tonalin cla vs cla
Tonalin CLA Review (UPDATE: 2020) | 15 Things You Need to KnowWarning: The NCBI website requires JavaScript to operate. Pros and cons of CLA consumption: a vision of clinical evidence Sailas BenjaminBiotechnology Division, Department of Botany, Enzyme Technology Laboratory, University of Calicut, Kerala, 673 635 India Priji PrakasanBiotechnology Division, Department of Botany, Enzyme Technology Laboratory, University of Calicut, Kerala, 673 635 India Sajith SreedharanBiotechnology Division, Department of Technology Botany, With a general introduction on CLA chemistry, the main clinical evidences related to intervention strategies, body composition, cardiovascular health, immunity, asthma, cancer and diabetes are evaluated. It also examines the suppressed adverse effects, such as oxidative stress, insulin resistance, irritation of the intestinal tract and depression of milk fat. It appears that there was no consistent result even in similar studies conducted in different laboratories, this may be due to variations in age, gender, racial and geographical disparities, along with the type and dose of supplemented CLA. Thus, the supposed promising results reported in mechanistic and preclinical studies cannot be extrapolated with humans, mainly due to lack of inconsistency in analysis, prolonged intervention studies, follow-up studies and international coordination of concerted studies. Briefly, the clinical evidence accumulated so far shows that CLA is not causing significantly promising and consistent health effects to keep it as either a functional or medical food. Introduction Conjugated linoleic acids (CLAs) cover a group of positional and geometric isomers of octadecadieneic acids (18:2) – polyunsaturated fatty acids or PUFA synthesized in the rumine, deer, sheep and goat by microbial biotransform of fatty acids derived from the forage It is also synthesized in humans of the VA diet by the activity of Ī9-desaturase [, ] (Figure ). The Ī9-desaturase (also called tropelo-CoA desaturase; EC 1.14.99.5) catalyses the addition of a double cis-9 bond in the VA, and was present in several tissues, including the breast gland, adipose, liver and intestine; during the process, cis-9, trans-11-CLA (designed as 9LA) Thus, VA is the fundamental precursor of 9-CLA in ruminants (probably in mammals as well); therefore, an essential FA in humans. Major ⋅ fatty acids with their common names, structures and systemic names. In fact, most commercially available CLAs are produced by alkaline isomerization of LA-rich oils, such as sunflower oil, and tend to contain a 9 and 10-CLA equimolar mixture, along with a mixture of variable quantities (up to 30%) of other CLA geometric and positional isomers, and that the CLA 100% pure isomer is not available on the market] [. Therefore, the primary focus of all the mechanistic, preclinical and clinical studies related to CLA were in 9- and 10-CLAs, especially a mixture of both or rarely one of these two isomers (with other isomers as impurities) [, ]. Over the past two decades, hundreds of reports, mainly based on in vitro, microbial, animal and late human clinical studies, have accumulated with the most outstanding aspects of the contrasting biological activities of CLA isomers, especially 9 and 10-CLAs [, ]. There has been an overwhelming interest for the consumer towards the role of improving the health of specific foods or food components, the so-called "functional foods". The term "functional food" is often used as a generic description for the beneficial effects of the health of ingested foods that go beyond their traditional nutritional values. The supposed benefit for the health of the CLA was discovered almost three decades ago, that is, Ha and her coworkers found that the ground meat contained an anti-carcinogenic factor consisting of a series of conjugated dienoid isomers of LA []. As biomedical studies with CLA expanded, it became clear that CLA showed a range of positive health effects in experimental animal models. These supposed health benefits were attributed to the suppression of cancer, the reduction of body fat aggravation, the delay in the initiation of type II diabetes, the delay in the development of atherosclerosis, the improvement of bone mineralization and the modulation of the immune system [–]. Therefore, foods rich in CLA can be considered as functional foods (a food offers an additional function in the form of prevention of the promotion of health or disease in combination with some supporting ingredients); and that CLAs themselves are neither a food nor a functional food, but a FA class with some bioactive properties. In the light of the above-mentioned antecedent, this review critically examines whether the health benefits attributed to CLA in humans are clinically tested or not. Taking this into account, this review is classified into different sections with appropriate illustrations when necessary. Areas of thrust addressed include: CLA structure, intervention strategies, physiological effects of CLA consumption associated with diseases such as obesity, cardiovascular disorders, diabetes, cancer, inmunitary disorders; certain adverse effects of CLA consumption such as oxidative stress, abdominal irritations, depression of milk fat, insulin resistance, along with possible inconveniences such as ignoring placebo ingredients; differences in duration CLA. CLACon frequency structure, CLAs are mistakenly classified as omega-6 (abbreviated as Ļ-6 or n-6) FAs. In fact, the CLA is a class of FAs that comprises up to 56 isomers with double pairs of union (juxtaposed or neighbor) (i.e., in positions 6,8-; 7,9-; 8,10-; 9,11-; 10,12-; 11,13-; 12,14-; and 13,15- with cys-cis, cis-trans, trans-or geometric trans-dition) In terms of geometric isomers, the cys and trans configurations unequivocally indicate the stereo relationships around a double bond (paid); however, instead of cis and trans, the Z symbols (of German zusammen, means together) and E (of German entgegen, means opposite), respectively are used in some classifications. It should not be confused with the counting of the carbon position of Ļ (-CH3) or –COOH ended along the acyl chain; the first is used in the Ļ classification, while the second in the systemic nomenclature. From this, it is evident that only isomers with double bonds conjugated in carbon positions from 10 (from –COOH terminus) have effectively their first double C-C bonus in the Ļ-6 position, while they have the term methyl (-CH3) (i.e., the last or omega-C in the acyl chain) (Figure ). Thus, trans-10, cis-12-CLA (designated as 10-CLA) is a typical CLA Ļ-6; while the biological and predominantly (natural) asset that occurs 9-CLA is a typical FA -7Ļ []. Although, VA (the main precursor of 9-CLA) lacks double bonds combined; it is also a Ļ-6 FA, while it has the terminus methyl in the acyl chain (Figure). Intervention Strategies Clinical studies are generally of two categories: cross and non-crossed designs (parallel or between patients); in the first, subjects are randomized into two groups of which the first receives X (e.g., a drug) followed by Y (e.g., a placebo), and the second group receives Y first, followed by X; while in the non-transverse category also two groups will be placed there – one of the parallel groups In the cross study, the influence of the covariates is reduced as each cross-patient serves as its own control; while in the non-crossed study, treatment groups can be unbalanced in certain covariations []. Unlike non-transverse study, cross-sectional studies are statistically efficient, and therefore less topics are required for the study. In fact, in uncrossed design, the placebo effect will not be mixed with the effect of the test material. Thus, both methods have some advantages and disadvantages in different situations, and therefore the selection of the design of the study depends on the situation of the study. In general, clinical studies on CLA effectiveness are randomized, double-blind and placebo-controlled designs that comprise two groups, i.e., a group of subjects (the experimental group) receive the active isomers of CLA (i.e., 9- or 10-CLA) or its mixture; and the other half (control group) receive a placebo, designed without CLA or its isomerica mixture. In such experiments, neither the researcher nor the subjects know whether they received CLA or placebo designed for purpose (i.e., they are "blind") until all data are recorded. Such types of clinical studies ensure that the personal expectations of neither the researcher nor the subjects influence the results, which makes it more reliable, and thus eliminate possible treatment prejudices. However, in the case of some life-threatening diseases such as cancer, the analysis of the implications of direct supplementation of CLA appears to be difficult. In such cases, epidemiological studies were conducted in which data