibility of repeated measurements of subcutaneous and intraabdominal fat volumes as determined on 2 separate occasions in our laboratory is 3% and 5% (30).

Ambulatory blood pressure monitoring
Noninvasive 24-h blood pressure monitoring was performed on a normal weekday by using an automatic ambulatory blood pressure monitoring device (Diasys Integra; Novacor SA, Rueil-Malmaison, France). The monitor was set to record blood pressure and heart rate every 15 min during the day and every 30 min during the night. Day and night were defined from awake and sleeping periods in each patient’s diary.

Other measurements
Percentage body fat was determined by using bioelectrical impedance analysis (BioElectrical Impedance Analyzer System model #BIA-101A; RJL Systems, Detroit) (31). To calculate the waist-to-hip ratio, waist circumference was measured midway between the spina iliaca superior and the lower rib margin, and hip circumference was measured at the level of the greater trochanters (32).

Serum free fatty acids and fatty acid composition of serum phospholipids
Serum free fatty acids were measured by using a fluorometric method (33). The fatty acid methyl ester composition of serum phospholipids was determined with gas chromatography after a thin-layer chromatography separation of phospholipids from serum fat extract (34) and interesterification to methyl esters (35). The HP 6980+ gas chromatograph (Hewlett-Packard, Avondale, PA) was equipped with a 25-m silica column (NB 351; HNU-Nordion Ltd, Helsinki) and a split injection system. Hydrogen was used as carrier gas. The interassay precision varied from 2% to 10%, depending on the peak size.

Other analytic procedures
Plasma glucose concentrations were measured in duplicate with the glucose oxidase method by using a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA; 36). Serum free insulin concentrations were measured by radioimmunoassay (Phadeseph Insulin RIA; Pharmacia & Upjohn Diagnostics, Uppsala, Sweden) after precipitation with polyethylene glycol (37). Glycosylated hemoglobin was measured with the use of HPLC using the fully automated Glycosylated Hemoglobin Analyzer System (BioRad, Richmond, CA; 38). Concentrations of serum total and HDL cholesterol and triacylglycerol were measured by using the respective enzymatic kits from Roche Diagnostics (Basel, Switzerland) and an autoanalyzer (Roche Diagnostics Hitachi 917; Hitachi Ltd, Tokyo). LDL-cholesterol concentrations were calculated by using the formula of Friedewald (39).

Statistical analyses
Paired and unpaired t tests, two-factor repeated-measures analysis of variance, and analysis of covariance with the baseline values as a covariate were used to compare changes before and after weight loss and mean values or changes between the orlistat and placebo groups. Nonnormally distributed variables were logarithmically transformed. Effects of group, group x time, and time (insulin) on serum free fatty acid concentrations were analyzed by using analysis of variance for repeated measures and SYSSTAT Statistical Package software (version 10; SysStat Inc, Evanston, IL). Pearson’s (for normally distributed variables) or Spearman’s rank (for nonnormally distributed variables) correlation coefficients were used to calculate correlation coefficients between selected variables. All calculations were made by using GRAPHPAD PRISM software (version 3.0; GraphPad Inc, San Diego). Data are shown as means ± SEs. A P value <0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Baseline characteristics
The orlistat and placebo groups did not differ significantly with respect to age, body mass index, waist-to-hip ratio (Table 1Go), and volumes of intraabdominal (1370 ± 109 and 1478 ± 112 cm3, respectively; NS), subcutaneous (5678 ± 233 and 5982 ± 230 cm3; NS), and whole-body (36 ± 1 and 37 ± 1%; NS) fat. Concentrations of fasting plasma glucose (5.7 ± 0.1 and 5.6 ± 0.1 mmol/L, respectively; NS), glycosylated hemoglobin (5.5 ± 0.1 and 5.6 ± 0.1%; NS), insulin sensitivity (4.0 ± 0.3 and 4.4 ± 0.4 mg · kg FFM-1 · min-1; NS), fasting serum free fatty acids (726 ± 35 and 704 ± 34 µmol/L; NS), and free insulin (10 ± 1 and 10 ± 1 mU/L; NS) did not differ significantly between the groups. There were no significant differences between the groups in dietary intake (Table 1Go) or in the fatty acid composition of serum phospholipids before weight loss (Table 2Go).


