801659 1129.1135

International Journal of Obesity (2001) 25, 1129±1135 ß 2001 Nature Publishing Group All rights reserved 0307±0565/01 $15.00www.nature.com/ijo PAPERConjugated linoleic acid (CLA) reduced abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trialU RiseÂrus1*, L Berglund1 and B Vessby1 1Clinical Nutrition Research Unit, Department of Public Health and Caring SciencesaGeriatrics, Faculty of Medicine, Uppsala BACKGROUND: Abdominal obesity is strongly related to metabolic disorders. Recent research suggests that dietary conjugated linoleic acid (CLA) reduces body fat and may improve metabolic variables in animals. The metabolic effects of CLA in abdominally obese humans have not yet been tested.
OBJECTIVE: To investigate the short-term effect of CLA on abdominal fat and cardiovascular risk factors in middle-aged men METHODS: Twenty-®ve abdominally obese men (waist-to-hip ratio (WHR), 1.05Æ 0.05; body mass index (BMI), 32Æ 2.7 kgam2 (meanÆ s.d.)) who were between 39 and 64-y-old participated in a double-blind randomised controlled trial for 4 weeks.
Fourteen men received 4.2 g CLAaday and 10 men recieved a placebo. The main endpoints were differences between the two groups in sagittal abdominal diameter (SAD), serum cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, free fatty acids, glucose and insulin.
RESULTS: At baseline, there were no signi®cant differences between groups in anthropometric or metabolic variables. After 4 weeks there was a signi®cant decrease in SAD (cm) in the CLA group compared to placebo (P ˆ 0.04, 95% CI; 71.12, 70.02).
Other measurements of anthropometry or metabolism showed no signi®cant differences between the groups.
CONCLUSIONS: These results indicate that CLA supplementation for 4 weeks in obese men with the metabolic syndrome may decrease abdominal fat, without concomitant effects on overall obesity or other cardiovascular risk factors. Because of the limited sample size, the effects of CLA in abdominal obesity need to be further investigated in larger trials with longer duration.
International Journal of Obesity (2001) 25, 1129 ± 1135 Keywords: conjugated linoleic acid (CLA); abdominal obesity; abdominal sagittal diameter; metabolic syndrome; cardiovascular risk factors; randomised controlled trial (RCT) CLA comprises a group of positional and geometric isomers Conjugated linoleic acid (CLA) is an unsaturated fatty acid of conjugated octadecadienoic acid, derivates of linoleic acid that has been shown to reduce body fat and increase lean (C18:2n-6) produced by bacterial biohydrogenation in the body mass in animals,1±5 by as yet unknown mechanisms.
ruminant gut.6 In humans, CLA is mainly derived from dairyand ruminant meat sources,7 and has been found in serum8and in human adipose tissue.9 Recent data have shownbene®cial effects of CLA on several components of themetabolic syndrome, in Zucker diabetic fatty rats (ZDF), *Correspondence: U RiseÂrus, Clinical Nutrition Research Unit, Department such as normalized glucose tolerance and reduced hyper- of Public Health and Caring SciencesaGeriatrics, Faculty of Medicine, insulinaemia, and plasma levels of free fatty acids (FFA).10 Uppsala University, Box 609, 751 25 Uppsala, Sweden.
Furthermore, in CLA-fed rabbits and hamsters, the blood lipid pro®le was signi®cantly improved11 and signs of early Received 4 February 2000; revised 31 July 2000; atherosclerosis were decreased as compared to controls.12,13 Conjugated linoleic acid and abdominal obesity Abdominal visceral obesity, has been suggested to be a key factor in the metabolic syndrome14 and the most prevalent The inclusion criteria were chosen to select obese men with cause of the atherogenic dyslipidaemic states associated with signs of the metabolic syndrome (abdominal obesity, dys- cardiovascular disease in Western populations.15 Thus, men lipidemia, hypertension and impaired fasting glucose). The with visceral obesity are an appropriate risk group to test the inclusion criteria were, as assessed by screening: age between putative bene®cial metabolic effects of CLA treatment.
30 and 65 y, abdominal obesity (waist circumference b94 cm Furthermore, epidemiological data from a population of and waist-to-hip ratio (WHR) b0.95), BMI b27 and elderly men showed an inverse correlation between esti- ` 39 kgam2, and with stable body weight the preceeding 3 mated dietary intake of milk fat and abdominal obesity,16 thus suggesting some indirect evidence for the postulatedmetabolic effects of CLA when consumed in high amounts.
