Diverging metabolic effects of 2 energy-restricted diets differing in nutrient quality: a 12-week randomized controlled trial in subjects with abdominal obesity

Sophie Schutte, Diederik Esser, Els Siebelink, Charlotte J R Michielsen, Monique Daanje, Juri C Matualatupauw, Hendriek C Boshuizen, Marco Mensink, Lydia A Afman, Wageningen Belly Fat Study team, Sophie Schutte, Diederik Esser, Els Siebelink, Henriëtte Fick, Mechteld M Grootte Bromhaar, Ya Wang, Suzanne E M de Bruijn, Monica Mars, Jocelijn Meijerink, Marco Mensink, Lydia A Afman, Edith J M Feskens, Michael Müller, Sophie Schutte, Diederik Esser, Els Siebelink, Charlotte J R Michielsen, Monique Daanje, Juri C Matualatupauw, Hendriek C Boshuizen, Marco Mensink, Lydia A Afman, Wageningen Belly Fat Study team, Sophie Schutte, Diederik Esser, Els Siebelink, Henriëtte Fick, Mechteld M Grootte Bromhaar, Ya Wang, Suzanne E M de Bruijn, Monica Mars, Jocelijn Meijerink, Marco Mensink, Lydia A Afman, Edith J M Feskens, Michael Müller

Abstract

Background: Despite the established relation between energy restriction (ER) and metabolic health, the most beneficial nutrient composition of a weight-loss diet is still a subject of debate.

Objectives: The aim of the study was to examine the additional effects of nutrient quality on top of ER.

Methods: A parallel-designed, 12-week 25% ER dietary intervention study was conducted (clinicaltrials.gov: NCT02194504). Participants aged 40-70 years with abdominal obesity were randomized over 3 groups: a 25% ER high-nutrient-quality diet (n = 40); a 25% ER low-nutrient-quality diet (n = 40); or a habitual diet (n = 30). Both ER diets were nutritionally adequate, and the high-nutrient-quality ER diet was enriched in MUFAs, n-3 PUFAs, fiber, and plant protein and reduced in fructose. Before and after the intervention, intrahepatic lipids, body fat distribution, fasting and postprandial responses to a mixed-meal shake challenge test of cardiometabolic risk factors, lipoproteins, vascular measurements, and adipose tissue transcriptome were assessed.

Results: The high-nutrient-quality ER diet (-8.4 ± 3.2) induced 2.1 kg more weight loss (P = 0.007) than the low-nutrient-quality ER diet (-6.3 ± 3.9), reduced fasting serum total cholesterol (P = 0.014) and plasma triglycerides (P < 0.001), promoted an antiatherogenic lipoprotein profile, and induced a more pronounced decrease in adipose tissue gene expression of energy metabolism pathways than the low-quality ER diet. Explorative analyses showed that the difference in weight loss between the two ER diets was specifically present in insulin-sensitive subjects (HOMA-IR ≤ 2.5), in whom the high-nutrient-quality diet induced 3.9 kg more weight loss than the low-nutrient-quality diet.

Conclusions: A high-nutrient-quality 25% ER diet is more beneficial for cardiometabolic health than a low-nutrient-quality 25% ER diet. Overweight, insulin-sensitive subjects may benefit more from a high- than a low-nutrient-quality ER diet with respect to weight loss, due to potential attenuation of glucose-induced lipid synthesis in adipose tissue.

Keywords: adipose tissue; clinical trial; dietary intervention; insulin resistance; mixed-meal challenge; nutrigenomics; precision nutrition.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

