A micellar formulation of coenzyme Q10 and α-lipoic acid may be a useful aid in weight reduction programs Overweight and obesity affect about half of the adult population in Germany and increase the risk for comorbidities. A promising approach to treat obesity is to regulate the food intake, and thus body weight, by targeting the hypothalamus. Adenosine monophosphate-activated protein kinase (AMPK) plays a central role in this mechanism. Therefore, suppression of the hypothalamic AMPK is a potential mechanism for enhancing satiety and decreasing food intake. α-lipoic acid (ALA) inhibits the hypothalamic AMPK and therefore delays the hunger sensation. By increasing the muscular AMPK, ALA promotes energy expenditure. In the respiratory chain, coenzyme Q10 is directly involved in electron transport and cellular energy generation. Therefore, the combination of ALA and coenzyme Q10 may represent an interesting approach. In this randomized, double-blind, placebo-controlled parallel human intervention trial, the effects of daily intake of 90 mg coenzyme Q10 und 100 mg α-lipoic acid were investigated in comparison to a placebo. Twenty-two overweight adults (BMI 27-33 kg/m 2 ) with no severe pre-existing diseases participated in the study. Over the course of 12 weeks, participants received regular nutritional counselling aimed at reducing body weight. Body weight, body composition (using bioelectric impedance analysis; BIA), and waist and hip circumference were measured regularly. Food intake was monitored prospectively using 3-day food records and the perceived satiety was documented using a visual analogue scale. During the intervention, participants reduced their energy intake, which resulted in an average weight reduction by 2.7±3.7 kg in the verum group and 1.2±3.3 kg in the placebo group. The weekly weight reduction in the verum group (0.220 kg/wk) was significantly different from the placebo group (0.094 kg/wk, p<0.05). The ratio of the fasting insulin and fasting blood glucose concentrations (HOMA-index) improved in the verum group as well. In the verum group, the HOMA-index improved from 2.4±1.2 (µu*dl)/(mg/ml) to 1.5±1.0 (µu*dl)/(mg/ml) with statistical significance (p=0.012 No significant improvement of the HOMA-index was found in the placebo group (from 3.0±1.3 (µu*dl)/(mg/ml) to 2.5±1.2 (µu*dl)/(mg/ml)). Follow-up studies should deal with the conditions under which hepatic insulin resistance (HOMA index) and weight reduction, as seen in the first part of the study, can be improved by a combined intake of coenzyme Q10 and α-lipoic acid.
Introduction Overweight is the most common consequence of inadequate nutrition in industrialized countries, which in turn increases the risk for comorbidities. In Germany, nearly half of the adult population is overweight or obese [Mikrozensus Gesundheit; 2009]. Overweight and obesity result from a permanently higher intake of energy compared to energy expenditure. In spite of the large number of available therapeutic and preventive strategies, the prevalence of obesity increases worldwide. Therefore, the search for new approaches to fight this epidemic is of great importance. In addition to a reduction in energy intake, increasing energy expenditure is another possible way to reduce body weight. Targeting the hypothalamus may be a promising approach to control food intake (and thus body weight). In the centre of this mechanism of action lies the adenosine monophosphate-activated protein kinase (AMPK) [Lee WJ et al.; 2005], a key regulator of glucose and lipid metabolism. AMPK is activated when cellular energy stores decline. This causes glucose uptake by muscle cells and an enhanced fatty acid oxidation. In the hypothalamus, AMPK is involved in the regulation of food intake. For this reason, suppression of hypothalamic AMPK is a possible mechanism to increase satiety, resulting in reduced food intake [Kahn BB et al.; 2005). α-lipoic acid (ALA, 1,2-dithiolan-3-pentanoic acid or thioctic acid) is a lipophilic antioxidant, which influences energy metabolism via AMPK. ALA inhibits hypothalamic AMPK and may thereby delay the sensation of hunger. By increasing the muscular AMPK, ALA facilitates energy expenditure [Lee WJ et al; 2005]. Coenzyme Q10 is an integral part of the mitochondrial respiratory chain and directly involved in electron transport and cellular energy generation. If a sufficient amount of Q10 is available, it can be assumed that it increases the mitochondrial thermogenesis, thereby contributing to higher energy expenditure [Echtay KS et al.; 2000]. The lipid-soluble Q10 and ALA are poorly bioavailable. For this reason, both substances were incorporated into micelles and this formulation with enhanced bioavailability was used in the present trial. The micellar formulation of Q10 and ALA is produced by AQUANOVA AG under the product name NovaSOL Sustain. The superior bioavailability of this formulation has already been demonstrated for different substances, such as coenzyme Q10 and vitamin E [Schulz C et al.; 2006; Back EI et al.; 2006]. Due to its water solubility, the micellar formulation does not depend on intestinal emulsification and, because of its small particle size (< 20 nm), it can be absorbed like other water soluble particles via the intestinal wall. The combination of micellar α-lipoic acid and coenzyme Q10 is therefore an interesting approach to aid in weight loss: Both substances influence energy expenditure. Additionally, α-lipoic acid may improve
