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\begin{document}

\title{The effect of soy and soy product supplementation on circulating
adiponectin and leptin concentration: A systematic review and
meta-analysis of randomized controlled trials}



\author[1]{Amirhossein farokhzad}%
\author[2]{Wolfgong  Marx}%
\affil[1]{Affiliation not available}%
\affil[2]{Sichuan University}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Adiponectin is a well-known adipokines with
anti-inflammatory effects. Leptin is known as its effect on food intake
and energy. Here in present study we aimed to evaluate possible effect
of soy supplementation on circulating adiponectin and leptin. Methods:
Systematic search performed up to April 2020 in the following databases:
PubMed, Scopus and Cochrane. All RCTs which evaluated the effect soy
supplementation on adiponectin and leptin concentration were included.
Results: According to our analysis on 14 studies, in overall, soy
supplementation had significant effect on adiponectin concentration.
Furthermore, soy supplementation has no significant effect on serum
leptin concentration, but subgroup analysis showed significant increase
in leptin concentration in studies with doses more than 20 g/day of soy
supplementation. Conclusion: Soy supplementation has significant
increasing effect on adiponectin level. Whilst pooled effect size did
not show any significant effect of soy product supplementation on leptin
level.%
\end{abstract}%



\sloppy


\textbf{What is already known about this topic?}

* Some previous studies have shown the beneficial effects of soy
supplementation.

* There has been no meta-analyses to summarize the effect of soy
supplementation on circulating adiponectin and leptin in adults.

\textbf{What does this article add?}

* This study is the first systematic review and meta-analysis that has
been designed to evaluate the effect of soy supplementation on
circulating adiponectin and leptin in adults.

* The present study suggests that soy supplementation has significant
increasing effect on adiponectin level.

* However, pooled effect size did not show any significant effect of soy
product supplementation on leptin level.

\textbf{Introduction}

Adiponectin is the most abundant circulating adipokine secreted from
adipose tissue in the blood. The fundamental role of adiponectin in
fatty acid oxidation and glucose homeostasis, suppressing fat
accumulation and promoting antioxidation reported in previous
studies\textsuperscript{1-3}. Lower adiponectin level reported in type 2
diabetes, metabolic syndrome, and cardiovascular disease
(CVD)\textsuperscript{4}; therfore in these patients lower adiponectin
level has the etiological importance of forming insulin
resistance\textsuperscript{5}. Higher adiponectin concentration
associated with lower risk of CVDs\textsuperscript{6}. Leptin, other
well-known adipokine also reported to be involved in glucose uptake and
glycolysis exactly effect on glycolytic enzymes; it`s role in production
of inflammatory cytokines also has been
reported\textsuperscript{7,8}.~Leptin mostly known as a hormone which
regulate food intake and energy expenditure \textsuperscript{9}.

Soy is a valuable plant protein source; its use is common in several
parts of the world particularly southeastern parts of
asia\textsuperscript{10}. Soy and soy products because of its
isoflavones known as one of the rich sources of micronutrients,
phytochemicals and powerful antioxidants. Biologically active
heterocyclic phenols of soy after ingestion could act sevral function in
body \textsuperscript{11}. Genistein and daidzein, the main isoflavones
of soy implicated in preventing metabolic diseases such as cancer,
osteoporosis, infertility, diabetes and CVDs \textsuperscript{12}. These
isoflavomnes are potent anti-inflammatory agents; Equol, the metabolite
of diadzein following function of gut microbiome, reported to possess
antioxidant effects and also it has a tendency for binding to estrogen
receptors \textsuperscript{13}. Apart from different varient of soy and
their possible different effect, some polymorphisms alter the
individual's response to isoflavones, worsening inflammatory status and
causing mutations, but in some polymorphisms, soy intake decreases tumor
growth by reducing inflammation \textsuperscript{14}.