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  		TABLE 1. Baseline characteristics of the study groups1

 

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  		TABLE 2. Fatty acid composition of serum phospholipid esters in obese women before and after taking orlistat or placebo1

 
Dietary intake during the study and side effects
Dietary intake averaged 1223 ± 125 and 1141 ± 115 kcal/d in the orlistat and placebo groups, respectively (NS). The percentage of fat in the total energy intake after weight loss decreased significantly in the orlistat group, from 36 ± 2% to 25 ± 3% (P < 0.001), but it was unchanged in the placebo group (before weight loss: 36 ± 2; after weight loss: 31 ± 3%; NS). The orlistat group had significantly more gastrointestinal but not other side effects than did the placebo group [total: 93% and 60%, respectively (P < 0.01); fatty stool: 81% and 17% (P < 0.005); soft stools: 37% and 17% (P < 0.001)].

Effects of weight loss on body composition
Weight loss averaged 7.3 ± 0.2 kg (8.3 ± 0.1%) and 7.4 ± 0.2 kg (8.2 ± 0.1%) of initial body weight in the orlistat and placebo groups. The mean time to achieve weight loss was 20 ± 1 wk in the orlistat group and 18 ± 1 wk in the placebo group (NS). As planned, weight changed similarly over time in both groups (Figure 1Go).



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  		FIGURE 1.. Mean (±SEM) weight loss plotted versus time in the orlistat (n = 23) and placebo (n = 24) groups. Differences between the groups were not significant (ANOVA for repeated measures).

 
The decrease in the percentage of whole-body fat after weight loss was similar in the two groups (orlistat group: from 36 ± 1% to 34 ± 1%; placebo group: from 37 ± 1% to 35 ± 1%). Weight loss induced a significant loss of fat from the intraabdominal (orlistat group: from 1370 ± 109 to 995 ± 65 cm3; placebo group: from 1479 ± 112 to 1199 ± 80 cm3; P < 0.0001) and subcutaneous (orlistat group: from 5678 ± 233 to 4903 ± 215 cm3; placebo group: from 5983 ± 230 to 5146 ± 200 cm3; P < 0.001) fat regions. Intraabdominal fat tended to decrease more in the orlistat group than in the placebo group, but the changes between the groups were not significant (Figure 2Go). Subcutaneous fat decreased similarly in both groups (Figure 2Go). The ratio between intraabdominal and total fat decreased significantly in the orlistat group after weight loss (from 19.5 ± 1.4% to 17.1 ± 1.1%; P < 0.005) but not in the placebo group (from 19.9 ± 1.4% to 19.1 ± 1.3%; NS). Similarly, the ratio between intraabdominal and subcutaneous fat decreased significantly in the orlistat group after weight loss (from 25 ± 2% to 21 ± 2%; P < 0.005), but it remained unchanged in the placebo group (from 26 ± 2% to 24 ± 2%; NS). The changes in both ratios were significant (P < 0.05).



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  		FIGURE 2.. Mean (±SEM) effects of weight loss on intraabdominal and subcutaneous fat volumes and the ratio of intraabdominal to total fat in the orlistat (n = 23) and placebo (n = 24) groups. **Significantly different after weight loss, P < 0.01 (paired t test). xChange after weight loss significantly different between groups, P < 0.05 (ANOVA).

