Effect of Conjugated Linoleic Acid on Leptin Level: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

The results of human clinical trials examining the effects of conjugated linoleic acid (CLA) on leptin concentration are inconsistent. Our objective was to elucidate the role of conjugated linoleic acid supplementation on leptin through a systematic review and a meta-analysis of available randomized placebo-controlled trials (RCTs). We searched the PubMed, SCOPUS, and ISI web of science up to February2017, in English, to identify RCTs investigating the effect of CLA supplements on plasma leptin concentrations. Weighted mean differences (WMDs) and their respective 95% confidence intervals (CIs) were calculated to assess the efficacy of CLA on leptin concentration by using random effects. Statistical heterogeneity, study quality, meta-regression and publication bias were used based on standard methods. Nineteen RCTs (comprising 26 treatment arms) with 1045 subjects were included in this meta-analysis. Random-effect meta-analysis found a slight but not significant reduction in plasma leptin concentrations (WMD: –0.38 ng/ml, 95% CI: –1.08, 0.32, p=0.286); I²=53.24%, p=0.001), following CLA supplementation. The pooled effect size was robust and remained non-significant in the leave-one-out sensitivity analysis. Subgroup analysis based on BMI status showed that the CLA supplementation significantly reduces leptin when used for obese subjects (WMD: –1.47 ng/ml, 95% CI: –2.15, –0.79, p<0.001) and in the subset of trials lasting<24 weeks of duration (WMD: –0.76 ng/ml, 95% CI: –1.40, –0.12, p=0.019). CLA supplementation might moderately decrease circulatory leptin levels only among obese adults for shorter than 24 weeks. Additional high-quality studies are needed to replicate our results.

Key words

adipokine - fatty acid - randomization - adipose tissue

• References

• 1 MacRedmond R, Singhera G, Attridge S, Bahzad M, Fava C, Lai Y, Hallstrand TS, Dorscheid DR. Conjugated linoleic acid improves airway hyper-reactivity in overweight mild asthmatics. Clin Exp Allergy 2010; 40: 1071-1078
• 2 Colakoglu S, Colakoglu M, Taneli F, Cetinoz F, Turkmen M. Cumulative effects of conjugated linoleic acid and exercise on endurance development, body composition, serum leptin and insulin levels. J Sports Med Phys Fitness 2006; 46: 570-577
• 3 Wallace RJ, McKain N, Shingfield KJ, Devillard E. Isomers of conjugated linoleic acids are synthesized via different mechanisms in ruminal digesta and bacteria. J Lipid Res 2007; 48: 2247-2254
• 4 Lopez-Plaza B, Bermejo LM, Koester Weber T, Parra P, Serra F, Hernández M, Palma Milla S, Gómez-Candela C. Effects of milk supplementation with conjugated linoleic acid on weight control and body composition in healthy overweight people. Nutr Hosp 2013; 28: 2090-2098
• 5 Park Y, Albright KJ, Liu W, Storkson JM, Cook ME, Pariza MW. Effect of conjugated linoleic acid on body composition in mice. Lipids 1997; 32: 853-858
• 6 Kelley NS, Hubbard NE, Erickson KL. Conjugated linoleic acid isomers and cancer. J Nutr 2007; 137: 2599-2607
• 7 Lee KN, Kritchevsky D, Pariza MW. Conjugated linoleic acid and atherosclerosis in rabbits. Atherosclerosis 1994; 108: 19-25
• 8 O'Shea M, Bassaganya-Riera J, Mohede IC. Immunomodulatory properties of conjugated linoleic acid. Am J Clin Nutr 2004; 79 6 Suppl 1199S-1206S
