The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial

Mediterranean (MED) diet is a rich source of polyphenols, which benefit adiposity by several mechanisms. We explored the effect of the green-MED diet, twice fortified in dietary polyphenols and lower in red/processed meat, on visceral adipose tissue (VAT).

In the 18-month Dietary Intervention Randomized Controlled Trial PoLyphenols UnproceSsed (DIRECT-PLUS) weight-loss trial, 294 participants were randomized to (A) healthy dietary guidelines (HDG), (B) MED, or (C) green-MED diets, all combined with physical activity. Both isocaloric MED groups consumed 28 g/day of walnuts (+ 440 mg/day polyphenols). The green-MED group further consumed green tea (3–4 cups/day) and Wolffia globosa (duckweed strain) plant green shake (100 g frozen cubes/day) (+ 800mg/day polyphenols) and reduced red meat intake. We used magnetic resonance imaging (MRI) to quantify the abdominal adipose tissues.

A green-MED diet, enriched with plant-based polyphenols and lower in red/processed meat, may be a potent intervention to promote visceral adiposity regression.

Visceral adipose tissue (VAT) accumulation is one of the main key factors that differentiate between metabolic healthy and unhealthy obese individuals [, ]. VAT is closely related to the development of multiple cardiovascular risk factors, including hypertension, dyslipidemia, type 2 diabetes (T2D), and an independent marker of mortality [,,,,]. Moreover, VAT was found independently associated with elevated 10-year cardiovascular risk, particularly in men, and is suggested as a tool for long-term cardiovascular disease (CVD) risk assessment []. In contrast, subcutaneous adipose tissue (SAT) is inconsistently associated with obesity-related morbidity [,,]. While superficial SAT is correlated with improved glycemic control and indices of cardiovascular health [], deep SAT is correlated with high blood pressure, obesity, and insulin resistance [].

The Mediterranean (MED) diet, high in polyphenol content [] and rich in plant food sources, was shown to have an enhanced effect on VAT reduction in combination with physical activity (PA), regardless of weight loss []. Polyphenols are diverse phytochemicals, common in plant-based foods, widely studied in recent years due to their possible antioxidant and anti-inflammatory properties and the potential for preventing unhealthy metabolic obesity, T2D, CVD, and hypertension [, , ]. As for the effect of polyphenols on adiposity, various mechanisms have been proposed, mostly based on animal and cell studies, including inhibition of adipocytes differentiation, increased fatty acid oxidation, decreased fatty acid synthesis, increased thermogenesis, and energy expenditure [,,,,,,].

In our previous randomized controlled trials (e.g., DIRECT [, ], CENTRAL [], CASCADE []), dietary interventions richer in polyphenol content tended to yield more successful cardiometabolic results, as well as mobilization of specific ectopic fat depots. Thus, we aimed to assess the effect of the MED diet, further enriched with polyphenols (green tea and Wolffia globose Mankai plant, high-quality green plant-based protein-rich in polyphenols), and lower in red and processed meat (“green-MED diet”) on visceral adiposity in the 18-month Dietary Intervention Randomized Controlled Trial-Polyphenols, Unprocessed (DIRECT-PLUS) trial.

Eighteen-month change in abdominal adipose tissues, weight, and waist circumference

As previously reported [], after 18 months, the total plasma polyphenol levels were higher in both MED groups (0.47 (0.4) mg/L for both) as compared to the HDG group (0.35 (0.4) mg/L; p < 0.05 for both MED vs. HDG).