derived from a validated food frequency questionnaire were introduced in relation to an existing or newly established nutrient database containing analytical data from the specific FA [–]. These studies may be limited by the variability of CLA in food supply, as well as by the difficulty of evaluating the intake of these minor dietary FAs, CLA. Some of the CLA preparations available commercially, commonly used for clinical studies are detailed in Table . Table 1 Commercial Possibility of common CLA mixtures with its FA composition, commercial name and manufacturer (%)Total CLA (37.3); 79,420,6 capsules Croklaan,[]10-CLA (37.6) Pharma, Norway[]10-CLA (19.1);other CLA (15.8)CLA-enriched Margarines and yoghurts9-CLA (14.6);19,3drinkNIZO Food Research,[]10-CLAcap (3.3) Most clinical studies monitored the effect of commercially available CLA supplements, which generally contain a mix of 9 and 10-CLA approximately 50:50 ratio, while other researchers used naturally-enriched CLA dairy products to evaluate biological activities. The typical level of CLA in cow's milk fat is approximately 0.5% [, ]; that would vary considerably depending on the composition of the diet [e.g., green forage, organic forage, nature and age of forage ( younger leaves of herbs better), grazing altitude, silage and concentrates complemented with food fortification], along with the stage of the brotheled bacteria, etc. For example, the content of CLA could improve up to 2.08% of total milk FAs, if 4% (in terms of the dry weight of the food) soy oil (it is supplemented as a food concentrate) []; as indicated in the case, in which the linen or fish oil supplemented to the diet []. Naturally, CLA-rich dairy products (in situ) such as butter, cheese, etc. were incorporated into a variety of recipes such as those used to make muffins, cakes, sauces, and are often used as spreads. CLA and body composition Overweight or obesity - one of the typical syndromes of lifestyle diseases - is called the excessive accumulation of fat that affects health. The occurrence of overweight and obesity has increased as the most common health problem of modern food style. Obesity is considered a cause for many health problems such as heart disease, infertility and insulin resistance []. In order to lose weight and improve body composition (i.e., increase fat-free mass and decrease body fat, several companies made available on the market many dietary supplements, health preparations/formations or weight loss medications. Among them, CLAs draw more attention, as many preclinical studies in animal models demonstrated their inverse relationship with obesity. Significant clinical studies that investigate the effect of CLA on body composition and its intervention strategies are shown in Table . Table 2 List of clinical trials investigating the effect of CLA consumption on body composition; ↑-increased; ↓- diminished; ↔ SubjectsType of bottleAgeBMI kg/m 2 Dosage (g/d)CompositionPlaceboDurationMeditionCLACountry/StateReference60Overweight/obese1.7, 3.4, 5.1 or 6.89 and 10-CLA (50:50)Olive oil12 wkDual-energy X-ray absorptiometry↓ bodyfatNorway mass[13na weight 1.20-5027. Netherlands[]17Normal20-41-3CLA Farmnutrients Inc.SunflowerAceite64 dDual x-ray absorptiometry (DXA) Which body weight United States[]60Overweight/obese confidence1827.5-39.03.4TonalinTMOlive oil12 wkbioelectrical impedance, Dual x-ray absorptiometry↓ Average body weight " BMINorway[]48Normal/obese18-5030-353.2 or 6.49 " 10-CLA (50:50)Sunflower oil12 wkAbsorption of energy-per-real X-rays↑ ## ################################### The simplest method is that, to measure the thickness of subcutaneous fat in multiple places in the body as abdominal area, arms, subscapulular region (major triangular muscle near the shoulder bone), buttocks and thighs [, , ]. Other common-use measures are the analysis of bioelectronic impedance [], hydrodensitometry and dual-energy x-ray absorptiometry (DEXA) [–]. Among them, DEXA is the most used method in clinical studies to evaluate body composition due to CLA consumption. In fact, DEXA measures the total composition of the body and the fat content with a high degree of accuracy and is considered as the gold standard to measure the composition of the body, as an image of the whole body can be obtained []. Another commonly used method is the measurement of body mass index, that is, a measure of body weight index at the height of a person who is calculated as weight in kilograms divided by the square of height in meters (kg/m2). According to the World Health Organization [], a BMI greater or equal to 25 is overweight, and a BMI greater or equal to 30 is considered obesity. In fact, the BMI is not necessarily a good measure, especially in terms of body composition; for example, individuals such as athletes with strong bone and greater muscle mass (lean) have a BMI higher than non-athletes, and therefore different overweight BMI classifications are justified in evaluating obesity in terms of body circumference []. Some of the clinical studies suggested a positive intake association of 3.4 to 6.8 g/d isomeric mixture of CLA (mainly 9- and 10-CLA) supplementation for 12 wk for obese and overweight volunteers (BMI, 25 to 35 kg/m2) of both sexes in the reduction of body fat (BFM) mass significantly []. In another study, the supplementation of 4.2 g/d isomeric mixture of 9 and 10-CLAs for 4 wk reduced the sagittal abdominal diameter in obese individuals; but body weight and BMI were not affected [, ]. In a different study composed of 60 volunteers with overweight or obesity, including men and women who received 3.4 g/d CLA during 12 wk showed reduction in the average weight and medium BMI, and these results indicated that CLA in the given dose was safe in healthy populations with respect to the security parameters investigated []. Steck et al. [] examined the effect of 2 doses of CLA (3.2 g/d or 6.4 g/d) for 12 wk (mixture of 9- and 10 CLA in 50:50 ratio) on body composition in obese individuals, who were free from chronic diseases. They concluded that the lean body mass (LBM) increased by the highest dose after 12 wk of intervention. The supplementation of 9- and 10-CLAs at a dose of 1.7 g/d for 12 wk in overweight and class I (low risk) of obese subjects (i.e., BMI = 30.0 – 34.9) of the Chinese population showed lower obesity rates without obvious adverse effects []. Curiously, CLA was considered to be effective in reducing weight gain associated with psychiatric drugs, one of the main side effects on psychological treatments. CLA consumption at a dose of 3.4 g/d along with green tea extract significantly reduced the total percentage of body fat in psychiatric patients by 5.1 to 8.1 per cent and increased LBM by 4.4 to 11% []. A possible explanation for this effect is that the high green tea extract in the porlocatechin can directly inhibit the gastric and pancreatic lipas, thus increasing thermogenesis and possibly preventing the enzyme degradation of the catechol O-methyltransferase, an enzyme that plays a role in the breathing rate of the brown adipose tissue []. Due to excessive and sedentary life, the incidence of weight gain during holidays (i.e. obesity and overweight) has increased considerably over the past two decades and currently affects most of the adult population. For example, CLA supplementation (3.2 g/d for 6 months) for 40 adults with healthy overweight (18–44 yr; BMI: 25–30 kg/m2), a significantly reduced body fat (for 1.0-2.2 kg) and prevented weight gain during their holiday season []. Thus, all these studies suggest some potential beneficial effects on the consumption of isomerica CLA (2 to 6 g/d) in the body composition of obese or overweight individuals. On the contrary, an inverse relationship between CLA and body composition has been shown. One of the first studies showing the negative effects of CLA was performed with 71 subjects, including obese men and women aged 20 to 50. The subjects were instructed to take 90% pure CLA (2.7 g/d active 9- and 10-CLA isomers in equal proportion) daily for 26 wk, and compare the effects to 3 g/d safflower oil as placebo. The body was measured by hydrodensitometry, but the results showed no effect on body composition []. In young sedentary women, the intake of 2.1 g CLA/d for 45 d did not induce any change in body composition []. Similarly, the consumption of 4.5 g/d isomeric mixture CLA showed no decrease in body weight, compared to the consumption of safflower oil as placebo in 85 male overweight and obese subjects [].Some of the studies observed specific gender effects of CLA intake. Riserus et al. [] showed that the supplementation of CLA (4.2 g/d) for 4 wk in 14 obese men (BMI: 32 ± 2.7 kg/m2; 39 – 64 years) with metabolic syndrome may decrease abdominal fat, without concomitating effects on general obesity or other cardiovascular risk factors. The size of the small sample and the short duration