 
Effects of weight loss on insulin sensitivity, lipids, and blood pressure
Insulin sensitivity (M-value) increased and serum fasting insulin concentrations decreased similarly in the 2 groups (Figure 3Go). Before- and after-weight loss concentrations of fasting plasma glucose (orlistat group: 5.7 ± 0.1 and 5.6 ± 0.1 mmol/L, respectively; placebo group: 5.6 ± 0.1 and 5.6 ± 0.1 mmol/L, respectively), glycosylated hemoglobin (orlistat group: 5.5 ± 0.1 and 5.5 ± 0.1%, respectively; placebo group: 5.5 ± 0.1 and 5.6 ± 0.1%), and serum fasting free fatty acids (orlistat group: 726 ± 35 and 671 ± 47 µmol/L, respectively; placebo group: 704 ± 34 and 664 ± 41 µmol/L) remained unchanged. Mean serum free fatty acid concentrations during the insulin infusion (30–120 min) were slightly (P < 0.05) lower after weight loss (233 ± 13 and 247 ± 13 µmol/L for the orlistat and placebo groups, respectively) than before weight loss (254 ± 16 and 265 ± 14 µmol/L, respectively), and there were no significant differences between the groups. Serum LDL cholesterol decreased significantly from 3.5 ± 0.2 to 3.0 ± 0.1 mmol/L (P < 0.01) in the orlistat group but remained unchanged in the placebo group (3.1 ± 0.1 and 3.0 ± 0.1 mmol/L; NS). The change differed significantly between groups (P < 0.05). Serum HDL cholesterol increased slightly but significantly in the placebo group (from 1.28 ± 0.06 to 1.34 ± 0.07 mmol/L; P < 0.05) but remained unchanged in the orlistat group (from 1.31 ± 0.1 to 1.29 ± 0.1 mmol/L; NS). The change did not differ significantly between groups. Twenty-four–hour systolic blood pressure decreased significantly in both groups (Figure 3Go). Twenty-four–hour diastolic blood pressure decreased from 83 ± 2 to 81 ± 2 mm Hg (P = 0.045) in the orlistat group and from 79 ± 2 to 77 ± 1 mm Hg (P = 0.064) in the placebo group.



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  		FIGURE 3.. Mean (±SEM) effects of weight loss on whole-body insulin sensitivity, serum fasting insulin, and 24-h systolic blood pressure in the orlistat (n = 23) and placebo (n = 24) groups. FFM, fat-free mass. *P < 0.05, ***P < 0.001 for treatment effect. There was no significant difference in the changes between the 2 groups.

 
Changes in serum phospholipid fatty acids in the orlistat and placebo groups
The proportion of palmitic acid (16:0), the most abundant SFA in serum phospholipids, increased significantly in the orlistat group but not in the placebo group. The proportion of the essential fatty acid linoleic acid (18:2n-6), the most abundant PUFA, decreased in both groups. MUFAs increased significantly in the orlistat group but not in the placebo group, and the sum of proportions after weight loss was significantly higher in the orlistat group than in the placebo group (P < 0.05).

Interrelations between changes in body composition, fatty acid composition of serum phospholipid esters, and whole-body insulin sensitivity
Before weight loss, when all data were analyzed together, intraabdominal (r = -0.46, P < 0.005) but not subcutaneous (r = 0.12, NS) fat volume was significantly correlated inversely with whole-body insulin sensitivity. Similarly, after weight loss, intraabdominal (r = -0.47, P < 0.005) but not subcutaneous (r = -0.20, NS) fat volume was significantly related inversely to whole-body insulin sensitivity. When all data were analyzed together (or within groups; data not shown), there were no significant correlations between weight loss–induced changes in body composition (body weight: r = 0.02, NS; waist-to-hip ratio: r = -0.17, NS; intraabdominal fat: r = -0.21, P = 0.17; subcutaneous fat: r = 0.08, NS; ratio of intraabdominal to subcutaneous fat: r = -0.22, P = 0.16) and insulin sensitivity (M-value expressed as mg · kg FFM-1 · min-1). Before weight loss, the sum of SFAs was negatively (r = -0.30, P < 0.05) and that of PUFAs was positively (r = 0.30, P < 0.05) significantly related to whole-body insulin sensitivity. The change in the ratio of intraabdominal fat volume to total or subcutaneous fat volume did not correlate with changes in any of the individual fatty acids or their sums (data not shown). There was, however, a highly significant inverse correlation between the proportion of dihomo-{gamma}-linolenic acid (20:3n-6) and whole-body insulin sensitivity both before and after weight loss (Table 3Go).


