Etudes cliniques Actif FIT-NS Minceur 360 : simplebooklet.com

MINCEUR 360 PERTE DE POIDS LE COMPLEXE FIIT NS TEST SCIENTIFIQUEMENT 1 Au coeur de la formule Le complexe Fiit NS combinaison unique de bioactifs provenant de plantes de fruits associ s la Vitamine B3 offre un large ventail de bienfaits pour la sant Il est compos de plantes sources de polyph nols et reconnues pour leur action minceur Guarana Th vert Marc de raisin Carotte pourpre Pamplemousse Un certain nombre de polyph nols peuvent affecter soit l adipogen se l hom ostasie nerg tique soit les voies de signalisation de l insuline et de l inflammation chronique Fiit NS peut alors tre utilis dans la gestion des troubles m taboliques associ s au surpoids et l ob sit 2 Fiit NS test scientifiquement Les bienfaits de Fiit NS ont t cliniquement d montr s par le biais de 2 tudes 2 me tude clinique 2021 1 re tude clinique 2014 UCAM University of Murcia Madrid American Hospital Paris tude clinique randomis e en double aveugle vs placebo tude clinique randomis e en double aveugle vs placebo 12 semaines 16 semaines 17 sujets 9 Femmes 8 Hommes IMC 30 33 kg m2 ge 39 44 ans 72 sujets 38 Femmes 34 Hommes IMC 25 40 kg m2 ge 25 55 ans 30 min semaine Activit physique habituelle Normo calorique Normo calorique 2 x 450 mg jour Analyse des valeurs anthropom triques des param tres sanguins de la tol rance 2 x 450 mg jour Analyse de la qualit de vie li e la sant de la composition corporelle de l activit physique de l tat de sant de la tol rance Crit res d exclusion des tudes 1 re tude clinique 2014 Prise de m dicaments aidant la perte de poids Chirurgie amaigrissante Troubles de l alimentation Troubles de la circulation ou hypertension Troubles du stress de l anxi t 2 me tude clinique 2021 Sevrage tabagique Enceinte allaitement M nopause D pression Pratiquant une activit physique plus de 2x semaine En commun aux 2 tudes Suivi d un programme perte de poids Allergies un des ingr dients de Fiit NS Maladies m taboliques chroniques Consommation lev e d alcool tabac

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http informahealthcare com ijf ISSN 0963 7486 print 1465 3478 electronic Int J Food Sci Nutr Early Online 1 6 2014 Informa UK Ltd DOI 10 3109 09637486 2014 971229 Int J Food Sci Nutr Downloaded from informahealthcare com by IBI Circulation Ashley Publications Ltd on 11 03 14 For personal use only RESEARCH ARTICLE Regular consumption of Fiit ns a polyphenol extract from fruit and vegetables frequently consumed within the Mediterranean diet improves metabolic ageing of obese volunteers a randomized double blind parallel trial Julien Cases1 Cindy Romain1 Constantin Dallas1 Alain Gerbi2 and Maurice Cloarec3 1 Fytexia SAS ZAE via Europe Vendres France 2RDVC Produits Sante Le Havre France and 3Association Nationale de Pre vention Me dicale Paris France Abstract Keywords Epidemiological studies suggest that metabolic ageing process of overweight and obese populations is associated with an increased risk of developing non communicable diseases NCDs Inflammation hyper glycaemia dyslipidemia and oxidative stress have been associated with early stages of NCDs development whereas cohort surveys have demonstrated health benefits of dietary polyphenols from various dietary sources to reverse such progress Obese volunteers were included in a double blind randomized parallel pilot trial where they received daily for a 12 week period 900 mg of a polyphenol rich treatment extracted from fruit and vegetables frequently consumed within the Mediterranean diet Anthropometric and blood parameters were assessed before and at the end of the intervention period After 12 weeks while the silhouette slimmed down metabolic parameters were significantly improved and general satisfaction considerably ameliorated These data suggest that over a 12 week period the synergistic action of bioactives within the treatment improves metabolic ageing process and quality of life in obese volunteers Chronic low grade inflammation dyslipidemia insulin resistance Mediterranean diet oxidative stress quality of life Introduction The improvement of medical care nutritional intakes and life conditions has significantly increased both quality of life and life expectancy Nevertheless ageing still remains the main death risk factor that progressively appears in lifecycle to gradually aggravate lifestyle and fitness conditions Such etiology habitually roots in cumulative concerns Among possible initiating issues sedentary behaviors and imbalanced diets are generally deeply linked to increased occurrence of non communicable diseases NCDs of which primary disorders are metabolic including cardiovascular diseases and insulin resistance as well as lack of vigor habitually connected to self esteem drop Such manifestations epidemiologically start from early middle age Niccoli Partridge 2012 and there is no sudden edge from healthiness to illness in the development of NCDs During this period warning lights gradually switch to orange and finally to red however there is only a weak consensus to define when is most appropriate to start any treatment This is particularly problematic with excessive abdominal fat that affects overweight and obese population In addition to causing various physical disabilities and psychological problems overweight and obesity drastically increase a person s Correspondence Dr Julien Cases Fytexia SAS ZAE via Europe 5 rue d Athe nes 34350 Vendres France Tel 33 467 219 098 E mail jcases fytexia com History Received 9 July 2014 Revised 11 September 2014 Accepted 12 September 2014 Published online 28 October 2014 risk of developing a number of NCDs Balkau et al 2007 Kaysen et al 2009 Wadden Phelan 2002 All these pathologies that are regularly related to unbalanced oxidative stress and adiposityassociated inflammation usually raise age related chronic and low grade metabolic disorders to such an extent that despite the non existence of clinical symptoms drug intervention is required to extend lifespan and improve quality of life Esposito Giugliano 2004 Probst Hensch 2010 In the meantime side effects of fitted drug treatment have to be more often considered to preserve quality of life during ageing process especially for long term treatments Rodenburg et al 2004 Polyphenol compounds constitute a group of bioactives that are abundant in the plant kingdom The biological effects of polyphenols have been largely attributed to their antioxidant properties however recent data suggest that polyphenols can exert modulatory action in cells by interacting with the cell signalling machinery Thus a number of polyphenols can affect either appetite adipogenesis and energy homeostasis insulin or inflammation signalling pathways Dallas et al 2008 Hollis et al 2009 Lin et al 2005 Tresserra Rimbau et al 2014 Wang et al 2014 hence these bioactives might be useful in the management of metabolic disorders generally associated to overweight and obesity The present study aimed at investigating how polyphenols and other bioactives from a characterized extract of various fruit and vegetables commonly consumed within the Mediterranean diet

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2 J Cases et al could improve volunteers health conditions in the absence of drug medication Materials and methods Subjects Int J Food Sci Nutr Downloaded from informahealthcare com by IBI Circulation Ashley Publications Ltd on 11 03 14 For personal use only Seventeen nine women eight men obese volunteers Class I body mass index BMI 30 1 33 3 kg m2 aged 39 to 44 years with moderate metabolic disorders but otherwise healthy were recruited from a health prevention coaching program run by a non profit organization Association Nationale de Pre vention Me dicale ANPM Paris France at the Hopital Ame ricain de Paris France accredited by the French Health Authorities HAS Haute Autorite de Sante after they agreed to fill a written informed consent form Inclusion criteria Inclusion criteria incorporated obese middle aged population 35 45 years old with BMI within the range 30 0 34 9 kg m2 People who enrolled in a weight loss program in the last 6 months or took weight loss medications or any other supplements were not eligible Exclusion criteria comprised history of weightreducing surgery eating disorders circulation weaknesses or hypertension chronic allergic or metabolic diseases stress or anxiety disturbances and high alcohol or smoking consumption Mean values for main anthropometric characteristics of subjects participating in this study were as follows age 40 7 0 7 years height 168 2 4 cm waist circumference 98 8 2 0 cm hip circumference 116 8 2 3 cm weight 88 9 3 1 kg body mass index 31 2 0 2 kg m2 abdominal fat ratio 38 9 2 0 Experimental design The study was approved by a French Ethical Committee for Human experimentation and was conducted according the Good Clinical Practice guidelines of the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for Human use in harmony with the Declaration of Helsinki and in accordance with the French drug laws A 12 week double blinded randomized and parallel pilot clinical trial was conducted Once enrolled subjects were assigned to one of two groups one receiving Placebo n 9 the other group n 8 receiving the treatment Fiit ns Subjects were instructed to take one capsule in the morning at breakfast and one capsule at lunchtime every day for 12 weeks Participants reported to the research center four times during the 12 week intervention study at baseline W0 at week 4 W4 week 8 W8 and at the end W12 Test treatment Fiit ns was obtained by alcohol and or water extraction from grapefruit Citrus paradisi Macfad green tea Camellia sinensis L Kuntze grape Vitis vinifera L black carrot Daucus carota L and guarana seed Paullinia cupana Kunth Fiit ns provided a total daily amount of polyphenols of 370 mg mg of gallic acid equivalent which is in the range of 373 mg mg of gallic acid equivalent of total polyphenols provided with the daily consumption of a minimum of five servings 400 g of fresh fruit vegetables among the most consumed Brat et al 2006 Kantar Worldpanel market data 2014 Rothwell et al 2012 in addition Fiit ns delivered 36 mg of caffeine per day and contained a level of 1 8 of vitamin B3 The Placebo was 100 maltodextrin which is polyphenol free Each pill contained 450 mg of either Fiit ns or Placebo Int J Food Sci Nutr Early Online 1 6 Diet and exercise The daily calorie level was recommended at 110 125 of the basal metabolic rate BMR according to the revised Harris Benedict equation Roza Shizgal 1984 which corresponds to 1700 2000 kcal d for women and between 2200 and 2500 kcal d for men For the whole duration of the study all subjects were instructed to have 30 min per week of physical activity Determination of anthropometric vital and nutritional parameters Anthropometrics BMI body weight waist hip circumference blood pressure and heart rate were monitored at each visit Body weight kg was measured in light clothing at each visit Waist circumference cm was measured at the narrowest point between the lowest rib and the iliac crest using a non stretchable tape Hip circumference cm was taken around the maximum circumference of the buttocks Total abdominal adiposity ratio was measured by the ViScan system Tanita Corporation at W0 and at W12 Dallas et al 2014 Blood analysis Subjects were sampled for blood after an overnight fast at W0 and at W12 Blood samples were prepared and stored appropriately until they were analyzed by enzymatic and colorimetric methods Randox reagents UK on a Hitachi 717 Chemistry Anlalyzer Japan for the following parameters in plasma lipid profile total cholesterol CHOL HDL chol LDL chol triglycerides TG glucose uric acid creatinine and enzymes from liver ALT ASAT g GT inflammation markers fibrinogen high sensitivity C reactive protein hs CRP oxidative status malondialdehyde MDA In the whole blood haemoglobin A1c HbA1c and superoxide dismutase SOD were measured to evaluate respectively the glycaemia of the past 3 months and the antioxidative response Well being questionnaire An in house questionnaire was developed to subjectively assess global satisfaction with regards to the treatment at W12 and included six items to rate Overall satisfaction perception of weight loss perception of losing body fat treatment tolerance perception of greater energy perception of well being Subjects were requested to score each item on a 0 10 rating scale with 0 being extremely unsatisfied and 10 being extremely satisfied Statistics Statistical analyses were performed using Statview software version 4 51 1 Abacus Concepts Berkeley CA The data are expressed as mean standard error to the mean SEM A Kolmogorov Smirnov test for normality and a Bartlett test for homogeneous variance were performed for each group Changes within and between groups at W0 and at W12 for the clinical and laboratory parameters were analyzed using unpaired Student t test Results of the questionnaire were analyzed with the Wilcoxon rank test Results were supposed significant at a minimum value p50 05 Results Anthropometric values Anthropometric parameters decreased continuously data not shown over the course of the study in both groups At W12 it appeared that the Fiit ns group significantly lost more weight 6 7 0 9 p50 005 and had more reduction in waist