were the main limitations of this study; therefore, the effects of CLA on abdominal obesity should be researched later in larger studies with longer duration. The long-term supplementation (1 yr) (the daily dose of CLA was 3.6 g; the mixture contained 39% 9-CLA, 41% 10-CLA) with CLA in free FA or triacylglycerol (TAG) did not show a significant improvement in BFM in adults with healthy overweight (the highest standard deviation found in the reported value makes the report neutral) []. In this double-blind, placebo-controlled study, 180 (women 149 and men 31) volunteers were included with BMI from 25 to 30. In another study, healthy adult women were examined for the effects of a 3 g/d CLA intake for 64 d in body composition, but there were no differences in parameters measured as fat-free mass, BFM and BFM percentage, body composition, energy expenditure, fat oxidation and respiratory exchange ratio against sunflower oil as placebo []. In a bicentric study (conducted simultaneously in Clermont-Ferrand, France and Maastricht, the Netherlands), eighty and one middle-aged men and women, with overweight and healthy, were registered and all subjects consumed a drinkable dairy product containing 3 g of OA sunflower oil daily (for 6 wk, the period of execution) []. The volunteers were then randomized over five groups receiving daily 3 g of OA high sunflower oil, 1.5 or 3 g each of 9 or 10-CLA administered as TAG in a drinkable dairy product for 18 wk. The BFM, fat and LBM percentage were evaluated at the end of the execution and experimental periods by DEXA. Dietary intake was also recorded. It was concluded that, a daily consumption of a drinkable dairy product containing up to 3 g of CLA isomers for 18 wk had no significant effect on body composition in men and women with overweight and medium-age []. A study from Greece reported that the CLA first managed 0.7 g/d for 4 wk and then 1.4 g/d for the next 4 wk, decreased the BFM in healthy volunteers []. Raff et al. [] compared the effects of the supplementation of 5.5 g/d mixture of CLA (50:50 mixture of 9- and 10-CLA) or only 9-CLA for 16 wk and evaluated the change in total and regional fat mass in healthy postmenopausal women and concluded that the consumption of 9- and 10-CLA was the result of the reduction of total and minor BFMs. In addition, the supplementation of 3 g/d of 80% CLA (50:50 ratio of 9- and 10-CLA) for 7 months attenuated the increase of the LBM by 0.5 ± 0.8 (SD is on the top). This study gained greater importance, as it was reported in children between 6 and 10 years old, who were overweight or obese, but otherwise healthy []. Curiously, in a study to examine the improvement of the reduction of BFM, CLA (500 mg/d) was supplemented in conjunction with 50 mg Ī³-orzanol, which effectively reduced the BFM by 1.14 kg (against the reduction of 0.36 kg in the CLA group) in healthy Korean women with overweight (n = 51, BMI garment 23) []. It is known that Ī³ -oryzanol is a phytochemical that has several biological activities such as antioxidant activity, anti-athergenic effect, triglyceride reduction and improves LBM []. This report also indicates that CLA per was less efficient to improve BFM; for example, a recent non-transverse clinical study conducted in 66 untrained healthy male students for 2 months showed that the supplementation of CLA did not have effect on LBM, BFM, trunk and visceral fats, and circumference of the waist []. From previous reports, it seems that a minimum daily dose (about 3 g/human) is required to induce fat reduction. Some clinical studies suggested that the administration of CLA could be the most effective strategy to control the regionalized reduction of the fat mass rather than its constitutional reduction, that is, evenly throughout the body. For example, the administration of 3.4 g/d CLA for 6 months reduced the fat mass significantly in the legs []. The relationship between waist and waist also decreased significantly in healthy, overweight and obese men, compared to the placebo group. Curiously, these effects were produced independent of the diet and specific lifestyle. Effect of CLA in exercise Individuals exercisers often add nutritional supplements to their diet to accelerate the increase of muscle mass and the strength of the formation of heavy stamina. Some short- and long-term studies using high doses of CLA in healthy and obese adults, sedentary and exercised have shown beneficial effects of CLA in reducing fat mass and increasing LBM. A daily supplementation of 1.8 mg CLA for 12 wk reduction of body fat (measured using near infrared lights); but no body weight in normal healthy exercise humans, compared to the placebo group that received hydrogel []. In this study, physical exercise was standardized as 90 min at the gym, three times a wk; and it concluded that CLA reduces fat deposition. These results seem to be encouraging, as a much lower dose of CLA produced the expected results - compared to other studies - in which 2 to 4 folds of higher concentrations of CLA were used comparatively. The effect of the CLA supplementation (Clarinol A-80) was investigated along with 6 aerobic training wk over 33 non-trained moderately trained men (average age 21.6± 2.8 yr). The CLA did not show ergogen benefits in neuromuscular fatigue, and field tests of muscle resistance and power. CLA also obtained attention among athletes trained by resistance as agents to reduce catabolism, body fat and improve muscle mass during training, but the supplementation of 6 g/d of CLA along with 3 g/d of FAs in formulation (Tonalin®) against 9 g/d placebo olive oil for 28 d did not show significant ergogen value, as it does not significantly affect changes in total body mass, However, the administration of 6 g/d CLA (in combination with 5 g/d of creatine monohydrate) followed by the formation of resistance exercises in older adults (about 65 yr, comprising 19 men and 20 women) for 6 months of increase in strength and improvement of body composition []. This combined strategy showed that supervised resistance training is safe and effective to increase strength in older adults, because aging is associated with lower muscle mass and increased body fat. In another study, the supplementation of CLA (6 g/d) along with creatine (9 g/d) and serum protein (36 g/d) also found beneficial to improve body strength and LBM during heavy resistance training in well-trained young adults (both men and women; 22.5 ± 2.5 yr) without changes in oxidative stress and kidney function []. Similarly, in another double-blind and placebo-controlled study of resistance to formation, no decrease was observed in visceral adipose tissue; however, a significant reduction was observed in the cross-section of visceral adipose tissue in the placebo group []. In this study, 30 men with overweight and moderately obese, but otherwise healthy middle-aged (35 to 55 years) received 3.2 g/d CLA for 4 wk []. Pinkoski et al. [] showed that the supplementation of CLA (5 g/d) or placebo for 7 wk while the resistance training (3 d/wk), which led to relatively minor changes in body composition, accompanied by a decrease in the catabolic effect of muscle protein formation. Thus, some of the studies showed the effectiveness of CLA in reducing fat mass in subjects during the resistance training program. Contrary to this, there were no specific effects of CLA on body composition, energy spending or non-obese appetite, regularly exercising individuals (composed 25 men and 27 women), who received either 3.9 g/d CLA or 3.9 g/d oleic acid rich sunflower oil (placebo) for 12 wk []. More recently, it was observed that the supplementation of CLA at a dose of 6 g/d increased the level of total testosterone in the blood of human men, but no significant change was observed before or after each bout resistance exercise []. He suggests that the supplementation of CLA can promote testosterone synthesis through a molecular pathway that should be thoroughly investigated. In addition, this study becomes very relevant, as the correlation between the production of testosterone and the construction of the body remains a controversy. CLA in mass of fat recover Some preclinical studies showed that 10-CLA reduces fat absorption in adipocytes by reducing lipoprotein lipasa and Ī9-desaturase activities, rather than improving lipolysis [, , ]. On the basis of this fund, some clinical research was conducted on the effect of CLA on the fat mass recover after weight loss, with the assumption that CLA could block body fat gain. To check this, overweight adults were administered a very low calorie diet during 3 wk, followed by the supplementation of CLA at a dose of 1.8 or 3.6 g/d for an intervention period of 13 wk []. The subjects took CLA at any dose showed increased recovery of fat-free mass and the metabolic rate of rest, thus reducing recovery of body fat relative to the control