• 9 Ryder JW, Portocarrero CP, Song XM, Yu M, Combatsiaris T, Galuska D, Bauman DE, Barbano DM, Charron MJ, Zierath JR, Houseknecht KL. Isomer-specific antidiabetic properties of conjugated linoleic acid. Improved glucose tolerance, skeletal muscle insulin action, and UCP-2 gene expression. Diabetes 2001; 50: 1149-1157
• 10 Raff M, Tholstrup T, Sejrsen K, Straarup EM, Wiinberg N. Diets rich in conjugated linoleic acid and vaccenic acid have no effect on blood pressure and isobaric arterial elasticity in healthy young men. J Nutr 2006; 136: 992-997
• 11 Herrera JA, Arevalo-Herrera M, Shahabuddin AK, Ersheng G, Herrera S, Garcia RG, López-Jaramillo P. Calcium and conjugated linoleic acid reduces pregnancy-induced hypertension and decreases intracellular calcium in lymphocytes. Am J Hypertens 2006; 19: 381-387
• 12 Nagao K, Inoue N, Wang YM, Yanagita T. Conjugated linoleic acid enhances plasma adiponectin level and alleviates hyperinsulinemia and hypertension in Zucker diabetic fatty (fa/fa) rats. Biochem Biophys Res Commun 2003; 310: 562-566
• 13 Nagao K, Inoue N, Wang YM, Hirata J, Shimada Y, Nagao T, Matsui T, Yanagita T. The 10trans,12cis isomer of conjugated linoleic acid suppresses the development of hypertension in Otsuka Long-Evans Tokushima fatty rats. Biochem Biophy Res Commun 2003; 306: 134-138
• 14 West DB, Delany JP, Camet PM, Blohm F, Truett AA, Scimeca J. Effects of conjugated linoleic acid on body fat and energy metabolism in the mouse. Am J Physiol 1998; 275 3 Pt 2 R667-R672
• 15 Takahashi Y, Kushiro M, Shinohara K, Ide T. Dietary conjugated linoleic acid reduces body fat mass and affects gene expression of proteins regulating energy metabolism in mice. Comp Biochem Physiol B Biochem Mol Biol 2002; 133: 395-404
• 16 Wang Y, Jones PJ. Dietary conjugated linoleic acid and body composition. Am J Clin Nutr 2004; 79 6 Suppl 1153S-1158S
• 17 Weiss ST. Obesity: insight into the origins of asthma. Nat Immunol 2005; 6: 537-539
• 18 Brown JM, Boysen MS, Jensen SS, Morrison RF, Storkson J, Lea-Currie R, Pariza M, Mandrup S, McIntosh MK. Isomer-specific regulation of metabolism and PPARgamma signaling by CLA in human preadipocytes. J lipid Res 2003; 44: 1287-1300
• 19 Baddini Feitoza A, Fernandes Pereira A, Ferreira da Costa N, Goncalves Ribeiro B. Conjugated linoleic acid (CLA): Effect modulation of body composition and lipid profile. Nutr Hosp 2009; 24: 422-428
• 20 Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543-546
• 21 Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O'Doherty R, Newgard CB, Unger RH. Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci U S A 1996; 93: 14795-14799
• 22 Medina EA, Horn WF, Keim NL, Havel PJ, Benito P, Kelley DS, Nelson GJ, Erickson KL. Conjugated linoleic acid supplementation in humans: Effects on circulating leptin concentrations and appetite. Lipids 2000; 35: 783-788
• 23 Sabogal JC, Munoz L. Leptin in obstetrics and gynecology: A review. Obstet Gynecol Surv 2001; 56: 225-230
• 24 Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes 1996; 45: 1435-1438
• 25 Mantzoros CS, Flier JS. Editorial: leptin as a therapeutic agent–trials and tribulations. J Clin Endocrinol Metab 2000; 85: 4000-4002
• 26 Bulut S, Bodur E, Colak R, Turnagol H. Effects of conjugated linoleic acid supplementation and exercise on post-heparin lipoprotein lipase, butyrylcholinesterase, blood lipid profile and glucose metabolism in young men. Chem Biol Interac 2013; 203: 323-329