satiety, thereby additionally reducing food intake. The combination of both (active) substances as therapeutic to treat overweight and obesity is the content of this study. The aim of this hypotheses-generating pilot study was to investigate if supplementation with the micellar combination product may result in enhanced weight reduction compared to nutritional counselling alone. Based on the described molecular mechanisms for both substances, it should furthermore be possible to observe effects on lipid and carbohydrate metabolism. Methods In this randomized, placebo-controlled parallel study, the effects of a supplement containing coenzyme Q10 and α-lipoic acid were studied with respect to satiety and body weight of overweight and obese volunteers during a reduced calorie diet. Fortyfour subjects (18 to 65 years of age, BMI 27-35 kg/m 2 ) participated in the study. The trial was performed in two parts with 22 subjects each, which were divided into a verum and placebo group. The presented data are the results obtained in the first part of the study. Exclusion criteria for this trial were diabetes mellitus, use of statins, antidepressants, or anti-obesity drugs. The following parameters were determined: body weight, waist and hip circumference, body composition by bioelectric impedance analysis (BIA 2000-S), concentrations of vitamins C and E, ß-carotene and lycopene in blood and buccal mucosal cells (by HPLC). Coenzyme Q10 was determined in blood and cells by HPLC. To monitor dietary behaviour, food intake was recorded at different time points for 3 days each. Satiety was measured using a visual analogue scale. Blood pressure and heart rate were measured regularly as control parameters. At the beginning and at the end of the study, blood count was measured and an oral glucose tolerance test (ogtt; 75 g glucose in 300 ml water) was conducted and plasma glucose and insulin were determined in the fasting state and 60 and 120 minutes after the glucose challenge. All volunteers underwent weekly dietary counselling from week 0 to 6, and every other week from week 6 to 12. The aim of the nutrition counselling was weight reduction with subsequent stabilization of the reduced body weight. Volunteers were taught how to reduce fat intake to approximately 60-80 g fat/day and energy intake by ca. 500 kcal/day during the first six weeks. Volunteers were instructed to consume at least 1,500 kcal/day. The placebo group was provided with placebo capsules and the verum group with capsules containing the micellar formulation of ALA and Q10. Placebo and verum capsules were taken daily during the 12 weeks trial and a follow-up meeting was scheduled after 24 weeks.
Data were processed and statistical analyses performed with the software packages Microsoft Excel 2003 and SPSS Statistics 2010, respectively. Results During the first 6 weeks, drop-outs were replaced by newly recruited volunteers. Twenty subjects (91%) attended the examinations at week 12 and 18 subjects (80%) at week 24. Three male subjects participated in the study and were randomly assigned to the placebo group. Therefore, body composition differed significantly between the verum and placebo groups at baseline (Table 1). Table 1. Characteristics of the study population at baseline Age [years] Weight [kg] BMI [kg/m 2 ] Cell content [%] Waist [cm] Hip [cm] MW 43 40 V # P p V P p V P p V P p V P p V P p 80 91 30 32 51 51 88 95 112 115 SD 13 14 9 13 2 3 2 3 5 10 7 8 0.69 0.03 0.18 0.52 0.06 0.39 Min 20 20 70 71 26 28 46 46 75 81 99 105 Max 63 63 96 112 34 37 57 54 95 114 127 128 # V, verum; P, placebo; p, significance level Body weight at baseline (week 0) differed significantly between the verum and placebo group (placebo group, 91.3 kg; verum group, 80.1 kg). Over the course of the study, neither waist nor hip circumference changed significantly and there was no correlation with body weight. Body composition differed significantly between groups. Extracellular mass (ECM) and body cell mass (BCM) differed significantly between the verum and placebo group at each examination, due to the three male participants in the placebo group. Cell content and body fat did not differ at any time and changes over time were seen only at some periods of time. Cell count did not differ significantly at any time. Food intake was determined at different time points by 3-day food records. Energy intake did not differ at any time between groups. After the intervention, there were no significant changes in energy intake in the verum or the placebo group. The intake of energy, macronutrients, dietary fibre or vitamins C and E did not differ between the verum and placebo group at any time.