However, some experimental studies have reported beneficial
anti-inflammatory effects of soya protein or isoflavone, shown by
increasing adiponectin\textsuperscript{15-17}. Previous studies reported
inconsistent results regarding effect of soy and soy products on
adiponectin and leptin level; several studies showed no statistically
significant change in the adiponectin\textsuperscript{18-26}. Of
interest, Llanos et al. \textsuperscript{27}reported soy protein
supplement (40 g) resulted in significant adiponectin reduction.
Furthermore, there was a trend toward decreased circulating adiponectin
with the soy supplement compared to placebo in Maskarinec et al.
study\textsuperscript{20}, consistent with the report by Llanos et
al.\textsuperscript{27}. Most studies did not report any change in
leptin as well; except but in two
studies,\textsuperscript{26,27}intervention of soy protein supplement
resulted in lower leptin reduction compared with control group. Due to
lack of comprehensive systematic review and meta-analysis on one hand,
and inconsistent results on the other hand, we aimed to systematically
review the effect of soy and soy products on circulating adiponectin and
leptin. Findings of present study enlighten our knowledge in this
context for recommendation.

\textbf{Methods}

Search Strategy

The systematic review and meta-analysis was reported based on the
guidelines of Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA)\textsuperscript{28}. A computerized literature
search was performed from inception to April 2020 using various
databases including PubMed (http://www.pubmed.com), ISI Web of Science
(http://www.webofknowledge.com), Scopus (http://www.scopus.com), and
Google Scholar (http://www.scholar.google.com) search. The following
phrases and their combinations of MeSH and non-MeSH terms were used,
including: ``soy protein'', ``soybean proteins'', ``soy isoflavones'',
``soy'', ``isoflavones'', ``soy diet replacement'', ``meal replacement
therapy'', ``adipokines'' ``adiponectin'', ``leptin'', ``controlled
trial'', ``randomized'', ``randomised'', ``random'', ``randomly'',
``randomized clinical trial'', ``RCT'', ``blinded'', ``double blind'',
``double blinded'', ``trial'', ``controlled clinical trial'',
``crossover procedure'', ``cross-over trial'', ``double blind procedure
''and ``equivalence trial''. Reference lists of all articles were
examined for identification of further eligible studies.

Eligibility Criteria

Studies were selected by applying the following
Population-Intervention-Comparator-Outcomes-Study design (PICOS)
criteria \textsuperscript{28}: 1) subjects received oral soy and soy
products supplementation, as a nutritional strategy; 2) original
randomized-controlled trial researches and 3) reporting at least one
outcome measure of adipokines (adiponectin and leptin) ; 4) presented
data of interest as mean and standard deviation (SD) of adiponectin and
leptin in both intervention and placebo groups; and 5) had a trial
duration of more than 4 weeks. Exclusion criteria were: 1) using a
mixture of soy protein or isoflavones extract only in intervention
group, not including a placebo group; 2) semi experimental,
nonrandomized trials and trials without control groups; 3) duplicate
studies with the same population (several papers reported the same
data); 4) enrolled pregnant or lactating women; 5) experimental and
animal studies; and 6) reviews, letters to editor, editorial articles,
or case reports.

Selection strategy

After a primary search, all recorded articles found from electronic or
manual searches were entered into endnote software for screening
(EndNote X6, Thomson Reuters, New York). Titles and received abstracts
of papers were screened by the search strategy. studies were evaluated
independently by two reviewers and selected according to the inclusion
criteria independently. Articles including eligibility criteria in the
title/abstract screening were selected to be checked by full-text. All
clinical trials were included in the present met analysis if our
inclusion criteria met. All categorized trials were retrieved by either
of the authors. On the basis of the information within the full
information, we used a standardized form to select the trials eligible
for inclusion in the review. Contradictions between the authors were
solved by consensus or third researcher.