Several limitations should be acknowledged. The low proportion of women reflects the workplace, and different VAT proportions at baseline across groups limit the generalizability of findings to women nor can we not identify the exact components responsible for the dietary effects as we compared dietary regimens and not specific nutrients. We assessed adherence by the self-reported dietary intake assessment tool, which is subject to error, although the instrument has been validated []. Yet, we analyzed the serum folate levels, which can reflect green leaf consumption []. Total lean body mass or fat mass measurements were not available from our MRI analysis. Abdominal adipose tissues were measured in a semiautomatic manner and recorded as area and not volume. However, we observed high inter- and intraclass correlations, supporting their reproducibility. The recommended PA was monitored by self-report for all groups and not direct objective means. The dietary assessment was inadequate to estimate the intake of polyphenols beyond the evaluation of the specific high polyphenol foods provided. Plasma and urinary polyphenol assessments provide objective data; however, these measurements are limited in reflecting polyphenol intake. Additionally, the urine polyphenol analysis was based on a spot sample rather than a 24-h collection. In general, we tried to confirm the beneficial effects of dietary polyphenols in a dietary pattern human study, as suggested in lab-based experiments. The strengths of the study include the relatively large sample size, high retention rate, and use of 3-T MRI measurements (considered one of the gold standards tools for the quantification of specific fat depots []) and the division of SAT into deep and superficial fat tissues, which are known to differ histologically and physiologically [, ]. Furthermore, the closed workplace enabled monitoring of the freely provided lunch, the presence of an onsite clinic, intense dietary guidance and group meetings with multidisciplinary guidance, and access to polyphenol-rich foods provided at no charge.

Our findings further support the clinical significance of different abdominal fat depots. In both the CENTRAL [] and DIRECT-PLUS trials, after diet-induced weight loss, VAT reduction was associated with an improved lipid profile, as the deep SAT reduction was associated with a beneficial glycemic profile. The superficial SAT was previously correlated with improved glycemic control (HbA1c and fasting glucose) and better indicators of cardiovascular health []. These differences may be explained by differential sensitivity to lipolytic stimulation hormones. VAT adipocytes show higher lipogenic and lipolytic activity and produce more proinflammatory cytokines, while subcutaneous adipocytes are the main source of leptin []. Therefore, a reduction in VAT accumulation, known as a key risk factor in CVD development, may reduce metabolic complications, improve the lipid profile, and decrease cardiometabolic risk. The two subcutaneous depots differ histologically and physiologically, with deep SAT having higher lipolytic activity and larger, polygonal, and better-organized fat lobules than the superficial SAT depot [, ]. This study further reinforces the hypothesis that the distribution of abdominal subdepots may be a key factor in cardiometabolic risk rather than total body weight.

A green-MED diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the MED diet for targeted VAT reduction. Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity.

The majority of results corresponding to the current study are included in the article or uploaded as supplementary material. No further data are available.

We thank the DIRECT-PLUS participants for their valuable contributions. We thank the California Walnut Commission, Wissotzky Tea Company, and Hinoman, Ltd. for kindly supplying food items for this study. We thank Dr. Dov Brikner, Efrat Pupkin, Eyal Goshen, Avi Ben Shabat, Benjamin Sarusi, and Evyatar Cohen from the Nuclear Research Center Negev and Liz Shabtai from Ben-Gurion University of the Negev for their valuable contributions to this study.

This work was supported by grants from the German Research Foundation (DFG), German Research Foundation - project number 209933838 - SFB 1052; B11 to I. Shai (SFB-1052/B11), N. Klöting, and M. Blüher; Israel Ministry of Health grant 87472511 (to I. Shai); Israel Ministry of Science and Technology grant 3-13604 (to I. Shai), and the California Walnuts Commission (to I. Shai). None of the funding providers was involved in any stage of the design, conduct, or analysis of the study, and they had no access to the study results before publication.

HZ had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: IS. Conduct of the study: HZ, AK, AYM, ER, GT, and IS. Collection, management, analysis, and interpretation of the data: all authors. Review and approval of the manuscript: all authors. Statistical analysis: HZ. Supervision: IS. All authors read and approved the final manuscript.

The Soroka University Medical Centre Medical Ethics Board and the Institutional Review Board approved the study protocol for the DIRECT PLUS trial. All participants provided written informed consent and received no financial compensation.

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