Food records were obtained in weeks 1, 2, 4, 8, 12, and 24 and accompanied by a documentation of satiety. No significant changes in satiety were observed in the course of the intervention and no differences between verum and placebo group were observed. Plasma α-lipoic acid was measured in weeks 0, 6 and 12. Prior to intervention, ALA plasma concentrations were below the detection limit of 1 µg/l in all subjects. In weeks 6 and 12, ALA could only be determined in 6 of 11 samples and in 4 of 10 samples in the verum group. Mean plasma concentrations of vitamin E, β-carotene and lycopene were in a normal range at each time point in the verum and the placebo group. No differences between groups or over time were observed. Intracellular concentrations of vitamins C and E did not differ over time. In weeks 0 and 12, triacylglycerols (TAG), total cholesterol, LDL, and HDL cholesterol were determined as blood parameters of fat metabolism. Only HDL cholesterol values in week 12 were different between verum and placebo group (verum 67±11 mg/dl, placebo 54±12 mg/dl; p<0.05). For all other parameters, no significant changes over time or between groups were evident. Q10 concentration in plasma significantly increased in the verum group during the intervention, but not in the placebo group (Table 2). Table 2. Plasma concentration of coenzyme Q10 [µmol/l]; n=11 per group; *** p< 0.001 Differences compared to week 0 Week 0 Week 6 Week 12 Verum 1.1 ± 0.5 3.2 ± 1.9*** 2.3 ± 0.7*** Placebo 0.9 ± 0.3 0.9 ± 0.2 0.9 ± 0.3 Q10 concentrations in buccal mucosal cells did neither change in the verum, nor in the placebo group (Table 3). In a previous biokinetics study in humans, using a watersoluble Q10 formulation, an increase in buccal mucosal cell concentrations of Q10 was identified as an indicator of Q10 intake [Schulz C et al., 2006]. Table 3. Concentrations of coenzyme Q10 in buccal mukosa cells [pmol/mg DNA]; n=11 per group; * p<0.02 compared to placebo; ** p<0.005 Week 0 Week 6 Week 12 Verum 6.7 ± 1.6 6.6 ± 1.9 6.4 ± 1.2 Placebo 4.8 ± 1.6* 5.6 ± 1.7 4.3 ± 1.4** The observed increase in Q10 plasma concentration is comparable to published data. Weber et al. observed an increase in plasma Q10 after a single oral dose of 30 mg Q10
with peak plasma concentration at 6 h; the initial mean value was 1.02 µmol/l. The baseline Q10 concentration and the magnitude of increase in that study are comparable with the results of the present study. Volunteers in the verum group reduced their body weight by 2.3 kg in the course of the intervention trial (week 12), whereas those in the placebo group gained 0.2 kg in body weight (Figure 1). Figure 1. Changes in body weight over the course of the trial (arithmetic mean and standard deviation; verum: n=11, placebo: n=11; significantly different from week 0; * p<0.05) One ogtt was performed at baseline and one in week 12. In the verum group, the HOMA-index significantly improved (compared to baseline), while the decrease in the HOMA-index in the placebo group was not statistically significant (Figure 2).