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Consumption of Fiit ns improves metabolic ageing DOI 10 3109 09637486 2014 971229 3 Table 1 Body weight body mass index BMI abdominal fat ratio waist hip circumference at baseline and after 12 weeks of treatment with Placebo or Fiit ns in class I obese middle aged adults Fiit ns Placebo Baseline Body weight kg BMI kg m2 Abdominal fat Waist cm Hip cm a 88 4 12 5 31 2a 0 3 38 4a 9 2 98 0a 8 7 115 1a 9 9 D0 12 W12 b 2 3 0 6 0 7 0 2 3 0 0 4 0 7 0 2 0 7 0 2 86 3 11 9 30 5b 0 3 37 3b 9 2 97 3b 8 6 114 3b 9 9 Baseline D0 12 W12 a b 89 5 14 0 31 0a 0 3 39 6a 7 9 99 6a 8 3 118 6a 9 2 83 4 12 3 28 9b 0 2 36 9b 8 1 97 6b 7 83 115 6b 9 0 6 7 0 9 2 1 0 3 7 1 1 2 2 0 0 2 2 5 0 6 Int J Food Sci Nutr Downloaded from informahealthcare com by IBI Circulation Ashley Publications Ltd on 11 03 14 For personal use only Values are means SEM n 9 Placebo or 8 Fiit ns Groups mean did not differ at baseline a bsuperscripts indicate an intragroup Placebo or Fiit ns difference between Baseline and W12 p50 005 superscript indicates D0 12 difference between Placebo and Fiit ns p50 005 Table 2 Changes for lipidemic profile at baseline and after 12 weeks of treatment with Placebo or Fiit ns in class I obese middle aged adults Table 3 Changes for fasting glucose in plasma and for glycated haemoglobin in whole blood at baseline and after 12 weeks of treatment with Placebo or Fiit ns in class I obese middle aged adults Fiit ns Placebo Normal range Baseline W12 Baseline W12 CHOL mg dL 5200 LDL mg dL 5100 TG mg dL 5150 HDL mg dL 450 261a 4 164a 1 163a 3 60a 2 249b 3 158b 1 149b 3 60a 3 263a 2 163a 2 165a 3 57a 1 240c 2 146c 1 142c 3 62b 1 Values are means SEM n 9 Placebo or 8 Fiit ns Groups mean did not differ at baseline a b csuperscripts indicate both an intragroup Pacebo or Fiit ns and a Placebo and Fiit ns difference between Baseline and W12 p50 005 2 0 0 2 p50 0005 hip circumference 2 5 0 6 p50 05 than the Placebo group Table 1 In addition beneficial effects of Fiit ns on body composition were confirmed with a significantly more important abdominal adiposity ratio reduction 7 1 1 2 p50 005 Table 1 As a matter of fact Fiit ns volunteers changed even their body mass index category from class I obesity 31 0 0 3 kg m2 to overweight 28 9 0 2 kg m2 Table 1 Blood parameters All volunteers had moderate dyslipidemia with CHOL greater than 200 mg dL LDL chol greater than 100 mg dL and TG greater than 150 mg dL at W0 and the basal level of lipids did not differ between both groups After 12 weeks CHOL LDL chol and TG levels of Fiit ns treated individuals decreased significantly more respectively 8 6 0 6 p50 05 10 1 1 4 p50 01 14 0 1 4 p50 05 and TG levels even reached normal healthy range below 150 mg dL while the amount of HDL chol significantly increased 8 8 0 8 p50 001 Table 2 Similarly to lipid parameters fasting glycaemia levels for both groups at the beginning of the study were analyzed within an established hyperglycaemia Table 3 according the American Diabetes Association 2014 guidelines It appeared that such fasting hyperglycaemia was long term deep rooted with HbA1c levels before the start of the study reaching 48 2 mg dL and 44 1 mg dL respectively for Placebo and Fiit ns groups Table 3 which is just beyond the normal non diabetic range of 20 42 mmlol L set by the International Federation of Clinical Chemistry and Laboratory Medicine IFCC 2009 Such levels of HbA1c respectively correspond to an estimated average glucose level of 139 5 and 132 7 mg dL within the 3 previous months according to the model by Nathan et al 2008 After 12 week treatment with Fiit ns HbA1c level significantly decreased 38 1 mg dL p50 005 this improvement corresponds to an Fiit ns Placebo Normal range Glycaemia mg dL 5125 Hb1Ac mmol mol 542 Baseline W12 Baseline W12 a a a 102b 3 38b 1 111 1 48a 2 108 1 44a 1 108 3 44a 2 Values are means SEM n 9 Placebo or 8 Fiit ns Groups mean did not differ at baseline a bsuperscripts indicate both an intragroup Pacebo or Fiit ns and a Placebo and Fiit ns difference between Baseline and W12 p50 005 estimated average glucose level of 115 5 mg dL for the 12 weeks of the study just at the lower limit set at 110 125 mg dL for impaired fasting glucose WHO 2006 Additionally the protective response to oxidative stress was evaluated with the levels of SOD activity and MDA release As a result with Fiit ns SOD activity is significantly increased p50 005 from W0 1312 43 IU g Hb to W12 1712 50 IU g Hb Table 4 This result is correlated with MDA release which significantly decreased p50 005 with Fiit ns from W0 4 0 0 1 mmol L to W12 2 6 0 2 mmol L Table 4 Finally inflammatory markers of Fiit ns treated subjects significantly decreased from W0 to W12 The cardiovascular risk factors fibrinogen and hs CRP were significantly diminished p50 005 from a low grade inflammatory status for fibrinogen 330 10 mg dL to a healthier rate 280 10 mg dL and with a similar pattern for hs CRP from a low level of systemic chronic inflammatory status 5 28 0 1 mg L to a value within the healthy range 2 25 0 0 mg L Table 4 Medsipo 2014 Tolerance Volunteers did not have any kind of metabolic disorders throughout the study as monitored with uric acid creatinine and liver enzymes ALT ASAT g GT data not shown Neither adverse event nor side effects were reported by the investigator In addition in the well being subjective questionnaire all items significantly p50 0001 scored higher values with the Fiit ns group Figure 1 except for Tolerance to the treatment which scored a similar and very good level for both groups Discussion The present study reports significant benefits of a daily supplementation for 12 weeks with Fiit ns a polyphenol extract from fruit vegetables commonly consumed within the Mediterranean diet It demonstrates that despite a certain tendency of class I