Data extraction

We extracted following required data using a pre-designed standardized
electronic form (Excel, Microsoft Office): first author's name,
publication year and country, research design, age and gender of
subjects, sample size, duration of intervention and soy dose. Also, we
extracted mean and standard deviation (SD) of plasma adipokines status
(adiponectin and leptin) at baseline and after the intervention. Any
reported standard errors of mean (SEM), were converted to SDs through
following formula by SD = SEM \selectlanguage{ngerman}× \selectlanguage{english}[?]n (n is the number of participants in
each group). Finally, in studies which reported data in graphical
figures, data extraction was performed by using GetData Graph Digitizer
2.24 \textsuperscript{29}.

Study quality

The Cochrane Collaboration tool was used for assessing the risk of bias,
since it has been accepted that trial inclusion with a high risk of bias
may distort the results of a meta-analysis\textsuperscript{30,31}. The
quality of all included studies were evaluated by based on the following
factors: randomization sequence generation; allocation concealment;
blinding of participants, personnel, investigator, and assessor;
attrition rates; and financial interest by companies. These were given a
rating of low, unclear, or high risk of bias. A randomized controlled
trial (RCT) was ranked as having low, medium, or high-risk overall based
on the key areas of allocation concealment, reporting of attrition
rates, and participants and assessor (high = all 4 factors rated high,
medium = 2 or 3 factors rated high or unclear, and low = all key areas
rated low).

Analyses and measures of treatment effect

Mean changes and SD were computed for continuous variables for every
study to calculate effect size. As for studies with no reported SD of
the mean difference, following formula were used: SD change = square
root {[}(SD baseline \textsuperscript{2} + SD final \textsuperscript{2})
- (2 x 0.8 x SD baseline x SD final){]}\textsuperscript{32}.
Standardized mean changes were used for variables pooled on the
different scales. Between-study heterogeneity was assessed using the
chi-squared (\selectlanguage{greek}χ\selectlanguage{english}2) test and quantified using the I\textsuperscript{2}
statistic, which represents the percentage of the total variation across
studies that is attributable to heterogeneity rather than to chance.
Significant heterogeneity was defined with a P-value of \textless{}0.05.

The random effects model was applied to compute the weighted mean
differences (WMDs) with 95\% confidence intervals (CIs) for estimating
the overall effect. To evaluate whether the results could have been
affected distinctly by a single study, an influence or sensitivity
analysis was carried out\textsuperscript{33}. Subgroup analysis was also
performed, based on the gender of participant (male, female or both),
baseline BMI (over 30 kg/m\textsuperscript{2} and 30
kg/m\textsuperscript{2} or lower), dose of soy protein (over 20 g/day
and 20 g/day or lower), duration of studies (over 12 weeks and 12 weeks
or lower), supplementation type (soy-based meal replacement, soy powder
or capsule supplement) and study design (randomized cross over or
parallel). Publication bias was assessed by Begg's rank correlation test
and Egger's regression asymmetry test. Funnel plots also depicted the
effect sizes (differences in means) against their corresponding standard
errors. Statistical analyses were performed using STATA 11.2 software
(StataCorp, College Station, Texas, USA).

\textbf{Results}

Search results and overview of included studies

Our search led to 462 relevant studies. After duplicates removing, a
wide range of screening of the titles and abstracts, the careful
assessment was performed on 454 related articles. Of these, 23 articles
remained after considering the inclusion and exclusion criteria for the
eligibility. Eventually, 18 articles, including, 14 effect sizes for
adiponectin and 14 effect sizes for leptin, which studied a total of
1042 and 1073 participants respectively and aged 28.9 -- 69 years, were
identified in the current systematic review and meta-analysis. One
study\textsuperscript{34} just reported baseline data in the article
paper and we did not receive raw data for after trial data from the
authors. This listed number is inclusive of people who were dropouts in
some studies. \textbf{Figure 1} represents the selection process and
reasons for excluding the studies. The data in\textbf{Table 1}
illustrates the main characteristics of the articles in our systematic
review and meta-analysis.

