Personalized Cardio-Metabolic Responses to an Anti-Inflammatory Nutrition Intervention in Obese Adolescents: A Randomized Controlled Crossover Trial

Aoibheann M McMorrow, Ruth M Connaughton, Tiago R Magalhães, Fiona C McGillicuddy, Maria F Hughes, David Cheishvili, Melissa J Morine, Sean Ennis, Marie-Louise Healy, Edna F Roche, Richard E Tremblay, Moshe Szyf, Fiona E Lithander, Helen M Roche, Aoibheann M McMorrow, Ruth M Connaughton, Tiago R Magalhães, Fiona C McGillicuddy, Maria F Hughes, David Cheishvili, Melissa J Morine, Sean Ennis, Marie-Louise Healy, Edna F Roche, Richard E Tremblay, Moshe Szyf, Fiona E Lithander, Helen M Roche

Abstract

Scope: Chronic inflammation and hypoadiponectinemia are characteristics of obesity-induced insulin resistance (IR). The effect of an anti-inflammatory nutrition supplement (AINS) on IR and adiponectin biology in overweight adolescents was investigated. The secondary objective was to examine the extent to which individuals' biomarker profiles, derived from baseline phenotypes, predicted response or not to the AINS. Additionally, the impact of DNA methylation on intervention efficacy was assessed.

Methods and results: Seventy overweight adolescents (13-18 years) were recruited to this randomized controlled crossover trial. Participants received an AINS (long chain n-3 PUFA, vitamin C, α-tocopherol, green tea extract, and lycopene) and placebo for 8 weeks each. Homeostatic model assessment (HOMA)-IR, adiponectin, inflammatory profiles, and DNA methylation were assessed. HOMA-IR was unchanged in the total cohort. High-molecular-weight (HMW) adiponectin was maintained following the AINS while it decreased over time following the placebo intervention. HOMA-IR decreased in 40% of subjects (responders) following the AINS. Responders' pretreatment phenotype was characterized by higher HOMA-IR, total and LDL cholesterol, but similar BMI in comparison to nonresponders. HMW adiponectin response to the AINS was associated with bidirectional modulation of adipogenic gene methylation.

Conclusion: The AINS modulated adiponectin biology, an early predictor of type 2 diabetes risk, was associated with bidirectional modulation of adipogenic gene methylation in weight-stable overweight adolescents. HOMA-IR decreased in a sub-cohort of adolescents with an adverse metabolic phenotype. Thus, suggesting that more stratified or personalized nutrition approaches may enhance efficacy of dietary interventions.

Trial registration: ClinicalTrials.gov NCT01665742.

Keywords: adolescents; inflammation; insulin resistance; pediatric obesity; personalized nutrition.

© 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figures

Figure 1
Figure 1
Trial profile. AINS, anti‐inflammatory nutrition supplement; HOMA‐IR, homeostatic model assessment‐insulin resistance.
Figure 2
Figure 2
Changes in HOMA‐IR and adiponectin following the AINS versus placebo. A) HOMA‐IR, B) high‐molecular‐weight adiponectin, C) total adiponectin, and D) adiponectin receptor mRNA expression following the AINS relative to placebo (intention‐to‐treat analysis, n = 70). E) Heterogeneity in response to the AINS with respect to HOMA‐IR in completers (n = 58). F) Change in HOMA‐IR following the AINS relative to placebo in responders and nonresponders (n = 58). Data are presented as mean (SEM). Data were analyzed using paired samples t‐tests between delta supplement and delta placebo values. ADIPOR1, adiponectin receptor 1; ADIPOR2, adiponectin receptor 2; AINS, anti‐inflammatory nutrition supplement; HMW, high‐molecular‐weight; HOMA‐IR, homeostatic model assessment‐insulin resistance; PBMC, peripheral blood mononuclear cells.
Figure 3
Figure 3
Modulation of DNA methylation in response to the AINS (n = 55). Reactome pathway families which demonstrated A) positive and B) inverse associations between DNA methylation and HMW adiponectin changes in response to the AINS. *indicates significant pathway enrichment (p ≤ 0.05), as determined by right‐tailed Fisher's exact test. Changes in the methylation status of CpG loci located on C) MED13L and D) EGR2 in relation to HMW adiponectin response to the AINS as determined by Illumina (completers only). E) Schematic demonstrating adipogenic genes (red) that contained CpG loci demonstrating significant associations between methylation status and HMW adiponectin response as assessed by Illumina analysis. Downstream targets are marked in black. Genes in which associations were verified by EpiTYPER are represented by a check mark. Genes in which associations were not confirmed upon technical validation are represented by an “x” mark. HMW, high‐molecular‐weight; FDR, false discovery rate.

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