The sagittal abdominal diameter (SAD) has been suggested tobe the best simple anthropometric measurement of visceral fat,17±19 and is strongly associated with cardiovascularrisk20±24 and mortality among men.25 Subjects with a history of signi®cant disease or with abnor-mal laboratory test results of clinical signi®cance were The antiobesity properties and metabolic effects of CLA excluded as well as those on medications or dietary supple- are at present only described in animals, and should there-fore be clinically tested in obese humans. The aim of the ments known to affect glucose and lipid metabolism, bodycomposition or eicosanoid production (eg salicylates and present trial was to investigate the short-term effects of CLAcompared to placebo on abdominal adipose tissue and car- ®sh-oils). Treatment with antihypertensive drugs wereaccepted if the subjects continued to take the same drug diovascular risk factors in men with signs of the metabolicsyndrome. To the best of our knowledge, the present study is the ®rst randomised controlled trial in humans, investigat- The primary outcome in the present trial was to investi- gate any statistical differences between CLA and placebo in ing the effects of CLA treatment in a cardiovascular high-riskgroup of abdominally obese middle-aged men.
SAD (representing visceral and total abdominal adiposetissue), serum cholesterol, fasting triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), FFA, plasma glucose and serum insulin. Secondary outcomes of interest were anthropometry and blood pressure.
Twenty-®ve abdominally obese men (all Caucasian),between the ages of 39 and 64 y, were recruited through anadvertisment in the local newspaper of Uppsala, Sweden.
Sixty men were invited to a screening test, which included anthropometry, serum lipids, plasma glucose, blood pres- The current trial was performed between April and May sure, kidney, liver, thyroid function and a medical question- 1999. All men were randomly assigned to treatment (CLA) naire. The men who ful®lled the inclusion criteria (described or placebo. Each group received seven CLA or placebo below) were informed about the study protocol and invited capsules per day (divided in two doses). Compliance was to participate. Twenty-®ve men ful®lled the inclusion cri- monitored by counting any returned capsules and by follow- teria, agreed to be randomly assigned to study groups, and up interview. The blinding was obtained using capsules identical in taste, colour, size and odour, packed in identical At the clinical baseline examination one patient was bottles, with one bottle per subject. The daily dose of CLA found to be hypertensive and was, after a re-examination, comprised 4.2 g and the same amount of olive oil was used as treated with a b-receptor blocker (metoprolol). This patient placebo. The predominant isomers used in CLA preparations wished to complete the trial and was included (data on blood are cis9, trans11 CLA 18:2 and trans10, cis12 CLA.1 The pressure from this patient was excluded from statistical isomer content of the current CLA preparation was as fol- lows: 37.0% t10c12 CLA, 36.9% c9t11 CLA, 1.4% t, t9, One subject declined on the ®rst day of the study and was 11 ‡ 10, 12 CLA, 1.3% c9c11 CLA, 0.9% c10c12 CLA, 13.9% excluded before taking any capsules. The reason for declin- 18:1c9, 4.3% 16:0, 1.4% 18:0. Both active (CLA 80) and ing was gastrointestinal disorders prior to the baseline exam- placebo capsules were prepared by Natural Lipids Ltd, Hove- ination. This subject did not differ in characteristics in terms bygda, Norway, which also was responsible for the individual of age or biochemical or anthropometric data as compared to randomisation and blinding of capsules. During the trial, the the men who completed the trial. The results and conclu- code was kept in sealed envelopes that were kept in a closed sions presented and discussed in this paper are based on the box located at the department of Geriatrics. None of the 24 subjects with complete data at 4 weeks. The protocol to investigators, nurses, analysts or patients knew the identity this study was approved by the Ethics Commitee of the of the treatments until the codes were revealed at the end of Faculty of Medicine of Uppsala University.
Conjugated linoleic acid and abdominal obesity magnesium chloride solution.30 LDL-cholesterol was calcu- The clinical examination was conducted in the morning lated according to the formula of Friedwald. Sample for the between 07:15 and 09:00, after written and oral instructions determination of insulin and FFA were stored at 770C. FFA to fast for 12 h, restrain from smoking, snuff or physical was measured by an enzymatic colorimetric method (Wako activity in the morning, and to avoid alcohol the day before Chemical GmbH, Germany). Insulin were measured in the clinical examination. All men were encouraged to main- serum by an enzyme immunoassay, ELISA-kit (Mercodia tain their usual diet and exercise habits throughout the AB, Uppsala, Sweden) in a Bio-Rad Coda automated EIA course of the study. After oral information, the same inves- analyser (Bio-Rad Laboratories AB, California, USA). Insulin tigator measured anthropometry and blood pressure, fol- and FFA were analysed at one run. Plasma glucose was lowed by blood samples taken by a nurse. Blood pressure measured with an enzymatic method, using a Hitachi ana- was measured on the right arm with the subject in the supine lysis system 717 (Boehringer Mannheim, Germany).