In brief, the studies were published between 2009 and 2019. The duration
of these RCTs ranged between 4 weeks to 24 months. The total number of
participants who completed the studies in inclusion criteria was 511
participants in the intervention and 531 in the placebo groups for
adiponectin and 544 participants in the intervention and 529 in the
placebo groups for leptin. Soy protein have been used in a variety of
forms in these studies like soy-based meal
replacement\textsuperscript{18-20,25,26,35,36}, soy powder or
formula\textsuperscript{15-17,21,22,24,27,37}and capsule
supplement\textsuperscript{19,23,38}. However most of studies have been
used soy powder or formula. The dose of soy protein supplementation was
6 to 50 g/day among these studies.

Three studies used a randomized crossover
design\textsuperscript{18,24,27}, two of them was also single
blind\textsuperscript{18,27}and the other study had the design of
double-blind\textsuperscript{24}. Among 18 studies 9 studies were
conducted in n the United States\textsuperscript{15,18-21,24,25,27,36}.
The effect of soy protein on both adiponectin and leptin concentration
was examined in 10 studies; and 4 studies only reported
adiponectin\textsuperscript{17,18,25,38}and 4 studies only reported
leptin\textsuperscript{35-37,39}. Overall, 18 effect sizes were
extracted from these studies for adiponectin and leptin concentration.

Results from quality assessments

The quality details of bias assessment are presented in \textbf{Table
2,} and the Cochrane Collaboration tool was applied for evaluating the
risk of bias \textsuperscript{32}. Briefly, participant's random
allocation was mentioned in all included trials. However, eight trials
described the method of random sequence
generation\textsuperscript{15-17,21-24,26}. Five trials reported
allocation concealment\textsuperscript{15,17,22,25,37}. Most studies
represented low risk of bias based on selective reporting; nevertheless,
5 studies had high risk of bias\textsuperscript{17,18,23,24,35}. All
studies had a low risk of bias for incomplete outcome data. Five studies
had a low risk of bias for blinding of participants and
personnel\textsuperscript{15,18,21,22,25}and six studies had high risk
of bias regarding blinding outcome
assessors\textsuperscript{15,16,22,26,37,39}. All of studies had low or
unclear risk of bias regarding other potential threats to validity.

Findings from the meta-analysis

Effects of soy protein supplementation on serum adiponectin
concentration

According to our analysis on 14 studies, in overall, soy and soy product
consumption had significant effect on adiponectin concentration: WMD =
0.09; 95\% CI: 0.04, 0.15; P = 0.001. There was significant heterogeneity
among the studies (Cochran's Q test = 165.27, P = 0.000,
I\textsuperscript{2} = 92.7 \%). Subgroup analysis of gender of
participant, baseline BMI, dose of soy protein, duration of studies,
supplementation type and study design had no significant effect on
adiponectin concentration in any subgroups. The results of subgroup
analysis are shown in \textbf{Table 3} and the forest plot is shown
in\textbf{Figure 2} .

Effects of soy protein supplementation on leptin concentration

As outlined in \textbf{Figure 2} , our preliminary analysis indicated
that soy and soy products consumption have no significant difference in
serum leptin concentration (WMD = 0.12; 95\% CI: -3.26, 3.51; P= 0.921)
Also, significant heterogeneity was observed among studies (Cochran's Q
test = 109.59, P= 0.000, I\textsuperscript{2} = 88.1 \%). Subgroup
analysis was conducted to check if the effect of soy protein
supplementation on serum leptin is different according to gender of
participant, baseline BMI, dose of soy protein, duration of studies,
supplementation type and study design (\textbf{Table 3} ). This analysis
revealed that the pooled effect of soy protein supplementation on leptin
concentration was influenced by dose of soy protein ([?]20 g/day
versus\textgreater{}20 g/day), in this way that, a significant increase
in leptin concentration was found in studies that used more than 20
g/day soy protein (WMD = 4.405; 95\% CI: 0.578, 8.232; P= 0.024).
Subgroup analysis didn't show any significant effect of soy protein
supplementation on leptin concentration in other subgroups.