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  		TABLE 3. Interrelations between the fatty acid composition of serum phospholipids and whole-body insulin sensitivity in obese women before and after weight loss1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, 2 groups of women—one group taking orlistat and the other taking placebo—lost equal, moderate amounts of weight. Whole-body insulin sensitivity and metabolic indexes, including fasting insulin, blood pressure, and lipids, improved similarly in both groups. Serum LDL cholesterol and the proportion of fatty acids in serum phospholipids changed differently between the groups. A significant decrease in the ratio of visceral to subcutaneous or total adipose tissue was observed in the orlistat group, but the decrease in the placebo group was not significant. This suggests that diet composition may alter fat distribution independent of changes in body weight and fat mass.

Analysis of dietary records based on a 3-d food intake diary and measurement of the molar proportions of fatty acids in serum phospholipids showed that the orlistat and placebo groups were similar before weight loss. During weight loss, orlistat reduced fat absorption, as shown by a decrease in serum LDL cholesterol that was expected on the basis of a previous report (12) and that corresponds to an {approx}25% decrease in cholesterol absorption and a 30% decrease in fat absorption (40-42). Moreover, the significant decrease in the proportions of linoleic and {alpha}-linolenic acid (18:3n-3) in serum phospholipids is consistent with a decrease in the proportion of diet-derived fatty acids and with our previous findings regarding orlistat’s effects on the fatty acid composition of serum lipid fractions in obese subjects who were taking a dose of orlistat similar to that in the present study (14). Dietary intakes in the 2 groups were similar during weight loss, but the orlistat group reduced fat intake more than the placebo group did, most likely because of gastrointestinal side effects.

In the orlistat group, the ratio of intraabdominal fat mass to subcutaneous or total fat mass decreased significantly, but it remained unchanged in the placebo group, whereas the absolute volumes of both fat compartments decreased similarly. Previous studies documented that weight loss decreases visceral fat (15-20), and that factors such as race (20) and the Trp64Arg ß3-adrenoceptor gene variant (43) may influence the response to weight loss. Studies in twins suggested that the sites of fat deposition or loss in response to overfeeding or negative energy balance are under strong genetic control (44). In addition, there are data showing that visceral fat can be reduced by hormones such as growth hormone (45), by physical training (46), and by the use of PPAR-{gamma} agonists in controlled studies (47-50). To our knowledge, there are no data on the effects of equal amounts of weight loss induced by the use of orlistat or the effects of different diets on visceral and subcutaneous fat volumes. However, the addition of conjugated 18:2n-6 to the diet has been shown to decrease abdominal adipose tissue in a double-blind placebo-controlled trial independent of effects on body weight (51). The present data would suggest that lowering fat absorption or altering the composition of fatty acids might have favorable effects on the ratio of intraabdominal to subcutaneous and total fat. The mechanism or mechanisms underlying such an effect remain speculative. PUFAs, in addition to possibly enhancing insulin sensitivity via effects on membrane composition, can suppress the transcription of lipogenic genes and induce genes encoding for proteins of lipid oxidation and thermogenesis, possibly by direct interaction with transcription factors such as sterol responsive element binding protein 1c (52). In the present study, there were several changes in fatty acid composition in both groups and some differences between the groups, as judged from phospholipid esters in serum (Table 2Go). None of the changes in fatty acid composition correlated with changes in body composition. Nonetheless, the orlistat intervention was associated with a favorable change in body composition, which implies that changing the amount of dietary fat absorbed or the fatty acid composition may differentially regulate the size of the fat depots.