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4 J Cases et al Int J Food Sci Nutr Early Online 1 6 Table 4 Changes for oxidative and for inflammation status at baseline and after 12 weeks of treatment with Placebo or Fiit ns in class I obese middle aged adults Fiit ns Placebo Normal range Oxidative status SOD IU g Hb 785 1 570 MDA mmol L 52 8 Inflammatory status Fibrinogen g L 1 5 3 hs CRP mg L 55 Baseline W12 Baseline W12 1 348a 50 3 9a 0 0 1 422a 45 3 8a 0 1 1 312a 43 4 0a 0 1 1 712b 50 2 6b 0 2 3 1a b 0 1 5 6a 0 1 3 1a b 0 1 5 3a 0 1 3 3a 0 1 5 8a 0 1 2 8b 0 1 2 2b 0 0 Int J Food Sci Nutr Downloaded from informahealthcare com by IBI Circulation Ashley Publications Ltd on 11 03 14 For personal use only Values are means SEM n 9 Placebo or 8 Fiit ns Groups mean did not differ at baseline a b superscripts indicate both an intragroup Pacebo or Fiit ns and a Placebo and Fiit ns difference between Baseline and W12 p50 005 Figure 1 Perception of Fiit ns efficacy after 12 weeks of supplementation in class I obese middle aged adults Values are means SEM n 9 Placebo or 8 Fiit ns superscript indicate an intragroup difference between Placebo and Fiit ns at W12 p50 0001 determined by the Wilcoxon rank test Score to ques ons 0 10 Percep on of well being Percep on of greater energy Tolerance of the product Fiit ns Percep on of losing body fat Placebo Percep on of weight loss General Sa sfac on 0 obese average BMI 31 04 middle aged average age 41 y volunteer s metabolism toward an uncontrollable ageing process a 12 week treatment with Fiit ns is able to significantly slow down this progression and to help individuals recover a better quality of life and healthy levels for some of their critical metabolic parameters Anthropometric results body composition Although the targeted population can have consistently elevated weight gain through their ageing process Niccoli Partridge 2012 whether they have regular sport activity or not it is noteworthy that a supplementation with Fiit ns can significantly reverse such a trend with obese volunteers subsequently going back to an overweight range Various authors have already reported decreased body weight correlated to polyphenol consumption however this observation either was made generally with polyphenol rich extracts from one single botanical source Baladia et al 2014 Flechtner Mors et al 2004 or was based on data from epidemiological studies on diets rich in fresh fruit and vegetables Konstantinidou et al 2014 Ros et al 2014 Tresserra Rimbau et al 2014 It was never observed from a methodologically designed dry extract such as Fiit ns is Thus and interestingly past studies have investigated the effects of green tea polyphenols which occur as well in Fiit ns in moderately overweight subjects average BMI of 28 9 Chantre Lairon 2002 Authors observed a 4 6 decrease in body weight versus baseline which is clearly over performed during the Fiit ns study with a 6 7 global body weight reduction This encouraging result highlights the benefits of green tea polyphenols probably through lipase inhibition and thermogenesis 1 2 3 4 5 6 7 8 9 10 augmentation as previously described Chantre Lairon 2002 and certainly considering additional enhancement with caffeine intakes Wang et al 2006 Besides the significant decrease of TG at W12 in plasma in the Fiit ns treated group tends to clarify the probable lipase inhibition activity of green tea polyphenols in the gut Juhel et al 2000 At the same time a supplementary synergistic effect seems possible within Fiit ns thanks to grapefruit polyphenols Indeed authors of a review on polyphenols and obesity suggested that polyphenols could positively interfere at various levels on obesity including increased lipolysis and stimulated energy expenditure Lee et al 2009 a mechanism of fat burning already described for a Citrus extract rich in flavanones Dallas et al 2008 The authors of a further clinical intervention reported a significant weight loss deeply linked to a 4 2 3 4 and 6 6 decrease of respectively waist hip circumference and abdominal fat ratio Dallas et al 2014 Interestingly these changes are similar to anthropometric values reported in the present study where volunteers lost more than 6 kg reduced 2 and 3 cm respectively for waist hip circumference and reduced their abdominal fat ratio by more than 7 after Fiit ns daily intakes during 12 weeks Oxidative stress and cardiovascular risks At W0 volunteers were affected with oxidative stress as observed with MDA production ranging beyond normal limit whereas SOD levels remained within the normal healthy range It has been reported that oxidative markers were significantly elevated while SOD activity decreased in diabetic rats which were completely counterbalanced with supplementation with proanthocyanidins extracted from grape GPE Okudan et al 2011 In parallel

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DOI 10 3109 09637486 2014 971229 Int J Food Sci Nutr Downloaded from informahealthcare com by IBI Circulation Ashley Publications Ltd on 11 03 14 For personal use only other authors confirmed grape seed benefit on increased SOD production with diabetic volunteers and with non diabetic rats Pourghassem Gargari et al 2011 Puiggros et al 2009 Authors suggested that supplementation with GPE might attenuate oxidative stress through the inhibition of lipid peroxidation with the beneficial consequence of a better restoration of endothelial function leading to a reduced risk of vascular disease Fiit ns is effective to significantly boost SOD activity which was probably and to some extent responsible for an indirect MDA decrease within the normal healthy range Such a benefit associated to both a noteworthy reduction of LDL chol and a significant increase of HDL chol demonstrates the decreased risk to develop an oxidized LDL chol associated vascular risk Insulin resistance and low grade inflammation In addition to oxidative stress dysregulation and dyslipidemia it is important to emphasize a specific aspect of ageing process deeply linked to declining mitochondrial efficiency where unbalanced level of reactive oxygen species is a serious concern and which is suspected to be a principle actuator of tissue destroying inflammatory mediators known as the inflammasome Dinarello 2011 Sorbara Girardin 2011 Accordingly cellular stress is able to trigger chronic inflammation which widely contributes to disease and age related worsening through various endogenous mechanisms Racchi et al 2008 Interestingly while abdominal fat and waist circumference start to increase beyond healthy limits during normal ageing process subsequently a systemic low grade inflammatory score arises generally linked with excessive oxygen reactive species overproduction Dallas et al 2014 Kalupahana et al 2012 Puiggros et al 2009 this phenomenon is enhanced in inactive population Olesen et al 2014 Szostak Laurant 2011 Various epidemiological studies have confirmed significant increases in inflammatory markers such as IL 6 TNFa and hs CRP with age potentially as a consequence of increase in visceral and abdominal adipose tissue Singh Newman 2011 In addition and unambiguously mitochondrial dysfunction leads to inflammation progress when during oxidative stress excessive blood sugars react with proteins and lipids leading to a damaging reaction forming advanced glycation end products AGEs Rolo Palmeira 2006 Sandireddy et al 2014 Shen 2012 Upon activation AGEs trigger the movement of the inflammatory mediator nuclear factor kappa B to the nucleus where it activates numerous inflammatory genes Mosquera 2010 generally leading to chronic low grade inflammation process Among the inflammatory markers usually reported in cohort studies of ageing fibrinogen and hs CRP are robustly related to multiple disease outcomes and increase in circulating AGEs as well as high fasting plasma glucose associated to hsCRP and fibrinogen are generally associated with several risk factors for type 2 diabetes mellitus and cardiovascular diseases Piche et al 2005 Yudkin et al 1999 It is noteworthy that significant low grade inflammation was observed in class I obese middle aged individuals before the start of the present study with levels rating just above the limits generally reported for a healthy population At the same time fasting plasma glucose levels of both groups raised respectively 1 08 and 1 11 g L and whole blood HB1Ac levels corresponded to 44 and 48 mmol mol just beyond the level corresponding to the upper healthy limit It is important to remind that such Hb1Ac levels correspond to an estimated average fasting glucose in plasma for the three previous months of 132 and 139 mg dL which is undoubtedly an additional risk of developing insulin resistance and type 2 diabetes Interestingly the 12 week Fiit ns treatment significantly improves both glucose plasma and Hb1Ac levels consequently decreasing the corresponding risk factors of individuals Such Consumption of Fiit ns improves metabolic ageing 5 positive evolution seems linked to concomitant inflammation decrease going back to normal healthy range with respective reductions by 10 and 15 for fibrinogen and hs CRP Conclusion In the present study it was demonstrated that polyphenols extracted from fruit and vegetables regularly consumed within the Mediterranean diet might exert health benefits through antiobesity action associated to oxidative stress decrease and chronic low grade inflammation reduction influencing at turn lipidemic and glycaemic parameters In addition the conducted trial indicated that such a polyphenol extract improve metabolic parameters without any side effects or adverse event which suggests that it is conceivable that Fiit ns could be recommended as part of a nutritional prevention behavior in primary intention to support the management of overweight and class I obesity and their associated metabolic disorders Nevertheless while the rationale for this age associated increase in inflammatory markers is not methodically understood it may reflect increase of risk factors associated with metabolic changes related to age evolution such as increase in abdominal and visceral body fat leading to cumulative mitochondrial dysfunction and associated oxidative damages In this context further investigations on bioavailability of polyphenols and their metabolic activities linked to the mitochondrial function inside the abdominal area should be performed to deeply understand the link between polyphenols oxidative stress and NCDs Acknowledgements The financial assistance of Fytexia is gratefully acknowledged Declaration of interest Fytexia is involved in the research development and marketing sales of polyphenol extracts from various fruit and vegetables regularly consumed within the Mediterranean diet for food and nutraceutical industries Therefore Fytexia has a commercial interest in this publication RDVC and Association Nationale de Pre vention Me dicale were paid by Fytexia to perform and report the scientific work that formed the basis of this publication Fytexia RDVC and Association Nationale de Pre vention Me dicale declare that the data in this report represent a true and faithful representation of the work that has been performed References American Diabetes Association 2014 Available at http www diabetes org Accessed on 04 July 2014 Baladia E Basulto J Manera M Martinez R Calbet D 2014 Effect of green tea or green tea extract consumption on body weight and body composition systematic review and meta analysis Nutr Hosp 29 479 490 Balkau B Deanfield JE Despres JP Bassand JP Fox KA Smith Jr SC Barter P et al 2007 International Day for the Evaluation of Abdominal Obesity IDEA a study of waist circumference cardiovascular disease and diabetes mellitus in 168 000 primary care patients in 63 countries Circulation 116 1942 1951 Brat P George S Bellamy A Du CL Scalbert A Mennen L Arnault N Amiot MJ 2006 Daily polyphenol intake in France from fruit and vegetables J Nutr 136 2368 2373 Chantre P Lairon D 2002 Recent findings of green tea extract AR25 Exolise and its activity for the treatment of obesity Phytomedicine 9 3 8 Dallas C Gerbi A Elbez Y Caillard P Zamaria N Cloarec M 2014 Clinical study to assess the efficacy and safety of a citrus polyphenolic extract of red orange grapefruit and orange Sinetrol XPur on weight management and metabolic parameters in healthy overweight individuals Phytother Res 28 212 218 Dallas C Gerbi A Tenca G Juchaux F Bernard FX 2008 Lipolytic effect of a polyphenolic citrus dry extract of red orange grapefruit orange SINETROL in human body fat adipocytes Mechanism of