position after at least 5 min rest, by indirect auscultation andby a mercury sphygmomanometer. Systolic and diastolicblood pressure were de®ned as Korotkoff phases 1 and 5, respectively. Clinical examination at 4 weeks also included a Values are expressed as meansÆ s.d. All data were continous systematic food frequency interview, for estimation of diet- and on an interval scale. Variables with skewed distributions ary CLA intake and to obtain the dietary history for the (TG and insulin) were log transformed before analyses. A preceding month.26 All men were asked about their habitual nonparametric test was used if data were not normally food consumption during the preceeding 4 weeks, with focus distributed after logarithmic transformation. The paired t- on sources of CLA. During the interview, various household test was used to analyse the differences within the groups measures were used to identify proper portion sizes. Dietary from baseline to 4 weeks. The mean differences between intake of CLA was calculated by use of food-composition groups at baseline and after 4 weeks were assessed with an data of the Swedish National Food Administration;27 when unpaired t-test, with 95% con®dence intervals (CI) calcu- necessary, the portion sizes of different food items were lated according to standard procedures. For variables (waist) converted to weight on the basis of standard portions.
that were not normally distributed after logarithmic trans- Calculations of the CLA content in various dairy and meat formation, the Mann ± Whitney nonparametric test was used products are based on the mean CLA content in dairy for analyses. All tests were two-tailed and a P-value ` 0.05 products (2.5 ± 17.7 mgag fat),28 butter (6.2 mgag fat) and was regarded as signi®cant. Statistical calculations were per- formed using the JMP software package (SAS Institute Inc., All anthropometrics were measured by one trained inves- tigator. Body weight was measured using an electronic scaleto the nearest 0.1 kg, with the subjects wearing light clothingand no shoes. Height was measured without shoes to the nearest 0.5 cm. Bod mass index (BMI) was calculated as the weight (kg) divided by the square of the height (m). SAD Twenty-four men completed the study after being randomly (antero-posterior) was measured with patients in underwear assigned to CLA treatment (n ˆ 14), or placebo (n ˆ 10).
and in a recumbent position with hips ¯exed, on a ®rm During the 4 weeks only one subject withdrew.
examination table. At the level of the iliac crest ( ˆ L4-5), the At baseline, there were no signi®cant differences between perpendicular distance between the examination table up to the two groups after randomisation, in age (Table 1), anthro- the horizontal level was measured during a normal expira- pometry or in any other characteristic (Table 2). Fourty-four tion to the nearest 0.1 cm.17 Waist circumference was mea- percent of patients were hypertensive, de®ned as a mean sured in standing position after a normal expiration, with a systolic pressure !140 mmHg or mean diastolic pressure nonstretchable tape measure, at the level midway between !90 mmHg or if the subject was receiving antihypertensive the caudal part of the lateral costal arch and the iliac crest.29 drugs. No patient in the study sample had a diagnosis of type Hip circumference was measured at symphysis trochanter 2 diabetes or history of cardiovascular events.
Table 1 Demographic and anthropometric characteristics at baseline Laboratory proceduresBlood was drawn from an antecubital vein, into vacuum tubes and centrifuged (20 min) at 2000 g after 2 h of coagula- tion at room temperature. Total cholesterol and TG levels in serum were assayed by enzymatic techniques, using a Mon- arch 2000 centrifugal analyser (Instrumentation Labora- tories, Lexington, MA). HDL was isolated by centrifugation aThere were no signi®cant differences between groups using unpaired t-tests.
and precipitation with a sodium phosphotungstate and Values are the meanÆ s.d. BMI, body mass index, WHR, waist-to-hip ratio.
Conjugated linoleic acid and abdominal obesity Table 2 Clinical characteristics of men at baseline and after 4 weeks of treatment with CLA (n ˆ 14) or placebo (n ˆ 10) BMI, body mass index; SAD, sagittal abdominal diameter; WHR, waist ± hip ratio; Chol, serum cholesterol; LDL, low density lipoprotein; HDL, high density lipoprotein; TG, triglycerides. Values are the meanÆ s.d. and 95% con®dence interval (CI).
