CLA and stress management -
As is often the case, some molecules and nutrients are beneficial when found in natural amounts in real foods — but become harmful when taken in large doses. Large doses of supplemental CLA can cause increased accumulation of fat in your liver, which is a stepping stone towards metabolic syndrome and diabetes 35 , 36 , Keep in mind that many of the relevant animal studies used doses much higher than those people get from supplements.
However, some human studies using reasonable doses indicate that CLA supplements may cause several mild or moderate side effects, including diarrhea, insulin resistance and oxidative stress The CLA found in most supplements is different from the CLA found naturally in foods. Several animal studies have observed harmful side effects from CLA, such as increased liver fat.
One review concluded that a minimum of 3 grams daily is necessary for weight loss Doses of up to 6 grams per day are considered safe, with no reports of serious adverse side effects in people 41 , Studies on CLA have generally used doses of 3.
Losing a few pounds of fat may not be worth the potential health risks — especially as there are better ways to lose fat. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.
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Health Conditions Discover Plan Connect. Nutrition Evidence Based CLA Conjugated Linoleic Acid : A Detailed Review. By Kris Gunnars, BSc — Updated on October 23, What It Is Sources Weight Loss Benefits Side Effects Dosage and Safety Bottom Line Studies suggest that CLA has only modest effects on weight loss.
Share on Pinterest. What Is CLA? Found in Beef and Dairy — Particularly From Grass-Fed Animals. Can It Aid Fat Burning and Weight Loss?
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Animal studies, reviews, in vitro research, research on kids and teenagers, grey literature, conference abstracts, opinion pieces, books, and RCTs without a placebo or control group were excluded. Studies that used CLA in combination with vitamins or minerals were also excluded.
In the present study, we searched for studies that assessed the effects of CLA supplementation on all inflammatory cytokines. After screening and finding eligible studies, we found that most studies evaluated CRP, IL-6, and TNF.
In addition, a limited number of studies have evaluated other inflammatory factors such as IL-1 and IL Therefore, we included studies that evaluated the effects of CLA on CRP, IL-6, and TNF. After quickly skimming the titles, abstracts, and full text to choose the most pertinent research following a separate review of each qualifying RCT, the following data were gleaned by two independent researchers OA and FS.
Name of the first author, country of origin, year of publication, type of clinical trial, participant characteristics mean age, body mass index BMI , sex , randomization, blinding, sample size, number of participants in the intervention and control groups, type and dosage of supplemented CLA, duration of the study, and related data were extracted for additional measurements.
The CLA dosages were converted to milligrams per day, whether they were given in grams per day or another unit. To rate the quality of the studies, the Cochrane Collaboration technique was utilized Two researchers SR and GS independently assessed the methods, and any disagreements between their assessments were resolved through discussion.
Each study was evaluated for any bias, including those caused by randomized sequence generation, allocation concealment, participant and staff blindness, outcome assessor blindness, insufficient outcome data, selective reporting, and other biases. Stata The pooled weighted mean difference WMD was calculated using a random-effects model to take into account any existing heterogeneity due to the different intervention doses, duration, participant health, sample sizes, and length of intervention developed by Der Simonian and Laird We computed the mean differences in CRP, IL-6, TNF-α, adiponectin, and leptin between the CLA supplementation and control groups from the preintervention to the postintervention.
Other subgroup analyses were performed according to gender man, woman , baseline BMI normal We used the leave-one-out approach to do a sensitivity analysis to identify how many inferences were dependent on a single sample to examine the influence of each study on the pooled effect size The flow chart presented in Figure 1 describes the selection process and the references retrieved from the database.
Figure 1 Flow chart of study selection for inclusion trials in the systematic review. Out of studies, 62 did not have the desired data. Finally, 42 studies 11 , 12 , 16 , 18 , 19 , 27 , 28 , 42 — 76 were included in the present meta-analysis, and their characteristics are illustrated in Table 1.
The risk of bias assessment is summarized in Table 2. All of these studies were RCTs published between and Study design characteristics are presented in Table 1. The two studies were conducted in the USA 42 , 67 , three in Sweden 43 , 45 , 49 , three in the Netherlands 44 , 52 , 65 , four in Canada 12 , 14 , 46 , 68 , two in Norway 27 , 47 , four in the UK 28 , 48 , 51 , 56 , two in France 50 , 53 , two in Turkey 11 , 72 , one in Japan 55 , one in Ireland 57 , one in Korean 58 , one in Finland 59 , one in Denmark 61 , one in China 62 , three in Germany 62 , 69 , 70 , one in Italy 64 , one in Spain 16 , one in Poland 75 , and the others in Iran 18 , 19 , 60 , 66 , 71 , 73 , 74 , Thirteen studies included only men and seven women, and 22 included both sexes.
The duration of the intervention varied from 4 to weeks. The CLA supplements were used in doses of 1. The mean age and baseline BMI ranged from 20 to Iwata et al. used two different CLA doses in their studies.