subjects. Curiously, they concluded in subsequent findings that appetite measures (hunger, satiety and fullness) favorably and independently affected by the same dose of CLA but had no effect on intake of energy in breakfast or better maintenance of body weight after weight loss []. CLA as dairy products Apart from some studies that investigated the effects of CLA supplementation on humans, there were some experiments designed to complement CLA-rich dairy products. Consumption of dairy products such as ultra-heated milk, butter and cheese enriched with 1.42 g of 9-CLA did not significantly affect BFM and body weight in healthy and middle-aged men []. Another experiment compared the effects of the consumption of a modified butter, naturally enriched with CLA (4.22 g /100 g of butter fat) in the body composition in men with overweight and obese, where the area of abdominal adipose tissue was measured by computed tomography [], which found no differences in the accumulation of abdominal or subcutaneous adipose tissue, compared to the control group that consumed CLA. The consumption of a drinkable dairy product containing up to 3 g of 10-CLA isommer for 18 wk did not give rise to any significant effect on body composition in men and women with overweight, of medium age [].Venkatramanan et al. [] examined the role of enriched CLAs (to obtain 1.3 g/d) milk (i.e., naturally enriched with only 9-CLA or modulus 9 More precisely, the consumption of milk enriched by CLA (in any form) did not alter the concentrations of TAG in the blood; body weight or fat composition []. The supplementation (14 wk) of 9 and 10-CLA isomers (in equal proportion, 70% purity) as a TAG form mixed in flavored yogurt products was also unable to alter body composition, although a significant increase in the metabolic rest rate was induced []. On the other hand, a study conducted in Spain with 60 healthy men and women (ages 35 to 65) with signs of metabolic syndrome (IMC, 25 to 35 kg/m2) showed a significant reduction (2 to 3 %) of overweight fat mass, but not in obese subjects; to the daily consumption of milk of 500 ml supplemented with mixture of 9 to 10 CLA (3 g/d) for 12 k []. Therefore, in general, the dairy products enriched with isomers of 9 or 10-CLA or its mixture could not establish a consistent effect on body composition. Long-term Consumption of CLAThe question of inconclusive results on the effectiveness and effectiveness of CLA in body composition and obesity can be answered by long-term intervention studies. The effects of any dietary supplement or dietary ingredient in body composition should be evaluated for a prolonged period of time to complete the results, as shock diet procedures seem inappropriate. In most studies, the intervention period lasted only for a few wk, and long-term studies were very few. In a study, 134 subjects including men and women were complemented with 3.4 g CLA/d on the TAG or FA free form for 12 months, and the extension study was also performed on the same topics during the next 12 month []. During the first month, a significant reduction in BFM and leptin levels was reported. These changes in body composition were not related to diet and exercise. Most of the effects on the BFM were observed during the first 6 months of the supplementation of the CLA and the extension study concluded that the CLA may be beneficial to prevent the weight recovery and long-term maintenance of the BFM and LBM. These studies seem to be important as most weight loss studies in overweight and obese subjects have shown that most subjects will recover the lost weight within the next 1 to 2 years [, ]. Gaullier et al. [] also reported similar effects in another study with CLA supplement for 1 yr in adults with healthy overweight. Energy spending, the use of substrates and the oxidation of dietary fats were measured before and after 6 months of CLA supplements, which showed that the expense of fat oxidation and energy increased during sleep in subjects received from CLA, compared to placebo []. The supplementation of CLA (6.4 g/d) for 36 wk) reduced BMI and the total mass of fat adipose without altering LBM in obese postmenopausal women with type 2 diabetes, who were not also in a diet plan or weight loss exercise []. These long-term studies should be carried out in a cross-sectional design (including men and women from different age groups) to generalize the beneficial effects of CLA. Of these tests, some clinical studies related to the long-term and short-term effects of CLA on obese, sedentary, healthy or exercising humans have shown some beneficial effects of CLA in reducing body fat and improving body composition. However, all of them did not reproduce the dramatic results reported in animal models and in vitro, especially mice. Extensive controversies in clinical studies merely propose a final declaration on the beneficial effects of CLA on body composition, in order to address the growing concerns of health professionals, bodybuilders and athletes. CLA and Cardiovascular HealthHigh plasma cholesterol is suggested as the main risk factors for atherosclerosis and cardiovascular diseases (CVD), and that the profile of blood lipids, blood pressure, BMI and blood sugar are generally considered as heart health indicators. The lipid profile is a blood test panel performed in the patient to determine the risk of VCE. These tests are good indicators if someone is likely to have a heart attack or stroke caused by blocking blood vessels or hardening of the arteries (atherrosclerosis). The lipid profile typically includes total cholesterol base measurements; high-density lipoprotein cholesterol (HDL-C), often called good cholesterol; low-density lipoprotein cholesterol (LDL-C), called bad cholesterol; and plasma TAG []. Normal cholesterol levels vary by age and sex. LDL-C is the main carrier of cholesterol in the blood, and if it is too much in circulation, it can slowly accumulate on the walls of the arteries of the heart and brain that lead to arteriosclerotic vascular diseases. According to American Heart Association, a high level of TAG combined with low HDL-C or high LDL-C increases the risk of CVD []. The main circulatory markers associated with heart health are C-reactive protein (CRP), tumoral-Ī± necrosis factor (TNF-Ī±), 15-keto-dihydroF2 prostaglandin (PGF2), 8-iso-prostaglandin F2-Ī± (PGF2Ī±), leptin, interleukin (IL)-6, plasma transamines and alan] Variations in the concentration of these markers in blood plasma (from the normal level) indicate dysfunctions in the human system. The main circulatory markers associated with heart health and their normal blood levels are listed in Table . Table 3 Main parameters of blood profile analysis, normal level and blood variations in relation to heart health ↑- increased; ↓- decreased TypeIndictionNormalFull color Low 200 mg/dL↑ risk of heart diseaseLDL-C100-129 mg/dL↓ risk of heart diseaseHDL-C40-50 mg/dL (menes)↑ protector against heart disease50-60 mg/dL (women)TriglycĆ©rida100-150 mg/dL↑ risk of heart diseaseVLDL-C2-30 mg/dL reactive disease 150 ng/L↑ oxidative stressTumor necrosis factor-Ī±extremely low/undetectable↑ inflammationLeptin1-5 ng/dL (men)↑ inflammation7-13 ng/dL (women)Some animal studies suggest the health benefits (anti-CVD effects) of CLA as antisclerotics and enhancements in the blood lipid profile. Two different isomers of CLA (i.e. 9 and 10-CLA) have different or opposite effects on atherosclerosis []. 10-CLA is pro-aterogenic and induces paths involved in the development of insulin resistance, while 9-CLA is associated with lower risk of CVD [–]. Effect of CLA on the blood lipid profileEchodemiological studies showed that HDL-C plasma concentrations have an inverse relationship with the risk of CVD, and it is expected that raising HDL-C plasma levels could protect against atherosclerosis []. The suppressed effects of CLA supplementation on the blood lipid profile also remain inconclusive. The supplementation of an isomeric mixture of CLA (9- and 10-CLA in 50:50 ratio) for 12 wk (1.7 to 6.8 g/d) decreased total cholesterol, HDL-C and LDL-C []. Similarly, a dose of 0.7 or 1.4 g/d CLA decreased HDL-C and TAG serum significantly and increased the CLA content of the serum lipids []. In this study, 22 volunteers were registered and divided into study and control groups into a double-blind design; the study group received 0.7 g of CLA for four wk and 1.4 g of CLA for the next four wk, while the control group received similar placebo dose at all. The diet was controlled, and there were no significant differences in energy intake or macronutrients between the two groups. A significant reduction in HDL-C was observed when 6.4 g/d of CLA was consumed, while no change in total cholesterol or LDL-C was observed. But 2.1 g/d of CLA (9- and 10 CLA in equal proportion) for 45 d showed no significant difference in serum TAG, total cholesterol, HDL-C in