2NIHR Clinical Research Network: Diabetes, Metabolic & Endocrine and Renal Disorders, Imperial College, London
3Department of Epidemiology & Prevention, Wake Forest University Health Sciences, Winston-Salem, North Carolina, US
4Department of Health and Human Sciences, London Metropolitan University, London, UK
5Institut für Bewegungs- und Arbeitsmedizin, Universitätsklinikum Freiburg, Germany
6Department of Nutrition, Institut für Sport und Sportwissenschaft, Universität Freiburg, Germany
7Medizinische Fakultät der Universität Freiburg, Germany
Methods: This study was a secondary analysis of data collected from a randomized controlled trial, conducted in 90 overweight adults (age: 47.5 ± 7.5 yrs.; BMI: 31.5 ± 2.3 kg/m2) who were followed over a 24-week control period. Changes in leptin levels were quantified to determine the influence of age, gender, leptin baseline levels, weight loss and intervention type. Participants were randomized into 3 interventions groups: 1) therapeutic lifestyle changes, (LS); 2) standardized meal replacement (Almased®) (MR); and 3) standardized meal replacement accompanied by supervised physical training (MRPT). For the analyses, both diet groups (MR, MRPT) were pooled into one common group and compared to the LS group in a parallel two-group study design with endpoint assessment after 24 weeks of intervention.
Results: In total, 83 participants completed the 24-week study. Significant improvements in body composition and metabolic regulation occurred in all intervention participants regardless of their group assignment (LS; MR, MRPT). Participants' consumption of the meal replacement (MR; MRPT) had an independent, significant effect on serum leptin levels (-15.5 ± 7.5 and -12.5 ± 7.8 vs. -8.7 ± 6.1 ng/ml). Greater body weight reductions were also observed in the diet groups (-8.9 ± 3.9 kg) compared to the LS group (-6.2 ± 4.2 kg). Conclusions our findings suggest that meal replacement can safely and effectively produce significant weight loss, which may be in part due to a reduction in plasma leptin levels. ClinicalTrials.gov Identifier: NCT00356785
Keywords: Leptin; Meal Replacement; Energy Metabolism; High Protein Diet; Weight Regulation;
Serum leptin levels may have a potential role in the prediction of weight loss and weight-loss maintenance [7]. Serum leptin levels may influence weight loss and weight-loss maintenance through lifestyle changes in overweight adults [8, 9]. Leptin, as a circulating adipokine, is a regulatory factor for food intake, energy expenditure and body fat distribution. Leptin also participates in a signalling system regulating the amount of adipose energy stored in the brain [5]. In addition, leptin resistance may be responsible, in part, for the development of obesity among the aging population [10].
Appropriate intervention strategies to reverse body weight gain and elevated body fat, respectively, are still a matter of debate because additional metabolic and endocrine effects may influence the course and outcomes of the weight loss process [11]. According to several studies, a high-protein, low-glycaemic diet may influence leptin regulation and weight management [11- 13]. For this reason, a subgroup analysis was performed on the data collected from an intervention study to examine the effects of a protein-rich meal replacement on the body composition and metabolic conditions of overweight adults.
For the main trial, participants were randomized into 3 intervention groups: 1) therapeutic lifestyle changes: LS; 2) standardized meal replacement (Almased ®), MR; and 3) standardized meal replacement accompanied with supervised exercise/physical training (MRPT). All participants completed a comprehensive medical examination before and after the intervention, including body composition analysis by air displacement plethysmography (Bod Pod®) [14] and laboratory investigations, i.e., blood glucose, insulin, plasma lipids, inflammatory markers (h-CRP, IL6) and leptin [11].
For this investigation, we analysed leptin and insulin changes to determine the effects of age, gender, baseline level, weight loss, and intervention type. In this analysis, the effects of the therapeutic lifestyle vs. diet with and without supervised exercise interventions on the selected laboratory criteria were evaluated. We also evaluated the change from baseline to the end of intervention at the 24-week visit.