Although the ratio of intraabdominal to subcutaneous and total fat decreased in the orlistat group but not in the placebo group, insulin sensitivity improved similarly in both groups. This should not necessarily be interpreted as suggesting that visceral fat does not regulate whole-body insulin sensitivity independent of overall obesity and fat mass, because the absolute volumes of intraabdominal and subcutaneous fat decreased similarly in both groups, and it is doubtful whether the small decrease in the ratio was big enough to have a discernible metabolic effect. In addition, whereas the M-value provides an accurate measure of whole-body insulin sensitivity, it does not allow distinction between the contribution of defects in suppression of hepatic glucose production and in stimulation of peripheral glucose uptake by insulin to whole-body insulin sensitivity. Intraabdominal fat could be better related to hepatic insulin sensitivity, at least according to the portal hypothesis—ie, the theory that the larger the visceral fat depot, the greater the flux of free fatty acid to the liver via the portal vein (53). We found no correlations between the change in liver enzymes and insulin sensitivity (data not shown) or C-peptide or fasting serum insulin concentrations. Alternatively, and as recently suggested by ourselves, the amounts of fat deposited within the liver (54, 55) and in intramyocellular depots (10) may be the most proximate correlates of insulin sensitivity. The improvement in insulin sensitivity measured as in the present study, but induced by biliopancreatic diversion, was recently shown to be closely correlated with the change in intramyocellular lipid (56). Intramyocellular triacylglycerol, which is an inert metabolite, may mediate this effect via a decrease in long-chain acylCoA. To summarize, the lack of difference in insulin sensitivity may not negate a role of intraabdominal fat in determining insulin sensitivity.

Both the amount of free fatty acids stored as triacylglycerols inside insulin-sensitive cells and the composition of free fatty acids in serum cholesterol esters are related to insulin sensitivity (57). When measured with the use of the euglycemic clamp technique, insulin sensitivity has been associated with low proportions of 16:0 and with high proportions of 18:2n-6 and especially of 20:3n-6 in serum cholesterol esters (57). In keeping with these data, we found a strikingly strong inverse correlation between the proportion of 20:3n-6 and whole-body insulin sensitivity both before and after weight loss. An increased proportion of 20:3n-6 has been found to be an independent risk factor for myocardial infarction (58). Both 18:2n-6 and 18:3n-3, which cannot be endogenously synthesized, are reliable indicators of dietary intake, whereas other fatty acids reflect the effects of metabolism and synthesis as well. Thus, the reduced proportions of 18:2n-6 and 18:3n-3 reflect either reduced intakes or reduced absorption of these fatty acids, or both. The fatty acid composition of serum phospholipids (59, 60) and recently also that of skeletal muscle membranes (61) were shown to reflect dietary fat composition and to correlate with insulin sensitivity in humans (4). Despite such cross-sectional data supporting the possibility that dietary fatty acid composition regulates insulin sensitivity, intervention studies were largely negative (62-64) until recently, when the KANWU study showed that insulin sensitivity can indeed be enhanced by replacing saturated fat with monounsaturated fat (3). In view of these data, the changes in the fatty acid composition of serum phospholipids in the orlistat group might be expected to have, if anything, a negative impact on insulin sensitivity. Thus, the proportion of 16:0 increased and that of 18:2n-6 decreased significantly more in the orlistat group than in the placebo group (Table 2Go). These changes may have counteracted a possible beneficial effect of orlistat on insulin sensitivity by reducing the ration of visceral to subcutaneous fat.

In conclusion, the present data show that weight loss induced with or without orlistat has beneficial metabolic effects, and they raise the possibility that the total amount of dietary fat absorbed or its composition influences the size of adipose tissue depots. The strong inverse relation between the proportion of 20:3n-6 in serum phospholipids and insulin sensitivity (and its components; data not shown) both before and after weight loss supports the prevailing view that the composition of fat may be of greater importance for the metabolic consequences of a diet than is the total amount of fat. The reduced bioavailability of 18:2n-6, observed especially while subjects were taking orlistat, may counteract the beneficial metabolic effects of weight reduction.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge dietitians Katriina Lammi and Katja Kettunen for their outstanding work; Maarit Toivonen, Katja Tuominen, and Pentti Pölönen for excellent technical assistance; and the volunteers for their help.