unobese healthy sedentary women []. On the other hand, CLA (9- and 10-CLA at 50:50 ratio) in a dose of 3.0 g/d for 8 wk increased total HDL-C concentrations by 8%. And the proportion of LDL-C to HDL-C was significantly reduced in subjects with type 2 diabetes stable and controlled by diet [].The supplementation (3 g/d) of an isomeric mixture of 50:50 of 9- and 10-CLAs or 80:20 mixture of 9- and 10-CLAs for 8 wk showed that the first combination significantly reduced the concentrations of TAG plasma in synergy, while the second blind These results further suggested that the supplementation of CLA significantly improved the profile of lipids in human subjects without any adverse effect on body weight, plasma glucose and insulin concentrations; and thus indicates the supposed cardioprotective effects of CLA. Contrary to this, the opposite effects 9- and 10-CLA were observed by Tricon et al. []. In this cross study, 49 healthy men (20–47 yr; IMC 18–34 kg/m2) were enrolled, and complemented with 79.3% (2.38 g/d of 9-CLA) 9-CLA or 84.1% (2.52 g/d of 10-CLA) 10-CLA for 8 wk consecutively. It proved that 10-CLA increased the ratios of LDL-C to HDL-C and total to HDL-C, while 9-CLA decreased, suggesting the beneficial effects of CLA on the blood lipid profile []. But, later, the same group showed that 9-CLA-enriched dairy products (1.42 g/d) had no significant effect on the blood lipid profile []. Some studies did not notice a beneficial or negative effect of an isomeric mixture of 9- and 10-CLA in a relationship that was not 50:50. A study of 93 d long in 17 healthy female volunteers to observe the effect of dietary CLA (on blood lipids, lipoproteins and composition of FA tissue) showed that the daily supplementation of 3.9 g/d CLA (the mixture contained 11.4% 9-CLA, 14.7% 10-CLA and 38.9% other CLAs) did not alter cholesterol in blood or healthy lipothe levels. In addition, no adverse effect of the supplementation of CLA was reported in this study, although the plasma concentration of CLA increased during the intervention period, that is, 95.77% of the total consumed CLA was metabolized in the body []. In a cross study (for 6 months, n = 401, 40 to 70 years and with a BMI or = 25), the consumption of 4 g CLA/d (4:1 ratio of 9 to 10 LC) did not influence the rate of aortic pulse wave (atherosclerosis marker), blood pressure, anthropometric characteristics and concentrations of lipid fasting, glucose, insulin However, human studies with the supplementation of CLA-rich dairy products (in situ enrichment) produced contradictory results. The intake of 1.3 g/d of CLA in the form of naturally enriched milk (containing only 9-CLA) or enriched milk with a synthetic mixture of 9- and 10-CLA for 8 wk did not alter cholesterol levels, LDL-C, HDL-C or concentrations of TAG in moderately overweight blood samples, hyperlipidic in border line []; However, the levels of CLA and VA in human milk can be modulated if mothers who breastfeed dairy and conventional meat products replace organic dairy products (enriched by natural food) []. Recently, Penedo et al. [] showed that the intake of butter, naturally enriched with 9-CLA (1.02 ± 0.167 g/d) for 8 wk induced beneficial changes in in inmunitary modulators associated with subclinical inflammation in individuals with overweight. In addition, naturally enriched sheep's cheese in VA, CLA and ALA improved lipid profile and reduced anandamide (a endogenous cannabinoid neurotransmitter and obesity markers) in adults with mildly diagnosed hypercholesterolemia []. CLA in circulatory markers The CRP is synthesized by the liver in response to inflammation. Inflammations may be due to a variety of reasons such as cancer, diabetes, cardiovascular disease, etc. [, ]. The normal concentration of CRP in healthy human serum is generally less than 10 mg/L, but slightly increasing with aging. Increased plasma concentration of CRP, a circulatory inflammation marker helps to predict CVD []. Supplementation with 10-CLA for 12 wk significantly increased PGF2Ī± (578%) and CRP (110%), compared to placebo in 60 men with metabolic syndrome []. A dose of 3 g 9-CLA/d significantly increased levels of urinary PGF2 and PGF2Ī± - in vivo inflammation markers and oxidative stress, respectively; after the supplementation of 3 months with 25 abdominally obese men against olive oil as placebo []. A mixture of 9 and 10-CLA isomers with equal proportions also reported an increased CRP, but not other inflammatory markers, that is, TNF-Ī±, TNF-Ī± 1 and 2 receptors, and vascular cell adhesion molecule (VCAM)-1 []. Another study concluded that a 9- and 10-CLA mixture had adverse effects on CVD markers, while the 9-CLA isomer appeared to be more neutral in healthy postmenopausal women. The daily supplementation of 5.5 g of CLA mixture significantly elevates the level of CRP, fibrinogen and plasminogen activator inhibitor-1 in plasma []. The CLA mixture at a dose of 3.0 g/d reduced fibrinogen concentrations but had no effect on other inflammatory CVD markers such as CRP and interleukins (IL) in subjects with type 2 diabetes. The high dose of CLA consumption (6.4 g/d of 9 and 10-CLA in 50:50 ratio) for 12 wk significantly increased CRP and IL-2 levels, suggesting an increase in inflammation during short-term supplementation. On the other hand, the CLA in the same composition (50:50 ratio), but in lower doses (i.e., 3.0 g/d showed) no effect on the inflammatory markers of the CVD (CRP and IL-6) []. The results of some recent studies suggest that CLA does not increase the risk of CVD. Pfeuffer et al. [] evaluated the effect of CLA against safflower oil in endothelial function and CV risk markers in men with overweight and obesity, i.e. by the consumption of 4.5 g/d of the CLA isomerica mixture for 4 wk. It was noted that the CLA did not undermine the endothelial function. Other parameters associated with metabolic syndrome and oxidative stress were not changed or improved slightly. Curiously, it was observed that oral supplementation of CLA along with calcium reduced the incidence of pregnancy-induced hypertension without changing the plasma levels of other circulatory markers such as PGF2Ī±, CRP and IL-6 []. Forty-eight healthy primitives with a family history of preeclampsia and diastolic node were included in this uncrossed double-blind, placebo-controlled study. The participants were randomized at daily oral doses of elemental calcium (0.6 g/d) with CLA (0.45 g/d) or placebo of lactose starch from wk 18 to wk 22 gestation to childbirth. The beneficial and harmful controversial effects of CLA on heart health observed during the clinical trial are summarized in Figure . All of these studies were too randomized in doses, composition and duration, making it difficult to conclude the positive effects of CLA on heart health. In addition, there is a total lack of uniformity in evaluating the effects of LLC on heart health, that is, some studies focused on lipid profiles, while others on circulatory markers; but none of them had a consistent effect. Although it was found that the isomeric mixture of 9 and 10 CLA (1:1) had some positive effects, it is necessary to clarify the mechanism of action to determine which of these isomers caused the effect. Proposed effects of CLA consumption on heart health. CLA and immune functionDifferentiated studies show that the effects of dietary CLA on immune functions in animal and human models are highly variable and inconsistent (Table). For example, a study of 93 d long in 17 young women feeding with an isomerica mixture of 3.9 g/d of CLA showed no alteration in any of the immune status indices such as circulating white blood cells, granulocytes, monocytes and lymphocytes []. Even after immunization with flu vaccine, the response of delayed hypersensitivity and serum antibodies tyre was not altered during the intervention period. These data suggest that the short-term supplementation of CLA in healthy volunteers was safe, but showed no added benefit to their immune status []. In addition, the short-term consumption of CLA did not produce any observable physiological change in blood clotting and placket function in healthy adult women []. CLA supplementation (3.9 g/d of a mixture of isomers of CLA: 17.6% 9-CLA, 10-CLA, 23.6% cis-11,trans-13 CLA, 16.6% trans-8,cis-10 CLA 19.6%) resulted in an increase of eight folds (0.12 to 0.97 wt %) in the concentration of CLA in the liquid fraction but mononuclear cells The supplementation with 9 to 10 CLAs in the 50:50 or 80:20 ratio, respectively, led to an increase of 35% of CLA levels in PBMC []. Curiously, in this non-crossed study, 62% of the subjects, who consumed the mixture of 9 and 10-CLA in the ratio 50:50 showed higher levels of protective antibodies after the vaccination against hepatitis B. Although the overall effect was not significant, the results at least suggested that 50:50 CLA could have a biologically relevant