n.s. p< 0,002* ) Figure 2. HOMA-index at week 0 and 12 (arithmetic mean and standard deviation; verum n=11, placebo n=11; *week 12 significantly different from week 0) Discussion The aim of the present study was to investigate potential supportive effects of α-lipoic acid and coenzyme Q10 on body weight and satiety sensation during a calorie-reduced diet aimed at weight reduction in overweight and obese subjects. There was no significant correlation between intake of the verum preparation and weight loss. Neither body composition, waist and hip circumference, nor satiety differed significantly between the verum and placebo group. The HOMA index, which was calculated from fasting blood glucose and fasting insulin plasma concentrations, significantly improved in the verum but not the placebo group during the study. The improvement in the HOMA index, as biomarker for a diabetic metabolic condition, can be interpreted as desirable effect of the Q10+ALA preparation. In overweight and obese subjects, a reduction in body weight and an improved HOMA index may decrease the risk for cardiovascular diseases. The improvement of the diabetic metabolic condition caused by both substances is more meaningful than a solitary weight reduction. After the commencement of the present study, two papers were published, one in vitro [Wagner AE et al., 2012] and one in vivo (animal) experiment with ALA and Q10 [Özdoğan S et al., 2012]), which present data that may help explaining the improvement in HOMA index after treatment with Q10 and ALA. Özdoğan et al. fed rats with a fructose solution. In rats receiving additional ALA or Q10,
fructose-induced effects on the HOMA index could be reduced. The authors concluded that coenzyme Q10 and α-lipoic acid may counteract fructose-induced insulin resistance. This effect was ascribed to the antioxidative effects of ALA and Q10. Additionaly, intake of Q10 and ALA also led to a reduction of body weight, serum LDL and serum triglycerides in the animals. To what extent these results are transferable to human studies, remains to be shown. The rats received 100 mg ALA and 10 mg Q10 per kg body weight and day. In the present human study, 100 mg ALA and 90 mg coenzyme Q10 were given as daily dose. The amount of ALA and Q10 was therefore many times higher (ALA approx. 80 times, Q10 approx. 9 times) compared to the human study. This, however, demonstrates that lower doses of the water-soluble formulation used in this study can have similar effects due to an increased bioavailablity of the substances. Contrary to the animal study, where oxidative stress was induced by fructose, decreased oxidative stress may have occurred in the present study as a consequence of the weight reduction diet. Decreased oxidative stress in our trial may also be a consequence of the increased blood concentrations of vitamin C. Furthermore, the decrease in oxidative stress and its effects on insulin resistance may also be controlled by the PPARγ (Peroxisome proliferator-activated receptor γ) und its co-activator PGC1α, an important master switch mechanism of energy homeostasis. Wagner et al. have impressively demonstrated these effects in skeletal muscle cells [Wagner AE et al., 2012]. Incubation of these cells with ALA and Q10 significantly increased PGC1α, resulting in activated PPARγ, and thereby increased glucose uptake into the cells (muscle and adipocytes) [Shen W et al., 2008]. The latter would explain the improved HOMA index in the verum group. In the present study, supplementation with ALA and Q10 did not provide a significant benefit for body weight reduction. Although the body weight in the verum group was significantly reduced compared to the placebo group (-2.3 kg vs. 0.2 kg; p<0.05 for the comparison of week 12 with week 0 in the verum group, n.s. for placebo), it should be noted that the initial body weight was significantly higher in the placebo group (80.1 kg vs 91.3 kg; p<0.05). It should be kept in mind, that both groups were on an energyreduced diet and any potential effects of the ALA/Q10 intervention on body weight might have been too small. Compared to the water-soluble micellar formulation with improved bioavailability, regular Q10/ALA formulations would need to be given at ca. three times higher doses. However, meaningful analyses regarding dose-response and the bioavailablity of different galenic preparations are still missing. Researcher at the University of Seoul/Korea carried out a randomized, placebocontrolled intervention study with 360 subjects to test whether supplementation with ALA might lead to a reduction in body weight in overweight subjects [Koh EH et al., 2011]. Subjects were divided into three groups: placebo; 1,200 mg ALA/day; or 1,800