MT carried out the most of the clinical studies, analyzed the magnetic resonance imaging data, and contributed to writing the manuscript. RB contributed to recruiting and screening the patients and to data analysis. AR supervised the weight-loss program in the Obesity Research Unit. AA and IS performed the phospholipid analyses. MT performed the clamp studies of the first 30 patients. KT helped to recruit the women. HY-J designed the study and wrote most of the manuscript.

AR is a member of a board of European scientists who advise Hoffmann-LaRoche, the manufacturer of the weight-reducing agent Xenical (orlistat; Hoffmann-La Roche, Basel, Switzerland), and receives honoraria for speaking engagements arranged or sponsored by Hoffmann-LaRoche. None of the other authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991;40:280-9.[Abstract]
  2. Rivellese AA, De Natale C, Lilli S. Type of dietary fat and insulin resistance. Ann N Y Acad Sci 2002;967:329-35.[Medline]
  3. Vessby B, Uusitupa M, Hermansen K, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU Study. Diabetologia 2001;44:312-9.[Medline]
  4. Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med 1993;328:238-44.[Abstract/Free Full Text]
  5. Decombaz J, Schmitt B, Ith M, et al. Postexercise fat intake repletes intramyocellular lipids but no faster in trained than in sedentary subjects. Am J Physiol Regul Integr Comp Physiol 2001;281:R760-9.[Abstract/Free Full Text]
  6. Bachmann OP, Dahl M, Brechtel K, et al. Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans. Diabetes 2001;50:2579-84.[Abstract/Free Full Text]
  7. Jacob S, Machann J, Rett K, et al. Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes 1999;48:1113-9.[Abstract]
  8. Pan DA, Lillioja S, Kriketos AD, et al. Skeletal muscle triacylglycerol levels are inversely related to insulin action. Diabetes 1997;46:983-8.[Abstract]
  9. Krssak M, Falk PK, Dresner A, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999;42:113-6. (Published errata appear in Diabetologia 1999;42:386 and Diabetologia 1999;42:1269.)[Medline]
  10. Virkamäki A, Korsheninnikova E, Seppälä-Lindroos A, et al. Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes 2001;50:2337-43.[Abstract/Free Full Text]
  11. Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 2001;50:1612-7.[Abstract/Free Full Text]
  12. Zhi J, Melia AT, Guerciolini R, et al. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Clin Pharmacol Ther 1994;56:82-5.[Medline]
  13. Sjoström L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998;352:167-72.[Medline]
  14. Vidgren HM, Agren JJ, Valve RS, Karhunen LJ, Rissanen AM, Uusitupa MI. The effect of orlistat on the fatty acid composition of serum lipid fractions in obese subjects. Clin Pharmacol Ther 1999;66:315-22.[Medline]
  15. Doucet E, St-Pierre S, Almeras N, et al. Reduction of visceral adipose tissue during weight loss. Eur J Clin Nutr 2002;56:297-304.[Medline]
  16. Gower BA, Weinsier RL, Jordan JM, Hunter GR, Desmond R. Effects of weight loss on changes in insulin sensitivity and lipid concentrations in premenopausal African American and white women. Am J Clin Nutr 2002;76:923-7.[Abstract/Free Full Text]
  17. Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes 1999;48:839-47.[Abstract]
  18. Purnell JQ, Kahn SE, Albers JJ, Nevin DN, Brunzell JD, Schwartz RS. Effect of weight loss with reduction of intra-abdominal fat on lipid metabolism in older men. J Clin Endocrinol Metab 2000;85:977-82.[Abstract/Free Full Text]
  19. Janssen I, Fortier A, Hudson R, Ross R. Effects of an energy-restrictive diet with or without exercise on abdominal fat, intermuscular fat, and metabolic risk factors in obese women. Diabetes Care 2002;25:431-8.[Abstract/Free Full Text]