Out of the 42 studies, CRP, IL-6, TNF-α, adiponectin, and leptin were reported in 20, 15, 16, 12, and 20, respectively. For supplementation, 47 study arms used mixed isomers 9cis,11trans-CLA and 10trans,12cis-CLA , four study arms used 9cis,11trans-CLA isomer, and five study arms used 10trans,12cis-CLA isomer.
In these studies, detection methods of CRP were Behring latex-enhanced high-sensitivity assays, Eckman Synchron CX7 System, enzyme-linked immunosorbent assay, enhanced turbidimetric immunoassay, highly sensitive immunoassay with a monoclonal antibody coated with polystyrene particles, immunoturbidimetric assay, and rabbit antihuman.
Diamonds represent pooled estimates from random-effects analysis. WMD, weighted mean difference; CI, confidence interval; CLA, conjugated linoleic acid; CRP, C-reactive protein; IL-6, interleukin 6; TNF-α, tumor necrosis factor-alpha.
Overall, 24 effect sizes from 20 studies for CRP were included in the analysis. In the other subgroups, the effect of CLA supplementation on serum concentrations of CRP was not significant Table 3. Table 3 Subgroup analyses of CLA supplementation on inflammatory cytokines and adipokines.
In the other subgroups, the effect of CLA supplementation on serum concentrations of IL-6 was not significant Table 3. In the other subgroups, the effect of CLA supplementation on serum concentrations of TNF-α was not significant Table 3. The present study conducted a nonlinear dose—response regression to analyze the dose—response relationship between CLA supplementation and inflammatory cytokines and adipokines.
Meta-regression analyses were performed to assess whether inflammatory cytokines and adipokines were affected by CLA supplementation doses and intervention duration. WMD, weighted mean difference; CI, confidence interval; CRP, C-reactive protein; IL-6, interleukin 6; TNF-α, tumor necrosis factor-alpha.
The sensitivity analysis demonstrated that no study had a significant impact on the overall findings. Although the overall result of studies reporting data on TNF-α was sensitive to the study by Song et al.
In the case of CRP, some studies had an impact on the overall effect size, including that of Whigham et al. It was shown that the exclusion of every individual study by the sensitivity analysis could not change the direction of the correlation but eliminated the significant effect of CLA on CRP.
Table 4 displays the Grading of Recommendations Assessment, Development, and Evaluation GRADE profile of CLA supplementation on inflammatory cytokine and adipokine variables together with the certainty in outcomes. For CRP, because of serious limitations in inconsistency, the quality of evidence was moderate.
In the case of IL-6, because of very serious limitations in inconsistency and for TNF-α because of very serious limitations in inconsistency ad serious limitations for publication bias, the quality of evidence was low.
For both outcomes, including leptin and adiponectin, because of very serious limitations in inconsistency and serious limitations in imprecision, the quality of evidence was very low. Table 4 GRADE profile of CLA supplementation for inflammatory cytokines and adipokines.
Using the GRADE methodology, which was previously outlined, the total degree of evidence certainty across the studies was evaluated and summarized In this review, an analysis of pooling 42 studies indicated that CLA supplementation increased CRP concentrations, decreased IL-6 and TNF-α values, and had no effect on adiponectin and leptin levels.
Taking CLA decreased IL-6 in male individuals and unhealthy subjects if the trial duration was less than 12 weeks and when a mixture of two isomers was used. However, in subgroup analyses based on isomer type, 10trans12cis- CLA isomer significantly increased TNF-α.
Supplementation with CLA reduced adiponectin in women. It also decreased leptin in women and unhealthy adults but increased in those with normal baseline BMI. Moreover, the results of the meta-regression analysis showed that there was no significant linear association between intervention doses and duration of supplementation with inflammatory cytokines and adipokines.
The majority of studies included in this meta-analysis used supplements consisting of mixed amounts of CLA isomers. Therefore, since CLA isomers have shown different effects on inflammation 30 , 78 , it is suggested that this issue be considered in research.
It is also important to consider the contents of the placebo used in studies. Some included RCTs have used vegetable oils as a placebo, such as safflower and olive oils.
One study has indicated the reduced effect of safflower oil on CRP levels compared to CLA Another study has elucidated the anti-inflammatory effect of olive oils through the prevention of lipooxygenase and enzymes that synthesize leukotriene In other words, prescribing these vegetable oils as a placebo might misinterpret results.
Diet and physical activity can play an important role in inflammatory conditions It is better to consider the effects of these two factors in the result of the present meta-analysis.
Although, in some studies, the confounding variables of physical activity and diet were controlled, in some trials, these factors were not considered. Diet is an important regulatory factor in the immune response.
Malnutrition leads to suppression of the immune system, whereas overnutrition leads to immune activation. Some foods have anti-inflammatory effects, and there are still controversies about others Also, a high-fat diet causes excessive body fat accumulation and impairs the immune system.