improvement effect on the response to hepatitis B vaccination, which justifies a further study []. Contrary to this, supplementation with isomers 9 and 10-CLA (80:20 mixture, respectively) significantly improved the content of phyto-hemagglutinin (PHA), a lymphocyte proliferator induced by T-cell. The CLA decreased the IL-2 baseline secretion, but increased the production of IL-2 and TNF-Ī± induced by the PHA - when 55 healthy volunteers received 3 g/d of 9 and 10-CLAs mix in ratios 50:50 and 80:20, respectively []. The levels of Plasma IgA and IgM were found to be increased over supplementation with 9- and 10-CLA (50:50), but the levels of IgE, TNF-Ī± and IL-1Ī² decreased. In addition to these effects, the response to delayed hypersensitivity was reduced during the supplementation of CLA []. Table 4 Main clinical trials investigating the effect of CLA consumption in the immune state; ↑-increased; ↓- diminished; ↔ TitlesDurationObservationRe↓17 women3.9 g CLA (Tonalin)/d93 d:7 10 woman3.9 g CLA (Tonalin)/d93 d^ PBMC[] circulatory cytokines71 males1.7 g 9 > 10-CLA (50:50), ClarinolTM/d12 wk^ 8 TNF-Ī±, IL-1Ī² and hyper retardant response A prominent study in this respect came from the group of MacRedmond et al. [], which showed that the supplementation of 4.5 g/d CLA as a supplement to the usual attention in slight overweight asthmatics (28 subjects; 19 to 40 years involved) for 12 wk was well tolerated, which was associated with improvements in the hyperresponsibility of the airways []. However, the daily supplementation of 4.8 g CLA for 8 wk did not attenuate the inflammation of the airway or the bronchus constriction induced by hyperpnea in asthmatic individuals []. One of the first studies in this direction measured the mean of serum phospholipid sterified the concentration of 9-CLA in peripheral blood; it was observed as significantly higher in 98 patients with chronic stable asthma, and 25 patients with acute severe asthma. Thus the supposed role of free radical activity derived from oxygen in the inflated lung tissue was predicted []. It shows that some attempts were made to estimate the effect of CLA on immunity with reference to asthma, but none of them managed to reproduce the positive effects such as the improvement of immune function, the regulation of autoimmunity and the growing proliferation of lymphocytes, consisting of clinical studies [–]. In addition, the activation of receptors activated by peroxidized proliferator (PPARs, a group of nuclear receptors), especially PPAR-Ī³ in the smooth muscle of the human airway would be a possible strategy to treat respiratory tract diseases []; therefore, aiming at PPAR-Ī³, 9-CLA could show therapeutic value in alleviating respiratory tract disease by affecting epithelial and eosinophil functions. The interest in the CLA emerged mainly from the discovery of the anticancer property of CLAs []. However, only a few studies have examined the specific effects of the ISLA isomers on humans. In fact, no clinical studies have been conducted to relate CLA consumption to the incidence of cancer, but the data available in this regard are only epidemiological studies. These data can be considered as a collection of statistical tools used to dilute CLA's exhibition associations to health outcomes. As for clinical cancer studies, many researchers focused on human breast cancer; for example, in an elaborate follow-up study using proportional risk models of Cox; Larsson et al. [] showed that CLA's dietary intake had no evidence for a protective role against the development of breast cancer in women. Chajes et al. [] carried out a case-control study between 297 women treated for breast cancer or benign breast disease at the University Hospital of Tours, France, to evaluate the hypothesis that CLA protects against breast cancer, and could not show a link to the negative association between CLA adipose tissue (before 9-CLA) and the risk of breast cancer. In 60,708 women aged 40-76 (such as Swedish mammography cohorts) high-fat dairy foods and CLA consumption were examined with 14.8 years of follow-up. It was found that women who consumed four or more portions of high-fat dairy foods per day (including whole milk, full-fat milk, cheese, cream, sour cream and butter) showed half the risk of developing colorectal cancer, compared to women who consumed less than one serving per day []. Regarding CLA intake, they found that it was associated with a reduction of almost 30% in the risk of colorectal cancer []. Likewise, the possible role of CLA in the prevention of testicular cancer was represented by the decrease in the content of CLA in mitochondrial fractions of testicular cancer against normal testicular cells; and that the incorporation of CLA into nuclei and cytosol was significantly greater than its incorporation into plasma membranes and mitochondria []. Tumors in the negative epithelial cells of the estrogen receptor (ER) in the breast are common among premenopausal women []. McCann and others. [] showed that the 9-CLA protective effect on women with the greatest intake, i.e. the number of ER-negative cells to ER-positives was reduced in those women. Another epidemiological study (Netherland cohort) with 6.4 follow-up yr evaluated the relationship between CLA intakes and other FAs did not confirm CLA anticarcinogenic property in humans with the incidence of breast cancer []. Some studies examined the relationship between dietary or serum CLA in women and the risk of breast cancer. Such studies found an inverse association between dietary and serum CLA and the risk of breast cancer in postmenopausal women []. But instead, the adipose tissue extracts of a population of French patients with invasive breast carcinoma did not reveal any positive correlation between the adipose tissue CLA and the incidence of breast cancer []. Since CLA accumulates in body fat stores, the fatty tissue of breast cancer obtained at the time of surgery could be used as a qualitative biomarker for CLA intake. Thus, the available human clinical studies could not determine the anti-cancer property of the CLA. An important limitation in epidemiological studies is the difficulty in obtaining precise estimates of dietary CLA intake. Most of the studies were conducted in small populations, where the diversity of eating habits was lower. In addition, no clinical study evaluated the effects of pure or individual isomers of CLA preparations on the incidences of cancer. It focuses on the need for well-defined and controlled studies to fully understand the effects of CLA intake on the incidence of human cancer. CLA and diabetes Life-style epidemics, diabetes and obesity are considered to be the main causes of morbidity and mortality worldwide; and that obesity and weight gain are associated with increased risk of diabetes []. Hormone, insulin is responsible for regulating blood glucose concentration. Insulin resistance is a state in which cells do not adequately respond to insulin (even if it is available in the blood), which leads to hyperinsulinemia (high insulin). Some animal studies showed that the supplementation of CLA increases insulin sensitivity; however, the underlying mechanism of this effect is not clear [, ].Relatively few studies have examined the antidiabetic properties of CLA in humans. The supplementation of 3.0 g/d of CLA (in 24 women) by 64 d showed no significant changes in the levels of circulatory glucose or insulin []. Isomeric mixtures of CLA at the same dose also did not show significant effects on plasma glucose or insulin levels in healthy human subjects []; in such studies, blood glucose and/or insulin showed an undemonstrable effect. The gold standard to quantify blood glucose is the "hyperinsulinemic-euglycemic clamp test" that measures the amount of glucose needed to compensate for an increase in insulin level without causing hypoglycemia []. However, another study using an euglycemic/hyperinsulinemic clamp in abdominally obese male subjects indicated a decrease in insulin sensitivity after supplementation with mixed and purified isomers of 9 and 10-CLA at a dose of 3.4 g/d for 12 wk []. Supplement 10-CLA increases oxidative stress and inflammatory biomarkers in obese men []. Oxidative stress seems to be closely related to insulin-induced resistance, suggesting a link between lipid peroxide induced by the FA; these defavorable effects of 10-CLA could be of clinical relevance with respect to CVD []. Recently, Shadman et al. [] showed that the supplementation of CLA (50:50 isomer mixture of 9- and 10-CLA) with or without vitamin E for 8 wk showed a tendency to increase in malondialdehyde (a marker of lipid peroxide) in type 2 diabetic patients with overweight. In non-diabetic abdominal obese men, 3.4 g/d 10-CLA supplementation for 12-wk-induced hyperproinsulin (plasma proinsulin, insulin, C-peptide and adiponectorin concentrations, including their associations