  20. Weinsier RL, Hunter GR, Gower BA, Schutz Y, Darnell BE, Zuckerman PA. Body fat distribution in white and black women: different patterns of intraabdominal and subcutaneous abdominal adipose tissue utilization with weight loss. Am J Clin Nutr 2001;74:631-6.[Abstract/Free Full Text]
  21. Rossner S, Sjoström L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res 2000;8:49-61.[Medline]
  22. Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999;281:235-42.[Abstract/Free Full Text]
  23. Heymsfield SB, Segal KR, Hauptman J, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med 2000;160:1321-6.[Abstract/Free Full Text]
  24. Dahl DB, Bachmann OP, Brechtel K, et al. Effects of orlistat (Xenical®) on insulin sensitivity (IS) in obese intentionally weight maintaining subjects. Diabetologia 2000;43:000 (abstr).
  25. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862-8.[Abstract/Free Full Text]
  26. Trouillot TE, Pace DG, McKinley C, et al. Orlistat maintains biliary lipid composition and hepatobiliary function in obese subjects undergoing moderate weight loss. Am J Gastroenterol 2001;96:1888-94.[Medline]
  27. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO Consultation. Geneva: World Health Organization, 1999.
  28. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214-23.
  29. Ryysy L, Häkkinen AM, Goto T, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000;49:749-58.[Abstract]
  30. Sutinen J, Häkkinen AM, Westerbacka J, et al. Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS 2002;16:2183-93.[Medline]
  31. Lukaski HC, Johnson PE, Bolonchuk WW, Lykken GI. Assessment of fat-free mass using bioelectrical impedance measurements of the human body. Am J Clin Nutr 1985;41:810-7.[Abstract/Free Full Text]
  32. World Health Organization. Measuring obesity—classification and description of anthropometric data. Report on a WHO consultation on the epidemiology of obesity. Geneva: World Health Organization, 1987.
  33. Miles J, Glasscock R, Aikens J, Gerich J, Haymond M. A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res 1983;24:96-9.[Abstract]
  34. Folch JS, Lees M, Stanley GH. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957;226:497-507.[Free Full Text]
  35. Stoffel W, Chu F, Ahrens EH Jr. Analysis of long-chain fatty acids by gas liquid chromatography. Anal Chem 1959;31:307-8.
  36. Kadish AH, Hall DA. A new method for the continuous monitoring of blood glucose by measurement of dissolved oxygen. Clin Chem 1965;11:869-75.[Abstract]
  37. Desbuquois B, Aurbach GD. Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassays. J Clin Endocrinol Metab 1971;33:732-8.[Abstract/Free Full Text]
  38. Stenman UH, Pesonen K, Ylinen K, Huhtala ML, Teramo K. Rapid chromatographic quantitation of glycosylated haemoglobins. J Chromatogr 1984;297:327-32.[Medline]
  39. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.[Abstract]
  40. Hill JO, Hauptman J, Anderson JW, et al. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study. Am J Clin Nutr 1999;69:1108-16.[Abstract/Free Full Text]
  41. Muls E, Kolanowski J, Scheen A, Van Gaal L. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study. Int J Obes Relat Metab Disord 2001;25:1713-21.[Medline]
  42. Mittendorfer B, Ostlund RE Jr, Patterson BW, Klein S. Orlistat inhibits dietary cholesterol absorption. Obes Res 2001;9:599-604.[Medline]
  43. Tchernof A, Starling RD, Turner A, et al. Impaired capacity to lose visceral adipose tissue during weight reduction in obese postmenopausal women with the Trp64Arg beta 3-adrenoceptor gene variant. Diabetes 2000;49:1709-13.[Abstract]