• 27 Desroches S, Chouinard PY, Galibois I, Corneau L, Delisle J, Lamarche B, Couture P, Bergeron N. Lack of effect of dietary conjugated linoleic acids naturally incorporated into butter on the lipid profile and body composition of overweight and obese men. Am J Clin Nutr 2005; 82: 309-319
• 28 Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4: 1
• 29 Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17: 1-12
• 30 Moher D, Cook D, Jadad A, Tugwell P, Moher M, Jones A, Pham B, Klassen TP. Assessing the quality of reports of randomised trials: Implications for the conduct of meta-analyses. Health Technol Assess (Winchester, England) 1999; 3: i
• 31 Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions. New York: Wiley Online Library; 2008
• 32 Duval S, Tweedie R. Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56: 455-463
• 33 Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive meta-analysis version 2. Englewood, NJ: Biostat; 2005: 104
• 34 Colakoglu S, Colakoglu M, Taneli F, Cetinoz F, Turkmen M. Cumulative effects of conjugated linoleic acid and exercise on endurance development, body composition, serum leptin and insulin levels. J Sports Med Phys Fitness 2006; 46: 570-577
• 35 Desroches S, Chouinard PY, Galibois I, Corneau L, Delisle J, Lamarche B, Couture P, Bergeron N. Lack of effect of dietary conjugated linoleic acids naturally incorporated into butter on the lipid profile and body composition of overweight and obese men. Am J Clin Nutr 2005; 82: 309-319
• 36 Gaullier JM, Halse J, Hoye K, Corneau L, Delisle J, Lamarche B, Couture P, Bergeron N. Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr 2005; 135: 778-784
• 37 Kuhnt K, Kraft J, Vogelsang H, Eder K, Kratzsch J, Jahreis G. Dietary supplementation with trans-11- and trans-12-18 : 1 increases cis-9, trans-11-conjugated linoleic acid in human immune cells, but without effects on biomarkers of immune function and inflammation. Br J Nutr 2007; 97: 1196-1205
• 38 MacRedmond R, Singhera G, Attridge S, Bahzad M, Fava C, Lai Y, Hallstrand TS, Dorscheid DR. Conjugated linoleic acid improves airway hyper-reactivity in overweight mild asthmatics. Clin Expl Allergy 2010; 40: 1071-1078
• 39 Medina EA, Horn WF, Keim NL, Havel PJ, Benito P, Kelley DS, Nelson GJ, Erickson KL. Conjugated linoleic acid supplementation humans: Effects on circulating leptin concentrations and appetite. Lipids 2000; 35: 783-788
• 40 Nazare JA, de la Perrière AB, Bonnet F, Desage M, Peyrat J, Maitrepierre C, Louche-Pelissier C, Bruzeau J, Goudable J, Lassel T, Vidal H, Laville M. Daily intake of conjugated linoleic acid-enriched yoghurts: Effects on energy metabolism and adipose tissue gene expression in healthy subjects. Br J Nutr 2007; 97: 273-280
• 41 Norris LE, Collene AL, Asp ML, Hsu JC, Liu LF, Richardson JR, Li D, Bell D, Osei K, Jackson RD, Belury MA. Comparison of dietary conjugated linoleic acid with safflower oil on body composition in obese postmenopausal women with type 2 diabetes mellitus. Am J Clinl Nutr 2009; 90: 468-476
• 42 Petridou A, Mougios V, Sagredos A. Supplementation with CLA: Isomer incorporation into serum lipids and effect on body fat of women. Lipids 2003; 38: 805-811
• 43 Riserus U, Arner P, Brismar K, Vessby B. Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. J Diabetes 2002; 25: 1516-1521
• 44 Shadman Z, Taleban FA, Saadat N, Hedayati M. Effect of conjugated linoleic acid and vitamin E on glycemic control, body composition, and inflammatory markers in overweight type2 diabetics. J Diabetes Metab Disord 2013; 12: 42