with a change in the insulin sensitivity assessed), which relates to insulin sensitivity with deficiencies, regardless of changes in insulin concentrations. These results are of clinical interest, as hyperproinsulinemia predicts diabetes and cardiovascular diseases. The same researchers also showed that the other active isommer of CLA (9-CLA) also increased insulin resistance in abdominal obese individuals after supplementation to a dose of 3 g/d for 3 months. []. But the isomeric mixture of 9 and 10-CLA (3.4 g/d for 6 months) showed no significant effect on the metabolism of glucose or insulin levels in individuals with overweight or obesity []. All of these studies did not support the antidiabetic ownership of CLA in humans; however, the administration of 4 g/d of mixed isomers of CLA improved insulin sensitivity in young sedentary humans []. Sixteen individuals (age, 21,5 ± 0,4 yr; body mass, 77,6 ± 3,4 kg) participated in this study. Ten subjects received 4 g/d of CLA mixed isomers (35.5% 9-CLA; 36.8%10-CLA) for 8 wk, while six subjects received placebo (solsolar oil); but this study was performed in a group of 16 subjects - too small to offer a generalized effect. Clinical studies on the antidiabetic effects of CLA are inconclusive. Rather, some of them speculated the reduction of insulin sensitivity; which attract the immediate attention of doctors, because the increase in the consumption of CLA through dietary supplements could be misadvised. Adverse effects of CLA consumption It seems that the use of weight loss supplements containing 9-CLA, 10-CLA or both as a mixture is worrying, because most of the clinical studies presented in the previous sections provide mainly neutral or inconclusive results with very few favorable impacts (table ). In association with this, some studies reported some adverse effects such as oxidative stress, insulin resistance, gastrointestinal irritation, etc., but no serious adverse effects were reported at the time of the intervention except the relapse of asthma in the consumption of 3.4 g/d of CLA []. Therefore, most of these side effects could be classified as 'mild to moderate'. Table 5 Proposed beneficial and harmful effects of CLA in clinical trials Insulin-reducing diseases Negative effects Obesity reduced body fat mass oxidative stress indexBlood-reducing abdominal irritation s Percentage of reduced body fatRecovery of lean body massImproved muscle mass Cardiovascular diseases Improved blood lipid profile Improved production of circulatory stress markersReduce total cholesterol Therefore, the immediate expected biological effect is oxidative stress. Oxidative stress is the reflection of an imbalance between the systemic manifestation of reactive oxygen species and the ability of the body system to detoxify them easily or repair the resulting damage given to cellular components such as proteins, lipids and nucleic acids. It is known that free radicals, such as reactive oxygen formed by lipid peroxide, "establish" electrons of lipids in cell membranes, which results in cellular damage []. Prolonged oxidative stress can lead to cancer and heart disease []. The supplementation with 10-CLA increased dramatically oxidative stress rates, at levels considerably higher than those observed in heavy smokers []; also improved the release of inflammatory biomarkers in obese men []. Long-term CLA supplementation studies of one and two years have found to be well tolerated, but there was an increase in circulatory markers of inflammation such as CRP, TNFs and ILs [, ]. Changes in these markers of inflammation and oxidative stress may be related to increased insulin resistance associated with the risk of cardiovascular disease [, ]. CLA administration (4.2 g/d) for three months significantly induced both non-enzymatic and enzymatic lipid peroxide, which was suggested to cause cell damage [].Insulin resistance Resistance is a physiological disorder, under which normal cells do not respond to the hormone. Less insulin sensitivity or resistance to CLA consumption was observed in some studies [, ]. Riserus et al. [] showed with obese men that10-CLA could modulate insulin resistance in humans, and that oxidative stress is closely related to induced insulin resistance, as demonstrated by the increase in marker levels, 8-iso-prostaglandin-F2Ī± in plasma. In addition, insulin resistance is closely related to the deterioration (decrease) of the expression of glucose-4 conveyor (GLUT4), glucose membrane conveyor. It was definitely found that 10-CLA decreases the expression of GLUT4 [], which shows that the indiscriminate use of 10-CLA to treat obesity would lead to type 2 diabetes as an immediate side effect, this would damage the blood vessels and thus increase the risk of CVD []. In addition, unused insulin (due to resistance) in plasma can contribute to increased appetite (especially for carbohydrates and sugary foods), which would add to the severity of the CVD. Irritation of the intestinal tract Some studies showed mild irritations of the intestinal tract as irritation [], laxative effects and flatulence [], gas swelling [], indigestion, diarrhea and nausea [, ] in CLA consumed subjects. Most of these effects were considered mild to moderate and transient; and it may be assumed that these effects may be due to the material of the capsule or to the fat nature of the substance or to the problem of initial adaptation with the lipid nutrient. Depression of Milk Fat Commercial CLA consumption reduced fat content in cows []. Since milk is the only source of nutrients for babies, the decrease in milk fat in infants is another concern regarding CLA consumption. Masters et al. [] showed that CLA consumption significantly reduced milk fat without affecting total milk production. However, two other human studies did not find changes in fat or milk protein [, ], but in these studies, the intervention period was too short (on a wk) to reach a conclusive result. Cross-talk on CLA consumptionGeneral view on CLAs is that the 10-CLA exercises specific effects on adipocytes and liver, whereas both the 9- and 10-CLAs appear to be active inhibiing carcinogenesis []. It is likely that inconsistent and often contradictory results on the effectiveness of HCM consumption in human health may be the result of several factors, including differences in thematic groups, age, quantity and duration of HLA intake, composition of the HLA mixture, purity of HLA, acceptance of the HLA by the body, intake of food, gender and race differences, genetic polymorphism and also measurements performed (to evaluate the studied effect). In addition, crucial factors that impact the results of the research include the nature of the control supplement (placebo), and the study design (cruce vs. non-transverse designs), because, the effectiveness of CLA supplements remains inconsistent in randomized, cross-sectional clinical studies []. Plasmatic content of CLAThe determination of a normal content of CLA in the blood plasma could help estimate whether a person consumes satisfactory amounts of CLA with the diet, and thus takes advantage of its possible beneficial effects on health. The only CLA isommer that appears in greater percentage than the detection limit (0.03% of the total FAs) is 9-CLA []. They came to this conclusion on the basis of data obtained from 3 groups of individuals (n = 12 for each group), that is, they did not consume dairy products, people consumed normal amounts of dairy products (about 50 g/d cheese) and people consumed 1.4 g CLA/d as a supplement (both 9 and 10 CL in equal proportion). The duration of this study was 6 months, and in the last group that consumed CLA supplement, the average content of CLA in plasma was 0.2% of total FAs without negative side effects. Blood samples were collected for morning analysis (in the fasting state) after a 12-h restriction on food and beverages. Thus, individuals who have 9-CLA levels in their blood plasma within the range of up to 0.09% of total FAs could serve as ideal participants in future studies of supplementation of CLA. Supplements CLA vs.placebo In most clinical studies, vegetable oils such as sunflower oil, olive oil, soy oil and soy oil (tabla) have been used as placebo in the form of capsules or pills [, , ]. In fact, the proportion of MUFA and PUFA, especially THE present in these placebo oils (e.g. sunflower oils and predominantly used olive oils) are not adequately addressed by researchers. According to WHO (Cdex International Food standards), sunflower oil, soy oil, olive oil and glow oil contained significant levels of MUFA and PUFA, including OA, LA and ALA (Table ) [, ]. AV was thought to be the only precursor of CLA in humans. However, non-ruminal bacteria that inhabit the human gastrointestinal tract (GI) as Lactobacillus acidophilus and L. casei isolated from the intestine [], Bifidobacterium bifidum and B. brief isolated