Signi®cant differences between the two groups using unpaired t-test: *P ` 0.05. Signi®cant differences within groups using paired t-test: {P ` 0.01, {P ` 0.001.
The supplements were well-tolerated in all patients, with no adverse events clinically detected or reported. Compli- The estimated mean CLA intake from dietary sources was, for ance did not differ between groups, with 96% of the capsules the whole group, 328 mg CLAaday. The mean intake of CLA from dietary sources was 311 mg (range 123 ± 470 mg) in theCLA group, and 346 mg (range 156 ± 590 mg) in the placebogroup, showing no statistical signi®cance between groups(P ˆ 0.24). These data suggest that the CLA supplementation corresponded to an average daily dose, which was approxi- The 4 week treatment with CLA induced a signi®cant reduc- mately 13-fold higher than what was usually obtained from tion of SAD, as compared to placebo (P ˆ 0.041, 95% CI; 71.12, 70.02; Table 2), with a signi®cant decrease of SADwithin the CLA group (P ˆ 0.003), while there was no mea-surable change in the placebo group (P ˆ 1.00). The mean decrease in SAD after CLA treatment was 0.6 cm. Waist The major ®nding in this randomised, controlled trial was circumference was not signi®cantly different after 4 weeks that CLA supplementation appeared to reduce abdominal compared to placebo (P ˆ 0.51). However, the CLA group adipose tissue in obese middle-aged men as indicated by a experienced a signi®cant mean decrease in waist circumfer- signi®cant decrease in SAD. It is possible that the decrease in ence with 1.4 cm (P ` 0.01), while in the placebo group the SAD represents a preferential loss of visceral fat.17±19,31,32 mean decrease (0.7 cm) was not signi®cant (P ˆ 0.08). WHR However, this assumption needs con®rmation by computed followed a similar pattern as waist circumference, with a tomography (CT) which is superior to SAD in the measure- signi®cant decrease only in the CLA group (P ` 0.01), ment of visceral fat. SAD is a valid measure of both intra- and although without difference between groups (P ˆ 0.20).
extra-abdominal fat,33 suggesting that CLA may have an Mean body weights were slightly decreased (non-signi®cant) effect on total abdominal adipose tissue. Within the CLA to a similar degree after CLA and placebo with 0.3 and 0.4 kg, group the decrease in abdominal fat was signi®cant for all respectively (data not shown) with no signi®cant difference measures of abdominal obesity, although there was no sta- between the groups (P ˆ 0.79). This pattern was also true for tistically signi®cant difference in changes of waist circum- BMI without any signi®cant mean difference between the ference or WHR between the two groups (Table 2). The absensce of any statistical changes or differences in BMIsuggests a reduction in abdominal fat rather independentof total obesity. The reduction of body fat as suggested by the decrease in SAD, is in concert with previous animal data that There were no signi®cant differences between groups in showed a reduced proportion of body fat after CLA treat- cardiovascular risk factors (Table 2). HDL was increased in ment.1±5 Moreover, the current ®nding is in agreement with both groups, signi®cantly for the placebo group only a recent controlled trial in healthy normal weight men and (P ` 0.01). Plasma glucose was also signi®cantly increased women.34 In that trial, the CLA-supplemented group experi- in both groups. No signi®cant changes were detected in enced reduced body fat, as measured by bioelectric impe- dance analysis and skinfold techniques.
Conjugated linoleic acid and abdominal obesity New data indicates that SAD has higher reliability (a lower results on CLA and lipolysis are in agreement with the intra-observer variation and a higher intra-class correlation) ®nding that CLA increased energy expenditure and fat as compared to other anthropometrics, independent of BMI.35 The high reliability and low degree of measurement Regarding, a possible thermogenic effect of CLA, skeletal error of SAD have been reported by others in a previous tissue analyses of uncoupling protein (UCP) gene expression study.36 To minimise measurement errors in the present trial, in prediabetic ZDF-rats have showed an increased brown there was a strong emphasis put on accurate assessment of adipose tissue UCP-2mRNA expression in CLA fed rats com- anthropometry, which was performed by one trained inves- pared to controls.49 This ®nding may also be related to the tigator in an identical fashion at both clinical examinations.