Sensitivity analysis and publication bias

Sensitivity analysis indicated that the removal of any of the studies
from the meta-analysis, create no change in the results of the
meta-analysis on leptin concentration whereas, the results on
adiponectin concentration were sensitive to omitting 1
study\textsuperscript{18}. Funnel plots for adiponectin and leptin were
visually symmetrical \textbf{(Figure 4 and 5)} , and the results of
Begg's test did not determine any evidence of publication bias in
studies that examine the effect of soy protein consumption on
adiponectin (Begg's test, P = 0.059) and on leptin (Begg's test, P =
0.861).

\textbf{Discussion}

To our knowledge, the efficacy of soy protein and soy products has not
been distinctly established for adipocytokines concentration; therefore,
this systematic review and meta-analysis provided insight into the
potential advantages conferred by such supplementation to allow healthy
and unhealthy people to make informed decisions on their usage. This
meta analysis suggests that soy protein supplementation have a
meaningful effect on plasma levels of adiponectin; however, pooled
effect size were not significant for leptin concentration.

The soy protein beneficial effects on traditional CVD risk factors,
blood pressure and primarily lipids, has been demonstrated
previously\textsuperscript{40,41}. The evidence for a dietary protein
intake association on novel CVD risk factors is less conclusive. A high
adiponectin concentration is related to insulin sensitivity and
decreased risk for CVDs. Adiponectin is also an independent marker of
risk for metabolic syndrome in patients with type 2 diabetes
\textsuperscript{42}. Generally, serum adiponectin concentration are
decreased in diabetes type-2 and obesity and this is considered to be of
etiological importance in causing insulin resistance\textsuperscript{5}.
Therefore, any measure that increases adiponectin concentration would be
predicted to improve insulin resistance. Contrary to adiponectin,
reduced plasma leptin levels are positively correlated with parameters
of overall obesity and CVDs \textsuperscript{43}. Leptin is secreted
exclusively by adipocytes, and this secretion is regulated by the size
of fat stores both in pathophysiological and in physiological
states\textsuperscript{44}. This protein provides the brain with
information about the body's fat deposits. This acts as a feedback
mechanism that can function as a lipostat\textsuperscript{45} via
control of satiety, energy expenditure, and other neuroendocrine
functions\textsuperscript{46}. Because of all of these pathological
conditions, it is important to design strategies to reduce leptin
levels.

Despite the heterogeneity of the data, our meta analysis showed that
serum adiponectin concentration increased in participant taking
isoflavones compared to placebo. However, performed subgroup analysis
based on sex, baseline BMI, dose, duration, type of supplementation and
study design were did not showed any significant effect of soy and soy
product supplementation on adiponectin serum level. We found that soy
protein supplementation resulted in no significant reduction in leptin
concentration, but we observed a significant increase in leptin
concentration in studies that used more than 20 g/day soy protein
compared with control group. The observed increase in plasma leptin was
not documented in any of studies, but in two
studies,\textsuperscript{26,27}intervention of soy protein supplement
resulted in lower leptin reduction compared with control group. Deibert
et al.\textsuperscript{26} have used lifestyle change group as control
group that attended 6 weekly teaching sessions about nutrition and
physical exercise. Also, Llanos et al,\textsuperscript{27} have designed
interventions included 10 weeks of consumption of a tomato-based diet
and 10 weeks of consumption of a soy-based diet. Although these two
studies have used more than 20 g/day soy protein, but may distorted the
results, because control group of these studies resulted more reduction
of leptin concentration compared with soy-based diet. As well as,
studies that used less than 20 g/day soy protein had a trend toward
decreased circulating leptin with the soy supplement compared to placebo
(p = 0.056). Due to standard method and strategy of supplementation in
these studies, this result is more reliable.