On the other hand, it has been reported that trans and saturated fatty acids are significantly associated with the inflammatory state Although ruminant trans fatty acids have different effects than industrial trans fatty acids, several studies show that industrial trans fatty acids promote inflammation, whereas ruminant trans fatty acids have been reported to be harmless or even beneficial to health, as well as also having anti-inflammatory properties One study reported that sedentary subjects had higher levels of inflammatory factors such as IL-6 and TNF-α compared to subjects with higher physical activity Other confounding factors that can affect inflammatory markers are sleep duration and sleep quality.
In addition, a study on healthy subjects reported that higher IL-6 levels were associated with lower sleep quality Here, we showed CLA consumption increased CRP concentrations, decreased IL-6 and TNF-α, and did not change adiponectin and leptin levels.
There are some meta-analyses that have investigated the effect of CLA on the abovementioned markers. For example, Derakhshandeh-Rishehri et al. A meta-analysis conducted by Haghighatdoost et al.
Another meta-analysis conducted on 19 RCTs demonstrated that CLA intake had a small but not significant decline in plasma leptin. However, it significantly decreased leptin in obese individuals, with trials lasting for less than 24 weeks A study carried out by Mazidi et al.
By combining previous and current results, it can be acknowledged that except for the effect of CLA in increasing CRP levels, there is no consensus on other markers i. Moreover, it is noteworthy to state that exercise, dietary intake, sleep duration, and sleep quality can alter the effects of CLA.
Therefore, further well-designed studies may clarify the role of CLA on the abovementioned markers. In the present study, the gender-dependent impact of CLA has also been shown in the reduction of IL-6, TNF-α, adiponectin, and leptin. Based on evidence, CLA can induce testosterone biosynthesis 91 , and subsequently, testosterone is able to decrease IL-6 expression It has also been stated that circulating CLA concentrations are greater in women than in men Therefore, the aforementioned evidence can justify the different effects seen between men IL-6 and TNF-α reduction and women adiponectin and leptin reduction after taking CLA.
The effect of CLA on inflammatory responses has generated inconsistent results. This may be due to isomers and tissue-specific responses of CLA. Moreover, across the included RCTs, administration doses of CLA varied from 1. Health characteristics, inflammation status, and even gut microbiome composition of the recruited individuals were also different These variations in the studies can influence the results and interpretations.
For example, in relation to isomer and tissue-specific response, 9cis,11trans-CLA isomer exerts its anti-inflammatory effect by activating the peroxisome proliferator-activated receptor-γ PPAR-γ -dependent pathway and ultimately reducing the production of proinflammatory cytokines such as TNF-α and IL-6 However, the 10trans,12cis-CLA isomer has been reported to have a proinflammatory effect in adipose tissue, in contrast to its effects on innate immunity and vascular cells.
In addition, in adipose tissue, activation of PPARγ is contrary to the physiological effects of 10trans,12cis-CLA in vitro and in vivo This isomer downregulates PPAR-γ gene expression and increases TNF-α, IL-6, and CRP production in adipose tissue 78 , It seems that the reason for this inconsistency is cytokines secreted from adipocytes, which in turn alter PPARγ expression and activity in the fat cell.
Therefore, inconclusive results regarding the anti-inflammatory properties of CLA are likely due to the subtle proinflammatory effects of the 10trans,12cis-CLA isomers in specific tissues 30 , Overall, it appears that CLA can elicit both anti-inflammatory and proinflammatory features.
Some proposed mechanisms for the effects of CLA isomers on inflammation include the following: 1 Modulation of eicosanoid signaling. This means that CLA reduces the production of inflammatory eicosanoids derived from arachidonic acid AA through the inhibition of several steps in the AA cascade.
Also, it suppresses the expression of the inducible NO synthase iNOS gene, which leads to a decrease in IL-6 production. This meta-analysis has some limitations that should be addressed.
Most of the included studies had a relatively small sample size, which can cause an overestimation of the results. Observation of publication bias for TNF-α findings suggests overestimation of CLA efficiency on TNF-α.
Moreover, TNF-α, IL-6, and CRP results were sensitive to some studies. In conclusion, it is suggested that CLA supplementation can have both proinflammatory and anti-inflammatory roles.
It can enhance CRP concentrations while reducing TNF-α and IL-6 levels. Furthermore, CLA is able to decrease adiponectin and leptin in women. It can also decrease leptin in unhealthy adults and increase it in subjects with a normal baseline BMI.
Finally, in order to improve the quality of studies, future clinical trials are encouraged to carefully consider CLA-isomer-specific regulation of inflammatory markers and take notice of the contents of the placebo used in their control groups.
It is also important to keep in mind the gender-dependent impact of CLA. Further inquiries can be directed to the corresponding authors. OA and SR contributed to the conception and design of the study. DA-L, MZ, and GS contributed to data extraction. FS and AK screened articles for inclusion criteria.
OA contributed to the data analysis. SR, MY, and EG contributed to manuscript drafting, OA and MZ supervised the study. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Asbaghi O, Ashtary-Larky D, Bagheri R, Moosavian SP, Nazarian B, Afrisham R, et al.
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