All volunteers were interviewed and screened before participating in this study at the Department of Sports Medicine of the Freiburg University hospital. The study was conducted in accordance with the Declaration of Helsinki guidelines. All procedures involving human subjects were approved by the Ethics Commission of Freiburg University (EK-Freiburg No. 230/01) and registered as a controlled clinical trial (ClinicalTrials. gov Identifier: NCT00356785). All participants provided written informed consent. The clinical trial was designed and performed according to an approved, published protocol [11].
The results are expressed as the means ± Standard Deviations [SD] for all parameters. Descriptive, multivariable analyses were performed to evaluate the changes from baseline using the exact Mann-Whitney test and the ANOVA test. For each participant, complete data sets were available in Microsoft® Excel XP spreadsheets. Significance was defined as p < 0.05 (Two-Way). All analyses were performed using SPSS version 18.02.
Therefore, for this secondary data analysis, both meal replacement groups using the meal replacement formula were merged into a single group (MR/MRPT) and compared to the lifestyle group (LS) with endpoint assessment after 24 weeks of intervention (Table 2). At baseline, all demographic, clinical and laboratory variables were not different between groups. Independent of the intervention (LS vs. MR/MRPT), the 83 patients who completed the study had significant improvements in body composition and metabolic regulation (Table 2). The MR and MRPT groups experienced changes in body weight (BW -8.9 ± 3.9 kg) (independent of training) and had significantly greater weight reductions compared to the LS group (-6.2 ± 4.2 kg).
We also detected significant differences from baseline in fat mass, serum leptin levels, and insulin between the interventions (Table 2). Even after adjusting for weight loss differences, participants in the MR/MRPT group showed significantly larger reductions in serum leptin levels (-13.9 ng/ml) compared with participants in the LS group (-9.8 ng/ml) post-intervention. This effect was not observed for insulin.
In 2003, for the first time, a team at Freiburg University published their findings regarding the positive effects of a soyyoghurt- honey-based meal replacement product (Almased®) on weight reduction and the regulation of insulin and leptin [11]. According to this randomized controlled trial, insulin and leptin levels decreased more in participants using the meal replacement compared to participants receiving lifestyle group counselling. In the current study, we conducted a secondary analysis of the first 24-weeks of intervention by merging the data of the MR and MRPT groups. The main trial findings were published in 2003 and indicated the beneficial effects of the meal replacement formula on reductions in leptin and insulin levels. These results were confirmed by our secondary analyses.
When the leptin results were adjusted for age, gender, baseline leptin level, body weight change, and intervention type (LS vs. MR/MRPT), the meal replacement approach clearly had an independent effect on plasma leptin levels and improved the effects on leptin reduction caused by weight loss. Therefore, the results suggest a relationship between protein intake and leptin regulation in the overweight adults examined. Several studies have demonstrated that an increase in the
Biochemical parameter |
Before |
MR group |
p -valuea |
Before |
MRPT group |
p -valuea |
p -valueb |
After |
After |
||||||
Total cholesterol (mg/dl) |