• 45 Syvertsen C, Halse J, Hoivik HO, Gaullier JM, Nurminiemi M, Kristiansen K, Einerhand A, O'Shea M, Gudmundsen O. The effect of 6 months supplementation with conjugated linoleic acid on insulin resistance in overweight and obese. Int J Obes 2007; 31: 1148-1154
• 46 Zhao WS, Zhai JJ, Wang YH, Xie PS, Yin XJ, Li LX, Cheng KL. Conjugated linoleic acid supplementation enhances antihypertensive effect of ramipril in chinese patients with obesity-related hypertension. Am J Hypertens 2009; 22: 680-686
• 47 López-Plaza B, Bermejo LM, Koester Weber T, Parra P, Serra F, Hernández M, Palma Milla S, Gómez-Candela C. Effects of milk supplementation with conjugated linoleic acid on weight control and body composition in healthy overweight people. Nutr Hosp 2013; 28: 2090-2098
• 48 Iwata T, Kamegai T, Yamauchi-Sato Y, Ogawa A, Kasai M, Aoyama T, Kondo K. Safety of dietary conjugated linoleic acid (CLA) in a 12-weeks trial in healthy overweight Japanese male volunteers. J Oleo Sci 2007; 56: 517-525
• 49 Taylor JS, Williams SR, Rhys R, James P, Frenneaux MP. Conjugated linoleic acid impairs endothelial function. Arterioscler Thromb Vas Biol 2006; 26: 307-312
• 50 Watras A, Buchholz A, Close R, Zhang Z, Schoeller D. The role of conjugated linoleic acid in reducing body fat and preventing holiday weight gain. Int J Obes 2007; 31: 481-487
• 51 Zhao WS, Zhai JJ, Wang YH, Xie PS, Yin XJ, Li LX, Cheng KL. Conjugated linoleic acid supplementation enhances antihypertensive effect of ramipril in Chinese patients with obesity-related hypertension. Am J Hypertens 2009; 22: 680-686
• 52 Syvertsen C, Halse J, Hoivik HO, Gaullier JM, Nurminiemi M, Kristiansen K, Einerhand A, O'Shea M, Gudmundsen O. The effect of 6 months supplementation with conjugated linoleic acid on insulin resistance in overweight and obese. Int J Obes 2007; 31: 1148-1154
• 53 Norris LE, Collene AL, Asp ML, Hsu JC, Liu LF, Richardson JR, Li D, Bell D, Osei K, Jackson RD, Belury MA. Comparison of dietary conjugated linoleic acid with safflower oil on body composition in obese postmenopausal women with type 2 diabetes mellitus. Am J Clin Nutri 2009; 90: 468-476
• 54 Taylor JS, Williams SR, Rhys R, James P, Frenneaux MP. Conjugated linoleic acid impairs endothelial function. Arterioscl Throm Vasc Biol 2006; 26: 307-312
• 55 Zhang B, Graziano MP, Doebber TW, Leibowitz MD, White-Carrington S, Szalkowski DM, Hey PJ, Wu M, Cullinan CA, Bailey P, Lollmann B, Frederich R, Flier JS, Strader CD, Smith RG. Down-regulation of the expression of the obese gene by an antidiabetic thiazolidinedione in Zucker diabetic fatty rats and db/db mice. J Biol Chem 1996; 271: 9455-9459
• 56 Changhua L, Jindong Y, Defa L, Lidan Z, Shiyan Q, Jianjun X. Conjugated linoleic acid attenuates the production and gene expression of proinflammatory cytokines in weaned pigs challenged with lipopolysaccharide. The J Nutr 2005; 135: 239-244
• 57 Nazare JA, de la Perriere AB, Bonnet F, Desage M, Peyrat J, Maitrepierre C, Louche-Pelissier C, Bruzeau J, Goudable J, Lassel T, Vidal H, Laville M. Daily intake of conjugated linoleic acid-enriched yoghurts: Effects on energy metabolism and adipose tissue gene expression in healthy subjects. Br J Nutr 2007; 97: 273-280
• 58 Havel PJ, Kasim-Karakas S, Mueller W, Johnson PR, Gingerich RL, Stern JS. Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: Effects of dietary fat content and sustained weight loss. J Clin Endocrinol Metab 1996; 81: 4406-4413