  44. Bouchard C, Tremblay A. Genetic influences on the response of body fat and fat distribution to positive and negative energy balances in human identical twins. J Nutr 1997;127:943S-7S.
  45. Johannsson G, Marin P, Lonn L, et al. Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab 1997;82:727-34.[Abstract/Free Full Text]
  46. Gutin B, Barbeau P, Owens S, et al. Effects of exercise intensity on cardiovascular fitness, total body composition, and visceral adiposity of obese adolescents. Am J Clin Nutr 2002;75:818-26.[Abstract/Free Full Text]
  47. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;87:2784-91.[Abstract/Free Full Text]
  48. Mori Y, Murakawa Y, Okada K, et al. Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 1999;22:908-12.[Abstract]
  49. Carey DG, Cowin GJ, Galloway GJ, et al. Sensitivity effect of rosiglitazone on insulin and body composition in type 2 diabetic patients. Obes Res 2002;10:1008-15.[Medline]
  50. Katoh S, Hata S, Matsushima M, et al. Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy—a randomized controlled trial. Metabolism 2001;50:414-7.[Medline]
  51. Riserus U, Berglund L, Vessby B. Conjugated linoleic acid (CLA) reduced abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trial. Int J Obes Relat Metab Disord 2001;25:1129-35.[Medline]
  52. Clarke SD. Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance. Br J Nutr 2000;83(suppl):S59-S66.
  53. Frayn KN. Visceral fat and insulin resistance—causative or correlative? Br J Nutr 2000;83(suppl):S71-7.
  54. Seppälä-Lindroos A, Vehkavaara S, H"kkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002;87:3023-8.[Abstract/Free Full Text]
  55. Tiikkainen M, Tamminen M, Häkkinen AM, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res 2002;10:859-67.[Medline]
  56. Greco AV, Mingrone G, Giancaterini A, et al. Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes 2002;51:144-51.[Abstract/Free Full Text]
  57. Vessby B, Tengblad S, Lithell H. Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70-year-old men. Diabetologia 1994;37:1044-50.[Medline]
  58. Ohrvall M, Berglund L, Salminen I, Lithell H, Aro A, Vessby B. The serum cholesterol ester fatty acid composition but not the serum concentration of alpha tocopherol predicts the development of myocardial infarction in 50-year-old men: 19 years follow-up. Atherosclerosis 1996;127:65-71.[Medline]
  59. Dougherty RM, Galli C, Ferro-Luzzi A, Iacono JM. Lipid and phospholipid fatty acid composition of plasma, red blood cells, and platelets and how they are affected by dietary lipids: a study of normal subjects from Italy, Finland, and the USA. Am J Clin Nutr 1987;45:443-55.[Abstract/Free Full Text]
  60. Kris-Etherton PM, Yu S. Individual fatty acid effects on plasma lipids and lipoproteins: human studies. Am J Clin Nutr 1997;65(suppl):1628S-44S.[Abstract/Free Full Text]
  61. Andersson A, Nalsen C, Tengblad S, Vessby B. Fatty acid composition of skeletal muscle reflects dietary fat composition in humans. Am J Clin Nutr 2002;76:1222-9.[Abstract/Free Full Text]
  62. Luo J, Rizkalla SW, Vidal H, et al. Moderate intake of n-3 fatty acids for 2 months has no detrimental effect on glucose metabolism and could ameliorate the lipid profile in type 2 diabetic men. Results of a controlled study. Diabetes Care 1998;21:717-24.[Abstract]
  63. McManus RM, Jumpson J, Finegood DT, Clandinin MT, Ryan EA. A comparison of the effects of n-3 fatty acids from linseed oil and fish oil in well-controlled type II diabetes. Diabetes Care 1996;19:463-7.[Abstract]
  64. Rivellese AA, Maffettone A, Iovine C, et al. Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care 1996;19:1207-13.[Abstract]
Received for publication January 16, 2003. Accepted for publication June 25, 2003.




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