225 ±30.4 |
196±23.1 |
0.000 |
221±34.8 |
198±32.6 |
0.000 |
0.396 |
HDL-cholesterol (mg/dl) |
59±14.1 |
52±10.4 |
0.003 |
59±14.0 |
54±15.6 |
0.002 |
0.763 |
LDL-cholesterol (mg/dl) |
128±25.6 |
114±15.2 |
0.003 |
127±29.2 |
112±26.3 |
0.000 |
0.897 |
Apo B (mg/dl) |
119±20.9 |
101±16.2 |
0.000 |
115±27.4 |
92.5±25.5 |
0.000 |
0.085 |
Leptin (ng/dl) |
37.9±26.7 |
22.5±13.9 |
0.000 |
33.9±24.2 |
21.3±16.3 |
0.000 |
0.226 |
Insulin ( |
11.7±8.92 |
6.3±3.97 |
0.003 |
13.8±11.35 |
7.8±5.90 |
0.001 |
0.139 |
Glucose (mg/dl) |
92±9.4 |
90.0±9.1 |
0.226 |
98±14.4 |
91.0±10.5 |
0.000 |
0.260 |
aFor changes before–after
bFor differences in changes between the groups
LS (n=28) Pre RCT |
MR/MRPT(n=55) Pre RCT |
LS (n=28) Post RCT |
MR/MRPT (n=55) Post RCT |
||
Body Weight (kg) |
91.2±11.6
|
90.2±11.3 |
84.9±10.8 c / y |
81.8±11.7 c / y |
|
Fat Mass (kg) |
36.9±6.27 |
36.2±6.38 |
30.4±7.60 c / x |
26.8±7.80 c / x |
|
Triglyceride |
127±68.4 |
143±66.0 |
137±55.2 - |
133±71.9 - |
|
(mg/dl) |
|||||
Apolipoprotein B |
115±20.3 |
117±23.9 |
105±20.9 - /c |
97±21.6 c / x |
|
(mg/dl) |
|||||
Fasting Blood Sugar |
95±14.1 |
95±12.2 |
90±9.9
a / - |
90±9.8
c / - |
|
(mg/dl) |
|||||
Insulin (µU/ml) |
8.8±3.92 |
12.7±10.1 |
7.4±3.98 - / y |
7.1±5.02 c / y |
|
HOMA- Index (U) |
2.2±1.26 |
3.1±2.65 |
1.7±1.00 - / y |
1.6±1.17 c / y |
|
Leptin (ng/ml) |
37±29.2 |
36±25.4 |
28±20.7 b / y |
22±15.0 c / y |
|
Interleukin-6 |
1.8±1.25 |
2.2±2.05 |
1.8±2.30 - |
1.7±1.29 a |
|
(pg/ml) |
|
||||
hs-CRP (mg/dl) |
0.27±0.22 |
0.30±0.28 |
0.23±0.16 - |
0.19±0.17 c |
Recent studies have shown that meal replacement regimens are safe and associated with greater weight loss than individualized diet plans [22, 23]. A meal replacement regimen high in soy protein may be more effective at improving body weight and body composition and reducing associated cardio-metabolic risk factors, such as insulin, leptin, endothelial function and anthropometric measures compared to lifestyle interventions (e.g., fat restricting low calorie diets and increased physical activity) [11, 24, 25]. When the meal replacement formula was consumed, significant changes occurred in metabolic and inflammatory markers (compared to baseline). As a soy and milk protein-based product, the meal replacement used in this study had an energy-sparing effect and may also have potential additional health benefits [26]. Soy proteins have been noted to improve receptor-mediated transport of insulin and leptin through the blood brain barrier and are responsible for an increased effect of these hormones in the hypothalamus. This effect not only impacts appetite regulation but may also impact peripheral insulin and leptin resistance in obese participants [27-30]. These effects may be mediated by isoflavones and attributable peptides, which exhibit a variety of biological and molecular activities [20,25].Soy isoflavones are involved in the regulation of enzymes and proteins important for lipid metabolism [31, 32]. The effects of soy protein on gene expression or the regulation of nuclear transcription factors might also, at least in part, be able to account for the alterations observed in insulin and leptin [33, 34]. Therefore, isoflavones and biologically active peptides in this meal replacement product [20] may account for some of the beneficial effects identified in this study. Specifically, we observed a reduction in body fat mass and hepatic fat accumulation, in addition to improved fatty acid metabolism, which led to lower plasma lipid levels and inflammatory markers and decreased insulin resistance [33].