mg ALA/day. Inclusion criteria were: age between 18 and 65 years and an initial BMI of 30 kg/m2 (or a BMI of 27-30 kg/m 2 with co-occurring hypertension, diabetes mellitus or hypercholesterolemia). During the 20 weeks intervention, participants were instructed at defined intervals to reduce their energy intake by 600 kcal/day while eating at least 1,200 kcal/day. Participants were instructed to plan their diets such that macronutrients would make up the following proportions of the total energy intake: carbohydrates, 55-60 %; fat, 20-25 %; and protein, 15-20 %. Only 63.3% of the participants (n=228) completed the study. All three groups significantly reduced body weight. Reduction of body weight did not differ statistically between the group taking 1,200 mg ALA/day and the placebo group (1.07 % v. -0.77 %). Participants that took 1,800 mg ALA/day reduced their body weight by 1.83%. No severe adverse effects were observed in that study and no differences regarding undesired effects were observed between the intervention groups and the placebo group. ALA was considered safe and therefore more advantageous compared to other weight-reducing agents (Orlistat, Sibutramin). The statistical power of the present study is limited because of the low number of participants and the preexisting significant differences between the placebo and verum group, particularly with respect to body weight. As demonstrated fort he first time in humans, intake of α-lipoic acid and coenzyme Q10 in micellized and thereby water-soluble form had a positive effect on insulin resistance. This change can be observed for parameters related to the metabolic syndrome. The observed effects on a possible pre-diabetic or diabetic metabolic status are considered beneficial. However, no effects on food intake and body weight were evident in this study. It is conceivable, that the effects of both substances are more prominent on a cellular and antioxidant level. Results from animal [Özdoğan S et al; 2012] and human intervention studies [Koh EH et al; 2011] indicate possible mechanisms that act on the somatic level (e.g. body weight) and should be pursued in further studies. Whether nonmicelliced formulations could achieve similar results is questionable. An improvement of the bioavailablity by a factor of 3, as previously demonstrated for micellar coenzyme Q10, is an important prerequisite for its effectiveness. In the future, the impact of genetic differences with respect to the absorption of the supplemented substances should also be considered. Are there genetic variants that could change the effects of Q10 or α-lipoic acid? If such research suggests the existence of genetic responders and non-responders, it could be helpful to determine the respective genotypes prior to supplementation with these compounds. For α-lipoic acid, no such investigations exist, whereas for coenzyme Q10, a small study was published in 2011 [Fischer A et al.; 2011]. Fifty-four male subjects received 150 mg Q10 daily and single nucleotide polymorphisms of genes possibly involved in biosynthesis and metabolism of Q10 were determined (CoQ3, CoQ6, CoQ7, NQO1, NQO2, und apoe).
Significantly higher Q10 plasma concentrations were found in carriers of a genetic variant of NQO1 and the apoe gene. The Pro Inno project The present study is part of the Pro Inno II project, an initiative of the Federal Ministry of Economics and Technology. The company AQUANOVA AG (Darmstadt, Germany) cooperated with the University of Hohenheim in the Pro Inno project: Development of a preparation for the stabilization of lipid metabolism after successful weight reduction. Literatur BACK EI, FRINDT C, OĆENÁSKOVÁ E, NOHR D, STERN M, BIESALSKI HK Can changes in hydrophobicity increase the bioavailability of α-tocopherol? Eur J Nutr; 2006; 45(1):1-6 KAHN BB, ALQUIER T, CARLING D, HARDIE DG AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab; 2005; 1(1):15-25 KOH EH, LEE WJ, LEE SA, KIM EH, CHO EH, JEONG E, KIM DW, KIM MS, PARK JY, PARK KG, LEE HJ, LEE IK, LIM S, JANG HC, LEE KH, LEE KU Effects of α-lipoic Acid on body weight in obese subjects Am J Med; 2011; 124(1):85.e1-8 LEE WJ, KOH EH, WON JC, KIM MS, PARK JY, LEE KU Obesity: the role of hypothalamic AMP-activated protein kinase in body weight regulation Int J Biochem Cell Biol; 2005; 37(11):2254-9. Review MIKROZENSUS GESUNDHEIT Statistisches Bundesamt der Bundesrepublik Deutschland; 2009 publiziert auf: www.destatis.de ÖZDOĞAN S, KAMAN D, ŞIMŞEK BҪ Effects of coenzyme Q10 and α-lipoic acid supplementation in fructose fed rats J Clin Biochem Nutr; 2012; 50(2):145-51
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