loss of body fat in animals. Interestingly, possible PPAR-g Previous studies that used CT, suggest that visceral fat is ligands such as CLA and thiazolidinediones have recently highly correlated to metabolic risk factors as compared to been reported to induce gene expression of UCP2 isoforms in other fat depots.37±40 However, in contrast to animal both skeletal muscle and adipose tissue.50 Moreover, there data,10,12,13 no differences between the groups in cardiovas- are also relevant data on the molecular level that give cular risk factors were detected in the present trial. If abdom- support to CLA as being a ligand of two isoforms of PPARs, inal fat decreases after CLA, one would expect some parallel both having important function in energy and adipose tissue improvements in fasting glucose and insulin levels, which metabolism. First, CLA is, in contrast to linoleic acid, a were not seen in the current study. In contrast, both plasma potent ligand and activator of peroxisome proliferator acti- glucose and insulin tended to rise slightly within both vating receptor alpha (PPAR-a),51,52 which pivotal role in groups. Because the increase in these variables occurred in obesity and lipid metabolism has been described in trans- both study groups it is dif®cult to evaluate the importance of genic mice,53 although the effects of PPAR-a activators on these ®ndings. DeLaney et al showed that CLA-fed mice human adipose tissue are still unknown.
experienced a rapid decrease in body fat accumulation (sig- Second, it was previously reported that CLA activates ni®cant after only 2 weeks of treatment), with the visceral PPAR-g response elements in vitro.10 Since PPAR-g genes depots being the most sensitive to CLA, which was accom- seem to regulate both metabolic functions and adipose panied by an increase in fasting insulin levels as compared to tissue development,54 it is interesting to note that the controls.41 They speculated that CLA may deteriorate pheri- mRNA levels of PPAR-g are subjected to regional variation pheral insulin dependent glucose disposal, as a consequence in adipose tissue,55 with different sensitivity to the fat-cell of increased lipolysis and fatty acid oxidation according to differentiation in response to PPAR-activators.56 In clinical the Randle glucose-fatty acid cycle,42 or by yet unknown trials, the PPAR-g agonist troglitazone was found to markedly decrease visceral fat in type 2 diabetic patients, withoutaffecting subcutaneous fat or BMI.57,58 Thus, it is temptingto speculate that the reduced SAD in the current trial might CLA and effects on adipose tissue Ð possible mechanisms be related to an effect of CLA on PPARs.
The mechanisms behind a possible fat reducing effect of CLA Some limitations of this study need to be adressed. First, are currently unknown, although there are some clues from the limited sample size does not exclude the possibility that in-vitro data and experimental animal models. Locally the observed decrease in SAD occurred by chance, although synthesized prostaglandins (PGs) may have antilipolytic we did calculate con®dence intervals to provide some com- effects in human adipose tissue.43 In vitro evidence have plementary information about the power of the study, there- indicated an inhibitory effect of CLA on PGE2 production,44 fore the ®ndings need to be con®rmed by CT measurements a prostaglandin with anti-lipolytic effects in vitro.45,46 Thus, in future studies. If CLA indeed has an affect on abdominal the modulation of PG production by CLA supplementation fat, it would be interesting to further study glucose and may contribute to increased lipolysis of adipose tissue. Park insulin metabolism after CLA administration. We are at et al suggested an enhanced noradrenaline-induced lipolysis present investigating the effect of CLA on obesity-related and hormone-sensitive lipase activity, with an accompany- insulin resistance in a larger trial which will provide informa- ing fatty acid oxidation in skeletal muscle, due to increased tion about the possible effect of CLA on glucose metabolism.
activity of carnitine palmitoyltransferase after CLA treat-ment.1 More recent data con®rm these in vitro effects ofCLA on lipolysis, lipoprotein lipase (LPL) activity and intra- cellular accretion of triglycerides and glycerol.47 It has been In conclusion, in men with marked abdominal visceral described that visceral fat cells in abdominally obese men obesity, CLA supplementation for 4 weeks may reduce seem to have a greater ability to mobilise fatty acids than abdominal fat as indicated by a signi®cant reduction in subcutaneous fat cells, in response to cathecholamines.14,48 SAD. However, many questions remain unanswered. The One might postulate that dietary CLA, as a possible inducer fact that the decrease in SAD occurred without concomitant of a cathecolamine-related lipolysis as shown in vitro by Park improvements in related metabolic variables also indicates et al,1 could cause a selective reduction of visceral fat, that the results of the current trial must be interpreted with indirectly measured as SAD in the present trial. The in vitro caution. Nevertheless, because abdominal obesity is a strong Conjugated linoleic acid and abdominal obesity risk factor these results are interesting, and further trials with 16 Smedman AEM, Gustafsson I-B, Berglund LGT, Vessby BOH.
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