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Int J Food Sci Nutr Downloaded from informahealthcare com by IBI Circulation Ashley Publications Ltd on 11 03 14 For personal use only 6 J Cases et al action by inhibition of cAMP phosphodiesterase PDE Phytomedicine 15 783 792 Dinarello CA 2011 Interleukin 1 in the pathogenesis and treatment of inflammatory diseases Blood 117 3720 3732 Esposito K Giugliano D 2004 The metabolic syndrome and inflammation association or causation Nutr Metab Cardiovasc Dis 14 228 232 Flechtner Mors M Biesalski HK Jenkinson CP Adler G Ditschuneit HH 2004 Effects of moderate consumption of white wine on weight loss in overweight and obese subjects Int J Obes Relat Metab Disord 28 1420 1426 Hollis JH Houchins JA Blumberg JB Mattes RD 2009 Effects of concord grape juice on appetite diet body weight lipid profile and antioxidant status of adults J Am Coll Nutr 28 574 582 IFCC 2009 HbA1c standardisation for clinical health care professionals NHS diabetes diabetes UK and Association for Clinical Biochemistry 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Arola L et al 2009 In vivo in vitro and in silico studies of Cu Znsuperoxide dismutase regulation by molecules in grape seed procyanidin extract J Agric Food Chem 57 3934 3942 Racchi M Uberti D Govoni S Memo M Lanni C Vasto S Candore G et al 2008 Alzheimer s disease new diagnostic and therapeutic tools Immun Ageing 5 7 Rodenburg J Vissers MN Daniels SR Wiegman A Kastelein JJ 2004 Lipid lowering medications Pediatr Endocrinol Rev 2 171 180 Rolo AP Palmeira CM 2006 Diabetes and mitochondrial function role of hyperglycemia and oxidative stress Toxicol Appl Pharmacol 212 167 178 Ros E Martinez Gonzalez MA Estruch R Salas Salvado J Fito M Martinez JA Corella D 2014 Mediterranean diet and cardiovascular health teachings of the PREDIMED study Adv Nutr 5 330S 336S Rothwell JA Urpi Sarda M Boto Ordon ez M Knox C Llorach R Eisner R Cruz J et al 2012 Phenol Explorer 2 0 a major update of the Phenol Explorer database integrating data on polyphenol metabolism and pharmacokinetics in humans and experimental animals Database 2012 bas031 Roza AM Shizgal HM 1984 The Harris Benedict equation reevaluated resting energy requirements and the body cell mass Am J Clin Nutr 40 168 182 Sandireddy R Yerra VG Areti A Komirishetty P Kumar A 2014 Neuroinflammation and oxidative stress in diabetic neuropathy futuristic strategies based on these targets Int J Endocrinol 2014 Article ID 674987 Available at http www hindawi com journals ije 2014 674987 Shen GX 2012 Mitochondrial dysfunction oxidative stress and diabetic cardiovascular disorders Cardiovasc Hematol Disord Drug Targets 12 106 112 Singh T Newman AB 2011 Inflammatory markers in population studies of aging Ageing Res Rev 10 319 329 Sorbara MT Girardin SE 2011 Mitochondrial ROS fuel the inflammasome Cell Res 2 558 560 Szostak J Laurant P 2011 The forgotten face of regular physical exercise a natural anti atherogenic activity Clin Sci Lond 121 91 106 Tresserra Rimbau A Rimm EB Medina Remon A Martinez Gonzalez MA Lopez Sabater MC Covas MI Corella D et al 2014 Polyphenol intake and mortality risk a re analysis of the PREDIMED trial BMC Med 12 77 Wadden TA Phelan S 2002 Assessment of quality of life in obese individuals Obes Res 10 50S 57S Wang S Noh SK Koo SI 2006 Epigallocatechin gallate and caffeine differentially inhibit the intestinal absorption of cholesterol and fat in ovariectomized rats J Nutr 136 2791 2796 Wang Z Lee Y Eun JS Bae EJ 2014 Inhibition of adipocyte inflammation and macrophage chemotaxis by butein Eur J Pharmacol 738C 40 48 WHO 2006 Report of a WHO IDF Consultation Available at http www who int diabetes publications Definition 20and 20diagnosis 20of 20diabetes_new pdf Accessed on 04 July 2014 Yudkin JS Stehouwer CD Emeis JJ Coppack SW 1999 C reactive protein in healthy subjects associations with obesity insulin resistance and endothelial dysfunction a potential role for cytokines originating from adipose tissue Arterioscler Thromb Vasc Biol 19 972 978

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Article Sixteen Weeks of Supplementation with a Nutritional Quantity of a Diversity of Polyphenols from Foodstuff Extracts Improves the Health Related Quality of Life of Overweight and Obese Volunteers A Randomized Double Blind Parallel Clinical Trial Cindy Romain 1 Linda H Chung 2 Elena Mar n Cascales 2 Jacobo A Rubio Arias 2 Sylvie Gaillet 3 Caroline Laurent 3 Juana Mar a Morillas Ruiz 4 Alejandro Mart nez Rodriguez 2 Pedro Emilio Alcaraz 2 and Julien Cases 1 Citation Romain C Chung L H Innovation and Scientific Affairs Fytexia 34350 Vendres France cromain fytexia com Research Center for High Performance Sport Catholic University of Murcia 30107 Murcia Spain lhchung ucam edu L H C emarin ucam edu E M C jararias ucam edu J A R A amrodriguez ucam edu A M R palcaraz ucam edu P E A 3 UMR 204 Nutripass Research Institute for Development University of Montpellier 34095 Montpellier France sylvie gaillet foulon univ montp2 fr S G caroline laurent univ montp2 fr C L 4 Department of Food and Nutrition Technology Catholic University of Murcia 30107 Murcia Spain jmmorillas ucam edu Correspondence jcases fytexia com Tel 33 467 219 098 1 2 Mar n Cascales E Rubio Arias J A Gaillet S Laurent C Morillas Ruiz J M Mart nez Rodriguez A Alcaraz P E Cases J 16 Week Supplementation with a Nutritional Quantity of a Diversity of Polyphenols from Foodstuff Extracts Improves Health Related Quality of Life of Overweight and Obese Volunteers A Randomized Double Blind Parallel Clinical Trial Nutrients 2021 13 492 https doi org 10 3390 nu13020492 Academic Editors Elena Gonz lez Burgo and Emad Abdol S Al Dujaili Received 14 December 2020 Accepted 28 January 2021 Published 2 February 2021 Publisher s Note MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations Copyright 2021 by the authors Licensee MDPI Basel Switzerland This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution CC BY license Abstract Overweight and obesity adversely affect health related quality of life HRQOL through day to day impairments of both mental and physical functioning It is assumed that polyphenols within the Mediterranean diet may contribute to improving HRQOL This investigation aimed at studying the effects of a polyphenol rich ingredient on HRQOL in overweight and obese but otherwise healthy individuals A randomized double blind placebo controlled study including 72 volunteers was conducted Subjects were randomly assigned to receive for a 16 week period either 900 mg day of the supplement or a placebo Dietary recommendations were individually determined and intakes were recorded Daily physical mobility was also monitored Improvement of HRQOL was set as the primary outcome and assessed at baseline and at the end of the investigation using the Short Form 36 SF 36 health survey Body composition was analyzed using dual energy X ray absorptiometry DXA Physical activity was calculated using the International Physical Activity Questionnaire IPAQ After 16 weeks despite there being no adherence to the Mediterranean Diet Serving Score MDSS supplemented individuals experienced significant HRQOL improvement 5 3 p 0 001 including enhanced perceived physical 11 2 p 0 002 and mental health 4 1 p 0 021 components with bodily pain vitality and general health being the greatest contributors Body fat mass significantly decreased 1 2 kg p 0 033 mainly within the trunk area 1 0 kg p 0 002 Engagement in physical activity significantly increased 1308 Met min Metabolic Equivalent Task minutes week p 0 050 Hence chronic supplementation with nutritional diversity and dosing of a Mediterranean diet inspired polyphenol rich ingredient resulted in significant amelioration in both perceived physical and mental health concomitant with the improvement of body composition in healthy subjects with excessive adiposity Keywords health related quality of life vitality body composition phenolic compounds Mediterranean diet http creativecommons org licenses by 4 0 Nutrients 2021 13 492 https doi org 10 3390 nu13020492 www mdpi com journal nutrients