- Andreyeva T, Puhl RM, Brownell KD. Changes in perceived weight discrimination among Americans, 1995-1996 through 2004-2006. Obesity (Silver Spring). 2008;16(5):1129-1134. doi: 10.1038/oby.2008.35
- Puhl RM, Andreyeva T, Brownell KD. Perceptions of weight discrimination: prevalence and comparison to race and gender discrimination in America. Int J Obes. 2008;32(6):992-1000. doi: 10.1038/ijo.2008.22.
- Nguyen DM, El-Serag HB. The epidemiology of obesity. Gastroenterol Clin North Am. 2010;39(1):1-7. doi: 10.1016/j.gtc.2009.12.014
- Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286(10):1195-1200.
- Jequier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002;967:379-388.
- Vasselli JR, Scarpace, PJ, Harris, RB, Banks WA. Dietary components in the development of leptin resistance. Adv Nutr. 2013;4(2):164-175. doi: 10.3945/an.112.003152
- Weigle DS, Breen PA, Matthys CC, Callahan HS, Meeuws KE, Burden VR, et al. A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations. Am J Clin Nutr. 2005;82(1):41-48.
- Wang P, Holst C, Andersen MR, Astrup A, Bouwman FG, van Otterdijk S, et al. Blood profile of proteins and steroid hormones predicts weight change after weight loss with interactions of dietary protein level and glycemic index. PLoS One. 2011;6(2):e16773. doi: 10.1371/journal.pone.0016773.
- Crujeiras AB, Goyenechea E, Abete I, Lage M, Carreira MC, Martinez JA, et al. Weight gain after diet induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels. J Clin Endocrinol Metab. 2010;95(11):5037-5044. doi: 10.1210/jc.2009-2566.
- . Carter S, Caron A, Richard D, Picard F. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging. 2013;8:829-844. doi: 10.2147/CIA.S36367.
- Berg A, Frey I, Deibert P, Landmann U, Koenig D, Schmidt-Trucksäss A, et al. Weight loss is possible: half-year results of a clinically controlled, randomized intervention study with obese adults. Ernaehrungs-Umschau 2004;28:1349-1352.
- Deibert P, König D, Schmidt-Trucksaess A, Zaenker KS, Frey I, Landmann U, et al. Weight loss without losing muscle mass in pre-obese and obese subjects induced by a high-soy-protein diet. Int J Obes Relat Metab Disord. 2004;28:1349-1352. doi:10.1038/sj.ijo.0802765.
- Larsen TM, Dalskov SM, van Baak M, Jebb SA, Papadaki A, Pfeiffer AF, et al. Diets with high or low protein content and glycemic index for weight-loss maintenance. N Engl J Med. 2010;363(22):2102-13. doi: 10.1056/NEJMoa1007137.
- McCrory MA, Gomez TD, Bernauer EM, Mole PA. Evaluation of a new air displacement plethysmograph for measuring human body composition. Med Sci Sports Exerc. 1995;27(12):1686-1691.
- Rolls BJ, Hetherington M, Burley VJ. The specificity of satiety: the influence of foods of different macronutrient content on the development of satiety. Physiol Behav. 1988;42(2):145-153.
- . Deibert P, König D, Vitolins MZ, Landmann U, Frey I, Zahradnik HP, et al. (2007). Effect of a weight loss intervention on anthropometric measures and metabolic risk factors in pre-versus postmenopausal women. Nutr J. 2007;6:31. DOI:10.1186/1475-2891-6-31
- Brand-Miller JC, Holt SH, Pawlak DB, McMillan J. Glycemic index and obesity. Am J Clin Nutr. 2002;76(1):281S-285S.
- . Miller M, Beach V, Sorkin JD, Mangano C, Dobmeier C, Novacic D, et al. Comparative effects of three popular diets on lipids, endothelial function, and C-reactive protein during weight maintenance. J Am Diet Assoc. 2009;109(4):713-717. doi: 10.1016/j.jada.2008.12.023.
- Skov AR, Toubro S, Ronn B, Holm L, Astrup A. Randomized trial on protein vs carbohydrate in ad libitum fat reduced diet for the treatment of obesity. Int J Obes Relat Metab Disord. 1999;23(5):528-536.