Graphical Abstract
Graphical Abstract
FIGURE 1
FIGURE 1
Study design of the 12-week randomized controlled trial. The 3 intervention arms of the dietary intervention trial are: a 25% ER high-nutrient-quality diet (n = 40); a 25% ER low-nutrient-quality diet (n = 40); or a habitual diet (n = 30). Postprandial measurements per time point during the mixed-meal shake challenge and MRI/MRS were performed before and after the intervention. ER, energy restriction; MRS, magnetic resonance spectroscopy; PWA, pulse wave analyses; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue.
FIGURE 2
FIGURE 2
Cumulative weight loss in the 3 study groups (high-quality ER diet group, n = 34; low-quality ER diet group, n = 39; control group, n = 27) over 12-weeks of the intervention. The error bars represent 1 SD. *Significant difference in cumulative weight loss between the 2 ER groups at a P value <0.05. ER, energy restriction.
FIGURE 3
FIGURE 3
Heat maps of individual changes in genes from differentially enriched pathways between the high-nutrient-quality (n = 27) and low-nutrient-quality (n = 27) ER diets. Individual changes in gene expression, clustered per diet (habitual diet, n = 18), of genes contributing to differential enrichment in the 3 clusters between the high-nutrient-quality and low-nutrient-quality ER diets. Genes related to (A) mitochondrial energy production, (B) metabolic pathways, and (C) PI3/Akt signaling. ER, energy restriction; OXPHOS, oxidative phosphorylation; PPAR, peroxisome proliferator–activated receptor; TCA, tricarboxylic acid cycle.
FIGURE 3
FIGURE 3
Heat maps of individual changes in genes from differentially enriched pathways between the high-nutrient-quality (n = 27) and low-nutrient-quality (n = 27) ER diets. Individual changes in gene expression, clustered per diet (habitual diet, n = 18), of genes contributing to differential enrichment in the 3 clusters between the high-nutrient-quality and low-nutrient-quality ER diets. Genes related to (A) mitochondrial energy production, (B) metabolic pathways, and (C) PI3/Akt signaling. ER, energy restriction; OXPHOS, oxidative phosphorylation; PPAR, peroxisome proliferator–activated receptor; TCA, tricarboxylic acid cycle.
FIGURE 3
FIGURE 3
Heat maps of individual changes in genes from differentially enriched pathways between the high-nutrient-quality (n = 27) and low-nutrient-quality (n = 27) ER diets. Individual changes in gene expression, clustered per diet (habitual diet, n = 18), of genes contributing to differential enrichment in the 3 clusters between the high-nutrient-quality and low-nutrient-quality ER diets. Genes related to (A) mitochondrial energy production, (B) metabolic pathways, and (C) PI3/Akt signaling. ER, energy restriction; OXPHOS, oxidative phosphorylation; PPAR, peroxisome proliferator–activated receptor; TCA, tricarboxylic acid cycle.
FIGURE 4
FIGURE 4
Pearson correlation coefficients between incremental area under the curve (iAUC) and changes in postprandial time points of plasma glucose (HOMA-IR ≤ 2.5: n = 25; HOMA-IR > 2.5: n = 39) and insulin (HOMA-IR ≤ 2.5: n = 29; HOMA-IR > 2.5: n = 42) after the mixed-meal shake test with postprandial changes in expression of genes involved in lipid synthesis in adipose tissue after 240 minutes. Red indicates a positive correlation and green indicates a negative correlation. Bold numbers indicate a significant Pearson correlation at a P value <0.05.
FIGURE 5
FIGURE 5
Cumulative weight loss in the 3 study groups over 12 weeks of intervention for insulin-sensitive (HOMA-IR ≤ 2.5) and insulin-resistant (HOMA-IR > 2.5) subjects. High-nutrient-quality ER diet: n = 15 insulin-sensitive and 19 insulin-resistant subjects; low-nutrient-quality ER diet: n = 17 insulin-sensitive and 22 insulin-resistant subjects; and control diet: n = 13 insulin-sensitive and 14 insulin-resistant subjects. Error bars represent 1 SD. The linear mixed model P value for the interaction of Diet*HOMA-IR*week is 0.010. Least significant difference (LSD) post hoc analyses showed significantly (P < 0.007) greater weight loss on the high-nutrient-quality ER diet compared to the low-nutrient-quality ER diet within insulin-sensitive subjects. ER, energy restriction.
FIGURE 6
FIGURE 6
Changes in fasting lipoprotein profiles compared to the control group (n = 27). Colored boxes indicate significantly changed (log2 ratio) particles within an ER group—(A) the low-nutrient-quality ER diet (n = 39) or (B) high-nutrient-quality ER diet (n = 34)—as assessed with a paired t-test, where the red color indicates an increased level and the blue color indicates a decreased level. The color intensity is related to the size of the effect, where a darker color indicates a larger change. The red outline on the boxes indicates a significant difference between an ER group (low-nutrient-quality or high-nutrient-quality groups) and the control, as analyzed using ANOVA and Hochberg's GT2 post hoc analyses on changes in metabolites in all 3 groups. P values were corrected for false positives using a false discovery rate of 0.05 in the simultaneous analysis of all 153 metabolites. C, cholesterol; CE, cholesterol esters; FC, free cholesterol; L, lipids; P, particles; PL, phospholipids; TG, triglycerides.
FIGURE 6
FIGURE 6
Changes in fasting lipoprotein profiles compared to the control group (n = 27). Colored boxes indicate significantly changed (log2 ratio) particles within an ER group—(A) the low-nutrient-quality ER diet (n = 39) or (B) high-nutrient-quality ER diet (n = 34)—as assessed with a paired t-test, where the red color indicates an increased level and the blue color indicates a decreased level. The color intensity is related to the size of the effect, where a darker color indicates a larger change. The red outline on the boxes indicates a significant difference between an ER group (low-nutrient-quality or high-nutrient-quality groups) and the control, as analyzed using ANOVA and Hochberg's GT2 post hoc analyses on changes in metabolites in all 3 groups. P values were corrected for false positives using a false discovery rate of 0.05 in the simultaneous analysis of all 153 metabolites. C, cholesterol; CE, cholesterol esters; FC, free cholesterol; L, lipids; P, particles; PL, phospholipids; TG, triglycerides.

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