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Nutrients 2021 13 492 2 of 16 1 Introduction The World Health Organization WHO defines quality of life QOL as an individual s perception of their position in life in the context of culture and value systems in which they live and in relation to their goals expectations standards and concerns 1 Such conception of QOL is subjective multidimensional and encompasses a broad range of life domains among which health is one of the most important determinants In addition to being an objective medical evaluation the health related quality of life HRQOL which typically combines physical psychological and social domains of health 2 is more recognized as a central outcome in healthcare strategies highlighting the fact that health is deeply intertwined with a patient s perspective Accordingly the use of HRQOL assessment is particularly relevant and is increasingly widespread in clinical practices 3 predominantly for ageing populations and for the inherent expansion in the prevalence of non communicable diseases NCDs which include cardiovascular diseases diabetes mellitus and hypertension NCDs are currently the leading cause of mortality in the modern world contributing to 38 million deaths each year 4 According to WHO the global burden of NCDs is imputable to ageing rapid urbanization and to globalization of unhealthy lifestyles Among modifiable risk factors overweight and obesity are significant contributors to the high prevalence rate of NCDs making them the priority target in various public health programs 5 A major cause of overweight and obesity is the excessive accumulation of body fat due to an imbalance between energy consumption and expenditure particularly in populations with sedentary behaviors The accumulation of body fat predominantly within the abdominal region is clearly associated with a chronic low grade inflammatory state and an impaired redox status 6 both being principal pathological pathways involved in the development of NCDs It is noteworthy that such disorders are also identified as validated metabolic indicators of ageing 7 suggesting that overweight and obesity are conditions that could potentially accelerate ageing and exacerbate the risk of ageing linked NCDs 8 In addition to their role in the etiology of these common medical conditions overweight and obesity have profound adverse physical social and psychological consequences that can negatively affect HRQOL and impair everyday life 9 10 which appears to be an increasingly important outcome for patients and clinicians as well as for policymakers As a result QOL has become a valuable endpoint assessed in both epidemiological and interventional weight management studies in overweight and obese volunteers 11 13 Measuring HRQOL is the subjective perception of one s health where patients are asked to rate several aspects of their life Numerous studies have demonstrated that self rated health measures are important predictors of mortality in various populations 14 The Short Form 36 Health survey SF 36 a commonly used measure in HRQOL research is a generic methodology developed and validated in the Medical Outcomes Study 15 that assesses eight important HRQOL domains that encompass health related social physical and mental dimensions The reliability of this questionnaire has been validated both in a healthy population 16 and among people with chronic and acute health conditions but also when comparing between different groups of patients 10 Furthermore several authors have demonstrated a negative correlation between BMI and SF 36 scores 17 18 and also an improvement of HRQOL correlated with weight loss in overweight people 13 Among the dietary patterns which are mostly studied for their health effects it appears that adherence to the Mediterranean diet has been correlated to a lower risk for NCDs 19 it is assumed that particular bioactive constituents of the Mediterranean diet namely polyphenols significantly contribute to the reported health promoted effects 20 Moreover along with their widely studied antioxidant properties recent studies demonstrate the modulatory effects of phenolic compounds on various cellular signaling pathways and responses such as inflammation and energy metabolism 21 22

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Nutrients 2021 13 492 3 of 16 highlighting the complex mode of their individual mechanism of action in preventing NCDs 23 Emerging large cohort studies that investigated the Mediterranean diet specifically the regular consumption of a diversity of its main polyphenol content have shown a positive correlation to HRQOL 24 25 suggesting that such bioactive constituents might be beneficial in improving overweight and obesity linked impaired HRQOL The aim of this clinical study was to investigate whether 16 weeks of supplementation with an accurately characterized ingredient formulated from extracts of certain fruits and vegetables commonly consumed within the Mediterranean diet could improve HRQOL in overweight and obese but otherwise healthy subjects 2 Materials and Methods 2 1 Subjects Ninety two healthy overweight and obese subjects were recruited through advertisements in the region of Murcia in southern Spain Both men and women between the ages of 25 55 years being overweight to obese BMI 25 40 kg m2 but otherwise healthy were included in the study Subjects were excluded if they had a metabolic or chronic disease had an allergy to carrot grape grapefruit green tea caffeine or to guarana were involved at the time of recruitment or within the previous 6 months in a chronic supplementation program engaged in smoking cessation or had high alcohol consumption were pregnant or were breastfeeding were in menopause were suffering depression or were involved in physical activity more than twice a week The study was approved by the Universidad Cat lica San Antonio de Murcia UCAM Spain Ethics Committee approval N 5551 and conducted per the guidelines laid out in the Declaration of Helsinki 26 and in compliance with Good Clinical Practices defined in the ICH Harmonized Tripartite Guideline 27 All participants were informed about the study procedures and signed written informed consent before entering the study This trial was registered at clinicaltrials gov as NCT03423719 2 2 Test Supplement Fiit ns developed by FYTEXIA France is principally obtained by alcohol and water extraction of grapefruit Citrus paradisi Macfad grape Vitis vinifera L and guarana seed Paullinia cupana Kunth by water extraction of green tea Camellia sinensis L Kuntze and black carrot Daucus carota L Fiit ns provides bioactive compounds specifically polyphenols from the flavonoid family and natural components of the methylxanthine family to from an extract of guarana seeds as well as vitamin B3 The placebo product was 100 maltodextrin which is polyphenol methylxanthine and vitamin B3 free Both Fiit ns and placebo were supplied in 450 mg capsules of identical appearance and flavor The supplement was analyzed by means of high performance liquid chromatography HPLC An Agilent HPLC 1260 apparatus Agilent Technologies Les Ulis France using software Openlab CDS Chemstation Edition version 1 3 1 coupled with a diode array detector was used Separations were carried out by means of a Zorbax Stablebond SB C18 column 4 6 150 mm 5 m particle size To detect different phenolic classes two different analytical methods were adopted one for bioflavonoids and caffeine and one for anthocyanins For flavonoids and caffeine mobile phase A consisted of water mobile phase B was acetic acid and mobile phase C was 100 acetonitrile The linear gradient program was used as follows a 0 to 5 min 94 A and 6 B b 5 to 10 min 82 4 A 5 6 B and 12 C c 10 to 15 min 76 6 A 5 4 B and 18 C d 15 to 25 min 67 9 A 5 1 B and 27 C e 25 to 30 min 65 A 5 B and 30 C f 30 to 35 100 C g 35 to 40 min 100 C h 40 to 45 min 64 A and 6 B Monitoring was performed at 280 nm at a flow rate of 1

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Nutrients 2021 13 492 4 of 16 mL min and injection volume of 25 L Flavanones flavanols and caffeine were respectively expressed as naringin catechin and caffeine Regarding anthocyanins mobile phase A was water mobile phase B consisted of formic acid and mobile phase C was acetonitrile The gradient program used is described as follows a 0 to 5 min 84 18 A 10 B and 5 82 C b 5 to 20 min 77 6 A 10 B and 12 4 C c 20 to 35 min 68 2 A 10 B and 21 8 C d 35 to 40 min 58 8 A 10 B and 31 2 C e 40 to 45 min 44 7 A 10 B and 45 3 C f 45 to 50 min 44 7 A 10 B and 45 3 C g 50 to 60 min 40 A 10 B and 50 C h 60 to 65 min 84 18 A 10 B and 5 82 C Monitoring was performed at 520 nm at a flow rate of 0 8 mL min and injection volume of 10 L Anthocyanins were expressed as cyanidin 3 O glucoside equivalents Naringin catechin and caffeine standards were purchased from Sigma Aldrich Co St Louis MO USA and cyanidin 3 O glucoside standard was purchased from Extrasynthese Genay France 2 3 Study Design and Interventions The study was designed as a 16 week randomized double blinded placebocontrolled clinical trial Eligible participants were randomized using a simple block randomization of 1 1 with an additional stratification for sex 40 minimum and 60 maximum each sex with a separated randomization list using computer generated random numbers Allocation concealment was achieved with sealed opaque envelops Once enrolled subjects received either the supplement n 43 or a visually identical placebo n 49 They were instructed to take two capsules daily for 16 weeks one in the morning at breakfast and one at lunchtime Throughout the course of the study volunteers were instructed by a dietitian to consume a normal caloric and balanced diet corresponding to their individual needs by determining their specific resting energy expenditure REE calculated from the revised Harris Benedict equation and adjusted per individual level of physical activity 28 At baseline W1 volunteers performed a 24 hour diet recall interview corresponding to the consumption of two days during the previous week and one day during the previous weekend in order to evaluate their usual dietary habits At the end of the studied period the same interview was performed to check compliance with dietary instructions A difference of 10 between the reported and recommended intakes at the end of the study was considered as satisfactory Moreover general adherence to the Mediterranean dietary pattern was assessed using the Mediterranean Diet Serving Score MDSS 29 This score ranges from 0 to 24 with an optimal cut off point of 13 5 which discriminates adherent and non adherent individuals Subjects were also encouraged to maintain their usual level of physical activity throughout the 16 week long intervention period The subjects were provided with a pedometer HJ 321 Omron Healthcare which was worn at the hip to record the physical mobility as the number of daily steps Subjects reported their daily level of activity in a diary Subjects reported to the UCAM Research Center for 5 visits i pre inclusion visit at week 0 W0 to verify the subject s eligibility to assess anthropometrics and to collect blood samples for the evaluation of safety parameters ii baseline visit W1 iii followup visits W4 W8 and W12 and final visit W16 During each visit subjects returned their physical activity diary and the unused investigational supplements and were questioned about possible occurrence of adverse events before they were provided with a new pill dispenser for the 4 following weeks

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Nutrients 2021 13 492 5 of 16 2 4 Measurements 2 4 1 Health Related Quality of Life HRQOL was measured at baseline W1 and at the end of the intervention period W16 using the Spanish version of the 36 item Short Form SF 36 health survey 30 This generic instrument assesses participants self reported HRQOL across physical and mental components Questions pertained to the individuals typical day during the past four weeks and usual experiences The 36 questions were distributed across eight subscales physical function PF role physical RP limitations caused by physical problems bodily pain BP general health GH perception vitality VT social functioning SF role emotional RE limitations caused by emotional problems and emotional well being EWB The eight dimensions ranged in score from 0 to 100 with higher scores indicating better HRQOL The SF 36 also included one Physical Component Summary PCS score and one Mental Component Summary MCS score as well as an overall score of quality of life 2 4 2 Body Composition At baseline W1 and at the end of the study period W16 body composition was assessed in the morning with volunteers in a fasted state and wearing light clothing and no shoes Body weight kg was measured with calibrated weighing scales TBF 300MA Tanita Corporation IL USA Waist circumference cm was measured at the narrowest point between the lowest rib and the iliac crest using a non stretchable tape The Index of Central Obesity ICO scores were calculated as the waist to height ratio Body fat mass was determined using a dual energy X ray absorptiometry DXA scan of the whole body XR 46 Norland Corp Fort Atkinson WI USA Discrimination of whole body fat mass FM and body trunk fat mass TFM was performed with a computerized software Software Illuminatus DXA v 4 4 0 Visual MED Inc Charlotte NC USA and Norland CooperSurgical Company Minneapolis MN USA using standardized procedures 2 4 3 Self Reported Physical Activity The self reported International Physical Activity Questionnaire IPAQ instrument was used to determine global physical activity levels 31 This self administered longform questionnaire consisted of 27 items that covered four different domains of physical activity working transportation housework and gardening and leisure time that occurred during the previous seven days The results are presented as an estimation of energy expenditure in metabolic equivalent minutes per week Met min week and a categorical score was calculated to classify volunteers as inactive moderately or highly active Volunteers completed the IPAQ questionnaire in the presence of an investigator at W1 and W16 2 4 4 Safety Parameters Safety parameters were assessed before inclusion into the study W0 and at the end of the intervention period W16 in order to verify and confirm the healthiness of the volunteers Safety parameters included liver function parameters alanine transaminase ALT aspartate aminotransferase AST gamma glutamyltransferase GGT renal function parameters urea creatinine sodium Na potassium K and heart rate 2 5 Statistical Analysis Data sets were analyzed using XLSTAT Biomed software v 2017 6 for Mac Addinsoft Paris France The data are expressed as the mean standard deviation SD At baseline the distribution was considered normal Changes within and between groups at W1 and W16 were analyzed using paired and unpaired Student s t test respectively To