- Singh BP, Vij S, Hati S. Functional significance of bioactive peptides derived from soybean. Peptides 2014;54:171–179. doi:http://dx.doi.org/10.1016/j.peptides.2014.01.022
- Berg A, Frey I, Landmann U, Deibert P, König D, Berg A, et al. Gewichtsreduktion durch Lebensstilintervention: Einjahresergebnisse einer klinisch kontrollierten, randomisierten studie mit übergewichtigen Erwachsenen. Ernährungs-Umschau 2005;52:310-314.
- . Noakes M, Foster PR, Keogh JB, Clifton PM. Meal replacements are as effective as structured weight-loss diets for treating obesity in adults with features of metabolic syndrome. J Nutr. 2004;134(8):1894-1899.
- Heymsfield SB, Mierlo CA, Knaap HC, Heo M, Frier HI. Weight management using a meal replacement strategy: meta and pooling analysis from six studies. Int J Obes Relat Metab Disord. 2003;27(5):537-549. DOI:10.1038/sj.ijo.0802258
- Berg A, König D, Deibert P, Frey I. Favorable metabolic properties of a soy-honey-yoghurt product for meal replacement in overweight subjects with atherogenic risk. Atherosclerosis Supp. 2008;9(1):253. DOI: http://dx.doi.org/10.1016/S1567-5688(08)71015-8
- Jang EH, Moon JS, Ko JH, Ahn CW, Lee HH, Shin JK, et al. Novel black soy peptides with antiobesity effects: activation of leptin-like signaling and AMP-activated protein kinase. Int J Obes. 2008;32(7):1161-1170. doi: 10.1038/ijo.2008.60.
- Gonzalez de Mejia E, Vasconez M, de Lumen BO, Nelson R. Lunasin concentration in different soybean genotypes, commercial soy protein, and isoflavone products. J Agric Food Chem. 2004;52(19):5882-5887. DOI:10.1021/jf0496752
- . Banks WA. The blood-brain barrier as a cause of obesity. Curr Pharm Des. 2008;14(16):1606-1614.
- Popescu BO, Toescu EC, Popescu LM, Bajenaru O, Muresanu DF, Schultzberg MN, et al. Blood-brain barrier alterations in aging and dementia. J Neurol Sci. 2009;283(1-2):99-106. doi: 10.1016/j.jns.2009.02.321
- . Flores MB, Fernandes MF, Ropelle ER, Faria MC, Ueno M, Velloso LA, et al. Exercise Improves insulin and leptin sensitivity in the hypothalamus of Wistar rats. Diabetes 2006;55(9):2554-2561. DOI:10.2337/db05-1622
- Deibert P, Solleder F, König D, Vitolins MZ, Dickhuth HH, Gollhofer A, et al. Soy protein based supplementation supports metabolic effects of resistance training in untrained middle aged males. Aging Male 2011;14(4):273-279. doi: 10.3109/13685538.2011.565091.
- Demonty I, Lamarche B, Deshaies Y, Jacques H. Role of soy isoflavones in the hypotriglyceridemic effect of soy protein in the rat. J Nutr Biochem. 2002;13(11):671-677.
- Wang Y, Jones PJ, Ausman LM, Lichtenstein AH. Soy protein reduces triglyceride levels and triglyceride fatty acid fractional synthesis rate in hypercholesterolemic subjects. Atherosclerosis. 2004;173(2):269-75. DOI:10.1016/j.atherosclerosis.2003.12.015
- Velasquez MT, Bhathena SJ. Role of dietary soy protein in obesity. Int J Med Sci. 2007;4(2):72-82.
- Udenigwe CC, Aluko RE. Food protein-derived bioactive peptides: production, processing, and potential health benefits. J Food Sci. 2012;77(1):R11-24. doi: 10.1111/j.1750-3841.2011.02455.x