To our knowledge, interactions between adiponectin and estrogens have
not yet been fully characterized. Higher concentrations of adiponectin
in women than in men of comparable BMI and age suggest that estrogens
might have a stimulatory effect on adipocytes production
adiponectin\textsuperscript{47,48}. The use of soy products clearly
appears to be beneficial from a viewpoint of cardiovascular disease,
leastways in part, because of the actions of isoflavones which resemble
estrogen effect\textsuperscript{49}. Because of these effects, 7 studies
that included in this meta analysis conducted trial on postmenopausal
women and hypothesized that adipocytokines concentration in
postmenopausal women using soy protein could be higher than in women
without soy protein using\textsuperscript{15,16,20,25,27,36,37}. Wide
array of both in vivo and in vitro studies done by investigators showing
an effect of estrogens on adipocyte for adipocytokines production. They
concluded that adiponectin concentrations in postmenopausal women using
estrogens could be higher than in women without hormone replacement
therapy\textsuperscript{50,51}. Also, Casabiell et al. found what
appeared to be a direct estradiol effect to stimulate leptin production
in a tissue organ culture\textsuperscript{52}. In fact, isoflavones of
soy are relatively potent agonists of the \selectlanguage{greek}β-\selectlanguage{english}of estrogen receptor
isoform, and its effects on adipocyte function and differentiation have
been reported\textsuperscript{53}, and we conclude soy protein effects
on adipocytokines is due to estrogen-like probable actions of
isoflavones.

Many studies have showed that soy isoflavones have multiple biological
functions and may help to restore adiponectin expression. Soy
isoflavones (Both genistein and daidzein) significantly inhibited the
TNF-a \selectlanguage{english}mediated downregulation of adiponectin expression in adipocytes.
Some possible molecular mechanisms are that these active components (I)
inhibit the TNF- a \selectlanguage{english}mediated JNK signaling pathway involved in
adiponectin expression, or (II) inhibit the TNF- a \selectlanguage{english}mediated
downregulation of FoxO1, which is involved in adiponectin expression,
(III) function as PPAR\selectlanguage{greek}γ \selectlanguage{english}agonists and increase the transcriptional
activity of PPAR\selectlanguage{greek}γ, \selectlanguage{english}which ultimately leads to the inhibition of the TNF-
a \selectlanguage{english}mediated downregulation of adiponectin expression\textsuperscript{54}.
Also, high dosage of soy isoflavones may enhance circulating leptin
level in insulin resistant rats by elevating the efficiency of
translating leptin mRNA into leptin protein \textsuperscript{55}.

The strengths of our study is that we considered all published clinical
trials conducted on the effect of soy protein supplementation on
adipocytokines. In addition, we considered all RCTs which were done on
individuals with different health conditions. Also different study
designs and the lack of controlling for baseline measures in some
studies should be taken into account. Moreover, many factors can affect
the high heterogeneity and the inconclusive findings stated different
manufacturers of soy protein and variations in soy protein
classifications between countries may contribute to the inconsistencies
in results.

\textbf{Conclusion}

Soy protein supplementation, had a beneficial effect on adiponectin.
Additional well-designed RCTs recruiting a homogenous group of
participants are required to further examine this subject. In addition,
the effects of soy protein on other adipocytokines, for example
chemerin, visfatin and omentin, metabolic parameters, and the
cost-effectiveness of this supplement, should be clarified in further
studies.

\textbf{Conflict of interest}

The authors declare no conflict of interest.

\textbf{Acknowledgments}

None.

\textbf{Funding source}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

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\verb`Table 1. Summary of relevant sources of data1.docx`  available at \url{https://authorea.com/users/355778/articles/478890-the-effect-of-soy-and-soy-product-supplementation-on-circulating-adiponectin-and-leptin-concentration-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials}

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\verb`Table 2. Cochrane Risk of Bias Assessment1.docx`  available at \url{https://authorea.com/users/355778/articles/478890-the-effect-of-soy-and-soy-product-supplementation-on-circulating-adiponectin-and-leptin-concentration-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials}

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\verb`Table 3. subgroup adipokines11.docx`  available at \url{https://authorea.com/users/355778/articles/478890-the-effect-of-soy-and-soy-product-supplementation-on-circulating-adiponectin-and-leptin-concentration-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials}

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