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Nutrients 2021 13 492 6 of 16 compare baseline differences between the SF 36 scales and population norms one sample t test was used A minimum value of p 0 05 was selected as the threshold for statistical significance The primary outcome addressed in this study was the difference in SF 36 total scores after the 16 week intervention period The power calculation was based on the previous results of a pilot study conducted with Fiit ns 32 0 05 power 1 0 8 and was performed based on an expected clinical difference in SF 36 total scores between W1 and W16 within the supplemented group of a 5 benefit minimum to determine the targeted final sample size n 28 per group Considering a drop out rate of 20 and failure rate risk of 20 inclusion of 92 subjects was recommended 3 Results 3 1 Characterization of the Supplement The total bioactive content corresponds to 29 27 g 100 g dry matter with a total flavonoid content measured at 24 75 g 100 g The flavanol content corresponded to 15 67 g 100 g and included catechin epigallocatechin gallate epicatechin and epicatechin gallate respectively measured at 1 47 9 55 2 37 and 2 28 g 100 g The flavanone content corresponded to 8 91 g 100 g among which isonaringin naringin hesperidin and neohesperidin contents were 0 54 7 65 0 03 and 0 13 g 100 g respectively whereas total unidentified flavanone was evaluated as the naringin equivalent at 0 56 g 100 g The total anthocyanin content corresponded to 0 17 g 100 g as the kuromanin equivalent The caffeine content was measured at 4 52 g 100 g and a third party laboratory measured the vitamin B3 content at 2 02 g 100 g Table 1 Table 1 Characterization of phenolic compounds and caffeine present in the supplement Compound Caffeine Catechin Epigallocatechin Gallate Epicatechin Epicatechin Gallate Flavanone like 1 Isonaringin Naringin Hesperidin Neohesperidin Flavanone like 2 Flavanone like 3 Cyanidin 3 xylosylglucosylgalactoside Cyanidin 3 xylosylgalactoside Cyanidin 3 sinapoylxylosylglucosylgalactoside Cyanidin 3 feruloylxylosylglucosylgalactoside Cyanidin 3 pcoumarylxylosylglucosylgalactoside Rt min Max nm 13 5 9 0 11 9 12 8 15 8 16 1 18 6 19 5 20 3 21 2 27 6 30 4 6 2 7 9 11 2 12 4 14 3 273 278 274 280 278 284 323 284 330 284 330 284 328 284 328 284 329 289 328 516 518 531 528 528 Content mg 100 g Mean SD 4523 2 450 4 1472 9 85 1 9549 9 282 9 2373 0 416 6 2279 3 372 9 97 6 27 7 540 8 156 1 7646 9 66 3 25 4 24 3 134 2 86 8 263 5 4 0 196 4 15 3 9 5 2 0 39 3 7 4 13 8 1 5 106 1 13 1 3 0 1 6 3 2 Baseline Characteristics From the 92 individuals who were randomly allocated to either the supplement n 43 or the placebo n 49 78 subjects completed the 16 week intervention 85 of the randomly assigned subjects after having started the intervention a total of 14 volunteers dropped out for personal reasons including 6 within the supplemented group and 8 within the placebo group Moreover at the end of the study period 6 subjects were excluded from final analysis because of protocol deviation including 2 subjects within the supplemented group and 4 within the placebo group who either did not complete the SF36 questionnaire or who were non compliant with the protocol Finally 72 volunteers

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Nutrients 2021 13 492 7 of 16 were included in the analysis with 35 individuals in the supplemented and37 individuals in the placebo group Figure 1 Baseline data of the study population are presented in Table 2 The two groups were similar with respect to age height body weight and SF 36 total scores At baseline the placebo group had a significantly higher average BMI compared with the supplemented group Figure 1 CONSORT Consolidated Standards of Reporting Trials flow diagram of study Table 2 Baseline characteristics of the study population Variable Subjects n M F Age years Height meters Body weight kg BMI kg m2 SF 36 score points Whole Population 72 34 38 Mean SD 40 6 1 69 0 09 87 0 12 6 30 5 3 5 81 6 9 2 Placebo Group 37 16 21 Mean SD 41 6 1 68 0 08 89 3 12 2 31 6 4 0 81 7 8 2 Supplemented Group 35 18 17 Mean SD 39 7 1 70 0 11 84 5 12 6 29 3 2 5 81 5 10 3 Significant at p 0 05 level M male F female BMI Body mass index SF 36 Short form 36 Health survey 3 3 Health Related Quality of Life Regarding the whole population at baseline Table 3 SF 36 subscales regarding vitality emotional well being and mental component scores were significantly lower than the age specific populations norms taken from the Spanish population reference values 33 At W1 placebo and supplemented groups exhibited similar SF 36 scores including both individual domains and summary scores Table 4 After 16 weeks of supplementation the supplemented group experienced a significant 5 3 increase p 0 001 Figure 2 in total SF 36 score while no change was observed in the total score of the placebo group The supplemented group showed statistically significant improvements in five out of eight domains of the health related quality of life Respective improvements were observed for the physical component summary PCS 11 2 p 0 002 including physical functioning PF 5 5 p 0 006 bodily pain BP 11 2 p 0 028 and general health GH 7 2 p 0 010 as well as for the mental component summary MCS 4 1 p 0 021 which included vitality VT 7 8 p 0 006 and emotional well being EWB 5 2 p 0 021 No statistically significant changes were shown within the placebo group after the 16 week intervention

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Nutrients 2021 13 492 8 of 16 Table 3 Mean scores for SF 36 eight subscales at baseline in the study and in the Spanish population aged 25 54 Scale Physical component score Physical functioning Role physical Bodily pain General health Mental component score Role emotional Vitality Emotional well being Social functioning Baseline 83 8 89 5 93 8 79 0 73 0 79 4 92 4 62 8 70 6 91 8 Age Specific Population Norm 83 0 91 9 87 5 82 6 72 7 82 3 91 3 70 2 74 9 92 9 Combined score for men and women ages 25 54 as the age specific population norm a significant difference at baseline from the age specific population norm for the scale at p 0 05 level Table 4 Mean scores for SF 36 eight subscales including both physical and mental components and total health related quality of life scores at baseline W1 and at the end of the study W16 Scale SF 36 Total score Physical component score Physical functioning Role physical Bodily pain General health Mental component score Role emotional Vitality Emotional well being Social functioning Placebo Group Supplemented Group W1 W16 W1 W16 Mean SD Mean SD Mean SD Mean SD 81 7 8 2 82 2 8 2 81 5 10 3 85 8 a 6 4 84 3 7 6 83 8 8 9 83 4 12 6 88 7 a 7 6 88 6 9 4 90 6 8 4 90 4 12 7 95 4 a 7 0 94 3 7 3 93 6 8 1 93 4 11 6 95 7 6 6 80 7 18 0 78 3 23 3 77 1 22 9 85 8 14 5 73 5 13 3 72 8 11 7 72 5 16 0 77 8 13 7 79 1 10 8 80 7 10 5 79 7 10 7 82 9 8 0 91 2 14 8 93 5 12 6 93 6 12 0 94 9 9 2 62 4 11 1 63 1 12 2 63 1 13 4 68 0 a 11 1 70 9 11 1 73 5 10 9 70 3 12 9 73 9 10 0 91 9 15 9 92 6 14 9 91 8 12 1 95 4 9 1 An intragroup difference between baseline W1 and end of the study W16 at p 0 05 a an intergroup difference at the end of the study W16 at p 0 05