from the fecal matter of the neonates [], and Ruberia spp. isolated from the intestine [] could effectively produce 9-LA From this, it is evident that a part of LA placebo oil would be biohydogenated by the bacteria that reside in the GI tract (as in the rumen) in the CLA through the mediation of the VA. Regardless of this fact, most clinical studies use the vegetable oils mentioned above as placebo, neglecting their effects on human health, especially their supposed complementary and complementary effects. It was found that the dietary intake of precursor VA had some important effects on heart health, blood lipid profile and immunity, and also protection against deadly ischemic heart disease [–]. This would lead to poor interpretation of results, i.e. false positive results. Therefore, during clinical studies, the composition of the FA in placebo and its effects on human health must be addressed with due respect, and independently to obtain reliable results. Table 6 Various vegetable oils used as placebo in clinical studies with its polyunsaturated fatty acids (PUFA) content including LA Vegetable oilTotal PUFA*LA*Sunflower oil6666Feed seed oil6613 Sunflower oil4241 Olive oil109 Soy oil5851*Units: grams of fatty acids for 100 grams of oil. Choice of topics Clinical studies with CLA lack a common protocol to select topics. The description of the topics, including gender and age, the medical treatments given before the intervention are the critical factors to consider when selecting the topics. The medical records of subjects should also be registered before concluding the safety concerns and effectiveness of CLA consumption. In most studies, the selected subjects were categorized and designated as normal, healthy obese, metabolic syndrome, insulin resistance, etc. This arbitrary classification for the convenience of the researcher poses a question, i.e. what is the most appropriate model for studying the health effects of CLA? Is it with the designation of normal, obese, immunocompromises with metabolic syndrome or other diseases? Another factor to be considered in clinical studies is the continental, racial and gender differences among subjects; for example, literature shows that most clinical studies on CLA were conducted in North America and Europe. The reproducibility of these results in separate racial and continental populations around the world, especially in Asia, Africa and South America, is another point of concern, which must be verified before accepting the nutritional status of CLA in the modulation of biological functions. Dosage and duration Other factors of concern are the composition, dose and duration of CLA consumption. If it is not declared otherwise, the composition and purity of the CLA are destined to 9 and 10 CLA. In general, human studies use a mixture of CLA (approximately 40:40) of 9 and 10-CLA; and the proportion of CLA isomers depends mainly on the nature of the substrate, the mode of synthesis (production), the physical-chemical parameters involved in the synthesis and the strategies of purification adopted [, ]. Even if it is declared as purified, purity would be about 80%; and the remaining 20% would be represented by other CLA isomers and unchanged FAs. These 'impurities' would also contribute to the inconclusive results, as different isomers proved to have different physiological actions in the human body. Most of the clinical studies evaluated the effects of CLA consumption during a short period, usually from 4 to 12 wk. But Gaullier et al. [,] carried out a comparatively long-term study covering between 1 and 2 years. Generally, in these studies, doses of CLA (isomer or mixture) varied from 0.7 g/d to 6.8 g/d per human and administered mainly in the form of TAGs or free FAs. The dosage of HLA administration in humans is also very low, compared to animal studies (in terms of body weight); thus, results in preclinical animal studies (high doses) may not be comparable to actual clinical studies. Therefore, the dose of CLA (intake) can be considered based on percentage of energy. Two people with the same body weight can have a very different body composition (e.g. women vs. men; bodybuilder vs. obese person), which in turn impacts metabolism differently. Another crucial issue is the retention of so-called good effects for a long time; of course, it could be expected that CLA would be consumed as if drugs were taken for chronic diseases. Unlike the in vitro mechanistic studies, the cross-signing pathway through which CLA induces its effects should be clearly clarified in clinical studies. In addition, the biological effects of the individual isomers of CLA, mainly 9- and 10-CLA, their synergistic interactions and even the possible opposition between isomers must be revealed. CLA and adjuncts Effect of CLA consumption along with several aggregates is another area of clinical research that has to be studied evidently. Some studies showed the positive health benefits of CLA are related to the reduction of body fat and heart health in consumption along with calcium, VA, serum proteins and orizanol [, , ]. CLA (6 g/d) supplementation along with creatine and serum protein resulted in strength improvements and LBM with high resistance training in well-trained young adults []. It was found that CLA consumption along with other PUFA had protective effect against renal carcinoma []. Therefore, an effective combination of CLA together with other supplements or with Ļ-3 FAs should be addressed to reveal the possible real effects of CLA consumption on human health. Conclusions Regarding the voluminous literature on CLA, only a few studies to date examined the effects of CLA on live humans. However, the results of these studies do not reflect the dramatic and consistent data shown in animal studies. Thus, these disappointing results in humans require more accurate experiments with humans. The interest in CLA research continues to persist, and therefore many questions related to the safety and effectiveness of CLA consumption have to be answered scientifically. Therefore, it is imperative to evaluate and critically consolidate the main conclusions on the human consumption of the CLA, i.e. the main actions of this minor lipid nutrient that it exerts on the human system so that future research focuses on specific isomers of the CLA and on the most reasonable mechanism of action due to them. One of the main limitations in human studies is that most studies depend only on blood cells or plasma, and fat deposition. Thus, most clinical studies did not provide conclusive evidence for the effectiveness of CLA in human health, except for the anti-obesitic properties that offered a small hope to avoid recovery of body weight despite the deposition of fat, increased oxidative stress and insulin resistance due to the overconsumption of CLA raises contradictory concerns. In addition, the age, gender, genetic polymorphism and the immune status of the subject, the role of other nutrients present in the diet, and the extent of absorption of individual isomers to different tissues have to be well addressed during the intervention period, to assess the safety and effectiveness of CLA consumption in human health. With regard to the human consumption of CLA, a final conclusion has not yet been reached for security and effectiveness. In this context, we strongly recommend the need for more accurate and well-designed long-term intervention studies, with the intake of controlled foods and the level of activity to assess the effectiveness of CLA in human health. Moreover, these studies should be duplicated in other laboratories, with emphasis on men and women, age groups, ethnic origin, food style, continental and even national singularity, cultural and geographical barriers, etc. without comparing animal studies data, that is, a true double-blind clinical study. Until now, clinical evidence indicates a possible bond of supplemental CLA per se to negative or inconclusive results; therefore, it can be considered the inclusion of CLA in the Codex Alimentarius (Food Book) – which describes internationally recognized standards of food. Recognition The authors thank the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India for a research grant (BT/PR 12714/FNS/20/411/2009). Competing interest The authors declare that there is no conflict of interest. SB authors' contribution designed and wrote the manuscript, and contributed substantially to the discussion, PP and SS collected the literature and structured the reference, FS and AGW edited it with interpretation. All authors read and approved the final manuscript. Taxpayer information Sailas Benjamin, Email: .Priji Prakasan, Email: .Sajith Sreedharan, Email: .Andre-Denis G Wright, Email: .Friedrich Spener, Email: .ReferencesFormats: Share , 8600 Rockville Pike, Bethesda MD, 20894 USA
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