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Nutrients 2021 13 492 10 of 16 Table 5 Body weight BMI waist circumference ICO total body fat mass and total trunk fat mass scores at baseline W1 and at the end of the study W16 Body weight kg BMI kg m2 Waist circumference cm ICO Total body fat mass kg Total trunk fat mass kg Placebo Group Supplemented Group W1 W16 W1 W16 Mean SD Mean SD Mean SD Mean SD 89 3 12 2 89 1 12 5 84 5 12 6 83 2 b 12 6 31 6 4 0 31 5 3 9 29 3 a 2 5 28 9 b 2 8 94 2 9 7 94 6 9 3 90 7 8 8 89 6 b 9 3 a b 0 560 0 05 0 563 0 05 0 533 0 04 0 526 0 04 35 2 10 4 35 2 10 8 30 5 a 7 4 29 3 b 7 9 a 18 1 5 4 18 1 5 9 15 7 4 1 14 7 b 4 2 An intragroup difference between baseline W1 and end of the study W16 at p 0 05 a b intergroup differences at baseline W1 and at the end of the study W16 at p 0 05 3 5 Self Reported Physical Activity and Average Daily Steps Recording At baseline both groups showed similar self reported levels of physical activity While it did not significantly change within the placebo population p 0 280 the supplemented subjects showed an increase of 1308 Met min week p 0 05 after 16 weeks of supplementation Table 6 Regarding categorical scores at baseline the rates of volunteers within each category i e inactive moderately active and highly active were similar between groups After 16 weeks the rates of inactive people remained the same in both groups within the placebo group the rate of highly active subjects decreased by 43 while the rate of moderately active individuals increased by 14 In contrast within the supplemented population the rate of moderately active subjects decreased by 14 but the number of highly active individuals increased by 43 The number of average daily steps was significantly different at baseline between placebo and supplemented subjects p 0 028 The placebo group did not experience any significant change in average daily steps monitored after 16 weeks while the supplemented subjects significantly decreased their average rate by 678 steps p 0 019 to reach a similar level to the placebo population Table 6 Mean total score for self reported physical activity IPAQ International Physical Activity Questionnaire and daily number of steps pedometer at baseline W1 and at the end of the study W16 IPAQ score Met min week Inactive Moderately active Highly active Daily steps Placebo Group W1 W16 Mean SD Mean SD 4798 4740 4231 4190 15 2 15 2 63 6 72 7 21 2 12 1 Mean SD Mean SD 6770 2239 7186 2679 Supplemented Group W1 W16 Mean SD Mean SD 4766 4721 6074 6631 12 5 12 5 65 6 56 3 21 8 31 2 Mean SD Mean SD 8169 a 2797 7491 2964 An intragroup difference between baseline W1 and end of the study W16 at p 0 05 a an intergroup difference at baseline W1 at p 0 05 MET min week Metabolic Equivalent Task minutes per week 3 6 Recommended and Reported Dietary Intake Recommended intake at baseline did not differ between the two groups p 0 770 Table 7 When recommended intake was compared with reported intake at baseline the differences were 13 7 and 7 8 for the placebo and supplemented groups respectively After 16 weeks the differences between recommended and reported intake in both groups were lower than 10 8 8 and 9 0 for the placebo and for the supplemented groups respectively Mediterranean Diet Serving Scores MDSS were similar between both groups at 8 4 and 8 6 for placebo and supplemented populations

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Nutrients 2021 13 492 11 of 16 respectively indicating a non adherence to the Mediterranean diet pattern during the intervention period Table 7 Recommended and reported dietary intake at baseline W1 and at the end of the study W16 Recommended intake Kcal Reported intake Kcal MDSS score Placebo Group Supplemented Group W1 W16 W1 W16 Mean SD Mean SD Mean SD Mean SD 2074 273 2084 281 2096 360 2039 342 1789 471 1899 502 1933 463 1855 392 Mean SD Mean SD 8 4 3 7 8 6 4 2 An intragroup difference between baseline W1 and end of the study W16 at p 0 05 3 7 Safety After 16 weeks both liver and renal function parameters were within the healthy range in both groups suggesting that no health impairment occurred throughout the course of the study Moreover heart rates stayed stable throughout the course of the study Table 8 No adverse events or side effects linked to the supplement were reported during the course of the study Table 8 Clinical safety values at baseline W1 and at the end of the study W16 Parameters normal range Liver function ALT 7 55 U L AST 8 48 U L GGT 6 48 U L Kidney function Urea 15 46 mg dL Creatinine 0 6 1 3 mg dL Na 135 145 mmol L K 3 6 5 2 mmol L Heart rate bpm Placebo group W1 W16 Mean SD Mean SD 21 4 20 2 19 1 9 1 5 5 11 7 21 0 20 1 19 9 35 4 0 79 141 2 4 3 71 8 9 1 33 0 0 18 0 74 1 2 141 2 0 3 4 3 10 2 72 1 Supplemented group W1 W16 Mean SD Mean SD 8 5 5 3 11 9 25 0 22 4 23 1 15 9 6 3 13 4 25 1 23 3 24 7 14 7 10 0 14 0 7 7 0 16 2 1 0 2 8 6 31 9 7 8 0 74 0 15 141 7 1 7 4 3 0 2 71 3 11 2 30 1 0 76 141 1 4 3 70 4 7 4 0 16 1 7 0 3 16 4 An intragroup difference between baseline W1 and end of the study W16 at p 0 05 4 Discussion The main results of this study demonstrate that a 16 week long supplementation period with an ingredient formulated from a blend of various botanical extracts which are rich in a diversity of polyphenols and usually consumed as part of the typical Mediterranean diet is associated with significant improvements of both the physical and mental components of the HRQOL in overweight and obese but otherwise healthy subjects of both sex At baseline volunteers showed an impaired HRQOL namely in vitality and emotional well being subscales for which values were below the Spanish age specific population reference norms 33 Although similar studies have previously reported impairment across all off the SF 36 subscales most of them were conducted either with a population displaying a significantly higher grade of obesity or with an additional manifestation of comorbidities 10 17 Here baseline impairments observed for vitality and emotional well being are in line with the work of Blissmer et al 11 who found similar decrements in a highly comparable population of healthy overweight and moderately obese subjects indicating higher feelings of tiredness and anxiety

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Nutrients 2021 13 492 12 of 16 Following a 16 week intervention period associated with a normal caloric diet both the physical and mental components of the HRQOL significantly improved in volunteers supplemented with the polyphenol rich ingredient compared to the placebo group Net improvements were shown by subjective ameliorations in bodily pain general health vitality physical functioning emotional well being It is noteworthy that after the 16week long period of supplementation both the vitality and the emotional well being values improved to achieve the level of the reference norms of the Spanish age specific population Improvements in these different subscales and in both the physical and mental component scores must be considered as clinically significant as it has been stated that absolute differences of 3 5 points are clinically relevant 34 In addition to these improvements the 16 week chronic polyphenolic supplementation induced significant body weight loss with an average difference between both groups of 1 1 kg It is noteworthy that this decrease was essentially driven by an 86 fat mass reduction for which 89 was located within the trunk area pointing out a particularly beneficial effect on body composition Such an improvement may to some extent positively impact the HRQOL Indeed some authors have demonstrated that weight loss was associated with improvement of both physical and mental health dimensions in several intervention trials 11 13 35 37 Moreover the amount of weight loss and the level of HRQOL improvement may be directly interconnected 37 38 Nevertheless here we did not demonstrate a significant correlation between weight or fat loss and HRQOL improvement hypothesizing that weight loss could be an indirect consequence of HRQOL improvement as it has been recently demonstrated with a bidirectional relationship between both parameters 39 Moreover catechins from green tea have previously been demonstrated to have antiobesity effects 40 through various mechanisms of action such as the inhibition of pancreatic lipase 41 as well as through the regulation of obesity related genes and proteins 42 However it is important to highlight that these interventional studies used significantly higher amounts of green tea catechins whereas in the current supplement it only corresponded to one cup of green tea daily Moreover caffeine content and flavanones from grapefruit extract could also potentiate the decrease in body fat mass as enhanced lipolysis leading to decreases in body weight and fat mass has previously been demonstrated in overweight and obese subjects supplemented with such kinds of bioactive compounds 43 Accordingly as each of the bioactive components in the supplement are present at lower levels compared to efficient dosages from the literature it could be assumed that the beneficial observations for the supplement should be attributed to the whole formulation In parallel to body composition improvement the level of physical activity as assessed through the IPAQ questionnaire significantly intensified p 0 05 after 16 weeks of supplementation Thus while 69 of volunteers from the supplemented group maintained their usual level of physical activity 25 moved into a higher category compared with the placebo population for which only 9 of volunteers improved their level of physical activity Contradictorily at the same time the supplemented group showed a decrease in daily steps as assessed with a pedometer while no change was observed in the placebo population This discrepancy may be explained by the fact that pedometers are not suitable for the measurement of certain types of physical activity such as swimming cycling or heavy lifting which are otherwise assessed through the IPAQ questionnaire making these both subjective and objective measurements two complementary tools in physical activity assessment As volunteers were encouraged to maintain their usual physical activity level throughout the course of the study it can be hypothesized that the significantly higher physically active lifestyle reported within the supplemented group is not the result of conditioned mental engagement only Indeed the increase of HRQOL and namely of the feeling of increased vitality may explain such a rise in physical activity A recent review that aimed at examining the link between physical activity and HRQOL concluded that there is a consistent cross sectional association between physical activity level and HRQOL namely in the vitality and in the

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Nutrients 2021 13 492 13 of 16 physical functioning domains however the finding could not confirm a causal relationship i e higher HRQOL leading to a higher level of physical activity or vice versa or mutual influence 44 Nevertheless the engagement in a more active lifestyle within the supplemented population may also have a positive effect on body composition improvement as discussed above Besides positive effects on body composition and engagement in physical activity it appears that phenolic compounds may induce through other various mechanisms observable effects in terms of HRQOL improvement Accordingly adherence to a Mediterranean dietary pattern characterized by wide consumption of fruits and vegetables cereals fish olive oil and red wine has been directly associated with better QOL in an analysis including more than 11 000 participants that belonged to the SUN Seguimiento University of Navarra cohort 45 46 While several nutrients and micronutrients may contribute to this effect phenolic compounds have been suggested to be the main mediators a large cross sectional study demonstrated a direct relationship between the antioxidant contents of the Mediterranean diet including the flavonoid content and HRQOL 25 In addition in another recent study including more than 13 000 women higher flavonoid intake at midlife was associated with increased odds of healthy ageing based on higher survival at older ages free of chronic diseases and maintenance of midlife HRQOL as assessed by the SF 36 survey 47 Here despite the studied population being Spanish and particularly prone to complying with the Mediterranean diet the MDSS did not demonstrate any significant adherence to this pattern in either groups for whom the consumption of fruits and vegetables the main sources of flavonoids was below the recommendations of the last updated version of the Mediterranean Diet Pyramid 48 Thus it can be hypothesized that a regular basic diet has no or only a minor impact on HRQOL since there were no improvements within the placebo population whereas the supplemented subjects that covered the gap of phenolic micronutrients significantly improved their HRQOL Bioactive compounds occurring in the supplement may positively impact physiological functions related to both physical and mental health status mainly vascular inflammation coagulation factors and endothelial function 25 which are all described to be impaired during overweight and obesity 49 The aptitude of certain phenolic compounds in improving vascular health has been demonstrated both in vitro and in vivo 50 Catechins from green tea positively impact vascular function through various complementary mechanisms linked to their antioxidative and anti inflammatory properties as well as to their capacity to activate endothelial NO synthase 51 Similarly grape polyphenols also demonstrated an aptitude to improving vascular impairments through similar molecular mechanisms 52 all contributing to a better peripheral and central blood flow which in turn may positively affect physical and mental health status 53 While modulation of both oxidative stress and inflammatory parameters the main contributors in the improvement of vascular function and blood flow has previously been demonstrated with the current supplement in a study involving obese subjects 32 specific mechanisms of flow mediated dilation improvements and subsequent blood flow increase have not yet been investigated Moreover as the beneficial effect of the supplement on HRQOL has been demonstrated further investigations will have to be conducted in attempts to confirm the causal relationship between the bioavailability and pharmacokinetics of the polyphenols metabolites and the mechanisms involved in improving vascular function Beyond the mentioned limitations the results of the present study reveal the beneficial and systemic effects of phenolic compounds on subjective physical and mental symptoms linked to overweight and obesity The study was designed to minimize bias and thus individualized calorie intake recommendations and diet interviews as well as monitoring of daily steps were identified as possible confounding factors Despite the studied population being recruited in a Mediterranean region neither of the two groups

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Nutrients 2021 13 492 14 of 16 adhered to the typical regional diet which strengthens the hypothesis that phenolic compounds certainly contribute to subjective health as previously proposed by others 25 47 In conclusion this study demonstrated that the 16 week long consumption of an ingredient obtained from polyphenol rich fruit and vegetable extracts associated with both caffein and vitamin B3 supports improvements in HRQOL specifically in both mental and physical subjective feelings In addition the decrease in body fat mass and the significantly increased engagement in physical activity probably established a virtuous cycle between body composition physical activity and perceived HRQOL The mechanisms of action likely involve improvements in vascular function via well known antioxidative and anti inflammatory properties of phenolic compounds Such beneficial effects may be extended to other situations where HRQOL is impaired particularly during the ageing process where an imbalance of body composition and a loss of vitality and of physical functioning associated with a more sedentary lifestyle are commonly observed Author Contributions Conceptualization C R and J C methodology P E A and L H C investigation P E A L H C J A R A E M C J M M R and A M R writing original draft preparation C R writing review and editing C R J C P E A L H C J A R A E M C J M M R A M R S G and C L All authors have read and agreed to the published version of the manuscript Funding This research received no external funding Institutional Review Board Statement The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Comite de etica de la UCAM protocol code N 5551 on April 24th 2015 Informed Consent Statement Informed consent was obtained from all subjects involved in the study Data Availability Statement The data presented in this study are available on request from the corresponding author due to privacy restriction Conflicts of Interest Fytexia is involved in the research and development and marketing and sales of polyphenol extract based ingredients for food and nutraceutical industries Therefore Fytexia has a commercial interest in this publication UCAM and UMR 204 Nutripass were paid by Fytexia to perform and report the scientific work that formed the basis of this publication Fytexia UCAM UMR 204 Nutripass and all authors declare that the data in this report represent a true and faithful representation of the work that has been performed The financial assistance of Fytexia is gratefully acknowledged References 1 2 3 4 5 6 7 8 9 Whoqol Group The World Health Organization Quality of Life assessment WHOQOL Position paper from the World Health Organization Soc Sci Med 1995 41 1403 1409 Testa M Simonson D Current concepts Assessment of quality of life outcomes N Eng J Med 1996 334 835 840 Fayers P M Machin D Quality of Life Assessment Analysis and Interpretation John Wiley and Sons Chichester UK 2000 WHO Noncommunicable diseases World Health Organization Available online http www who int mediacentre factsheets fs355 en accessed on 7 March 2018 Gortmaker S L Swinburn B A Levy D Carter R Mabry P L Finegood D T Huang T Marsh T Moodie M L Changing the future of obesity Science policy and action Lancet 2011 378 838 847 doi 10 1016 s0140 6736 11 60815 5 Fern ndez S nchez A Madrigal Santill n E O Bautista M Esquivel Soto J Morales Gonz lez Esquivel Chirino C Durante Montiel I S nchez Rivera G Valadez Vega C Morales Gonz lez J A Inflammation Oxidative Stress and Obesity Int J Mol Sci 2011 12 3117 3132 doi 10 3390 ijms12053117 Rahman I Bagchi D Inflammation Advancing Age and Nutrition Rahman I Bagchi D Eds Academic Press London UK 2013 Ahima R S Connecting obesity aging and diabetes Nat Med 2009 15 996 997 doi 10 1038 nm0909 996 Fontaine K R Barofsky I Obesity and health related quality of life Obes Rev 2001 2 173 182 doi 10 1046 j 1467789x 2001 00032 x

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Nutrients 2021 13 492 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 16 of 16 Rippe J M Price J M Hess S A Kline G Demers K A Damitz S Kreidieh I Freedson P Improved psychological wellbeing quality of life and health practices in moderately overweight women participating in a 12 week structured weight loss program Obes Res 1998 6 208 218 doi 10 1002 j 1550 8528 1998 tb00339 x Kolotkin R L Fujioka K Wolden M L Brett J H Bjorner J B Improvements in health related quality of life with liraglutide 3 0 mg compared with placebo in weight management Clin Obes 2016 6 233 242 doi 10 1111 cob 12146 Ross K M Milsom V A Rickel K A DeBraganza N Gibbons L M Murawski M E Perri M G The contributions of weight loss and increased physical fitness to improvements in health related quality of life Eat Behav 2009 10 84 88 doi 10 1016 j eatbeh 2008 12 002 Samsa G P Kolotkin R L Williams G R Nguyen M H Mendel C M Effect of moderate weight loss on health related quality of life An analysis of combined data from 4 randomized trials of sibutramine vs placebo Am J Manag Care 2001 7 875 883 Cameron A J Magliano D Dunstan D Zimmet P Hesketh K D Peeters A E Shaw J A bi directional relationship between obesity and health related quality of life Evidence from the longitudinal AusDiab study Int J Obes 2011 36 295 303 doi 10 1038 ijo 2011 103 Suzuki T Pervin M Goto S Isemura M Nakamura Y Beneficial effects of tea and the green tea catechin epigallocatechin3 gallate on obesity Molecules 2016 21 1305 Grove K A Sae Tan S Kennett M J Lambert J D Epigallocatechin 3 gallate Inhibits Pancreatic Lipase and Reduces Body Weight Gain in High Fat Fed Obese Mice Obesity 2012 20 2311 2313 doi 10 1038 oby 2011 139 Yang C S Zhang J Zhang L Huang J Wang Y Mechanisms of body weight reduction and metabolic syndrome alleviation by tea Mol Nutr Food Res 2016 60 160 174 doi 10 1002 mnfr 201500428 Dallas C Gerbi A Elbez Y Caillard P Zamaria N Cloarec M Clinical Study to Assess the Efficacy and Safety of a Citrus Polyphenolic Extract of Red Orange Grapefruit and Orange Sinetrol XPur on Weight Management and Metabolic Parameters in Healthy Overweight Individuals Phytother Res 2014 28 212 218 doi 10 1002 ptr 4981 Bize R Johnson J A Plotnikoff R C Physical activity level and health related quality of life in the general adult population A systematic review Prev Med 2007 45 401 415 doi 10 1016 j ypmed 2007 07 017 Ruano Rodr guez C Henriquez P Patricia Martinez Gonzalez M Miguel ngel Bes Rastrollo M Maira Ruiz Canela M Miguel Sanchez Villegas A Almudena Empirically Derived Dietary Patterns and Health Related Quality of Life in the SUN Project PLoS ONE 2013 8 1 10 doi 10 1371 journal pone 0061490 S nchez P H Ruano C De Irala J Ruizcanela M A Mart nez Gonz lez M Sanchezvillegas A Adherence to the Mediterranean diet and quality of life in the SUN Project Eur J Clin Nutr 2012 66 360 368 doi 10 1038 ejcn 2011 146 Samieri C Sun Q Townsend M K Rimm E B Grodstein F Dietary flavonoid intake at midlife and healthy aging in women Am J Clin Nutr 2014 100 1489 1497 doi 10 3945 ajcn 114 085605 Bach Faig A Berry E M Lairon D Reguant J Trichopoulo A Dernini S Medina F Battino M Belahsen R Miranda G et al Mediterranean diet pyramid today Science and cultural updates Public Health Nutr 2011 14 2274 2284 Perticone F Ceravolo R Candigliota M Ventura G Iacopino S Sinopoli F Mattioli P L Obesity and body fat distribution induce endothelial dysfunction by oxidative stress Protective effect of vitamin C Diabetes 2001 50 159 165 De Pascual Teresa S Moreno D A Garc a Viguera C Flavanols and Anthocyanins in Cardiovascular Health A Review of Current Evidence Int J Mol Sci 2010 11 1679 1703 doi 10 3390 ijms11041679 Moore R J Jackson K G Minihane A M Green tea Camellia sinensis catechins and vascular function Br J Nutr 2009 102 1790 1802 doi 10 1017 s0007114509991218 Dohadwala M M A Vita J Grapes and Cardiovascular Disease J Nutr 2009 139 1788S 1793S doi 10 3945 jn 109 107474 Watson R R Preedy V R Zibadi S Polyphenols in Human Health and Disease Elsevier Sandiego CA USA 2014 Volume 1