Grape polyphenols decrease circulating branched chain amino acids in overfed adults

Abstract

Introduction and aims: Dietary polyphenols have long been associated with health benefits, including the prevention of obesity and related chronic diseases. Overfeeding was shown to rapidly induce weight gain and fat mass, associated with mild insulin resistance in humans, and thus represents a suitable model of the metabolic complications resulting from obesity. We studied the effects of a polyphenol-rich grape extract supplementation on the plasma metabolome during an overfeeding intervention in adults, in two randomized parallel controlled clinical trials.

Methods: Blood plasma samples from 40 normal weight to overweight male adults, submitted to a 31-day overfeeding (additional 50% of energy requirement by a high calorie-high fructose diet), given either 2 g/day grape polyphenol extract or a placebo at 0, 15, 21, and 31 days were analyzed (Lyon study). Samples from a similarly designed trial on females (20 subjects) were collected in parallel (Lausanne study). Nuclear magnetic resonance (NMR)-based metabolomics was conducted to characterize metabolome changes induced by overfeeding and associated effects from polyphenol supplementation. The clinical trials are registered under the numbers NCT02145780 and NCT02225457 at ClinicalTrials.gov.

Results: Changes in plasma levels of many metabolic markers, including branched chain amino acids (BCAA), ketone bodies and glucose in both placebo as well as upon polyphenol intervention were identified in the Lyon study. Polyphenol supplementation counterbalanced levels of BCAA found to be induced by overfeeding. These results were further corroborated in the Lausanne female study.

Conclusion: Administration of grape polyphenol-rich extract over 1 month period was associated with a protective metabolic effect against overfeeding in adults.

Keywords: NMR; branched chain amino acids; grape polyphenols; human trials; metabolism; metabolomics; obesity; overfeeding.

Conflict of interest statement

Authors SB, JC, JH, and SoM were employees of Nestlé Research when this study was conducted. The remaining 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.

Copyright © 2022 Bartova, Madrid-Gambin, Fernández, Carayol, Meugnier, Segrestin, Delage, Vionnet, Boizot, Laville, Vidal, Marco, Hager and Moco.

Figures

FIGURE 1

Metabolomics blood sample analysis of the male “Lyon” human clinical intervention. Forty-two sedentary male adult subjects were recruited to a randomized parallel-controlled trial where all subjects were submitted to an overfeeding intervention for 31 days with ∼50% additional energy requirement. Half of the subjects took a placebo, while the rest were given 2 g/day of polyphenol-rich grape extract. The fasting blood collection days are indicated (0, 15, 21, and 31 days). Plasma metabolomics was performed in samples from 40 subjects (19 placebo and 21 polyphenol).

FIGURE 2

Discrimination capacity of intervention groups across time points of the male “Lyon” study. The plot is based on the area under the curve of the receiver operating characteristic (ROC) curves between placebo and polyphenol groups at all-time points of the intervention: time point 0 (T0), at 15 days (T15), at 21 days (T21) and at the end, time point 31 days (T31).

FIGURE 3

Relative plasma metabolite concentrations of highlighted metabolites during an overfeeding and polyphenol clinical interventions for the male “Lyon” study (A–C) and the female “Lausanne” study (C). (A) Overfeeding (placebo arm) in males (Lyon study) leads to increased plasma concentrations of the BCAA valine, leucine and isoleucine and glucose. (B) A 31-day polyphenol administration in an overfeeding intervention (polyphenol arm) in males (Lyon study) leads to decreased plasma concentrations of the BCAA valine, leucine and isoleucine and glucose compared to the overfeeding arm. (C) Heatmap of log2 fold changes of plasma metabolite relative concentrations, adjusted per each individual’s baseline (T0), in the male (Lyon) and female (Lausanne) studies. T0, T15, T21, and T31 correspond to days 0, 15, 21, and 31 of the intervention; the NMR intensities relate to metabolite concentrations (arbitrary units); p-values obtained by t-test (*p-value ≤ 0.05, and **p-value ≤ 0.01).

FIGURE 4

Metabolic effects induced by overfeeding and polyphenol administration. (A) Metabolite correlation matrix obtained from the plasma metabolome analysis of the male “Lyon” study across all time points for all subjects for the placebo arm (overfeeding), and (B), for the polyphenol arm (overfeeding and polyphenol administration). Non-significant correlations (p-value > 0.05) were excluded. (C) metabolic pathways involved in diet-induced obesity, as observed in this study by plasma metabolomics: a profile with elevated circulating branched chain amino acids, BCAA (valine, isoleucine and leucine) and branched chain keto acids, BCKA (α-keto-isovalerate, α-keto-β-methylvalerate, and α-keto-isocaproate) highlighting increased BCAA catabolism, leading to decreased TCA cycle activity (lower levels of citrate) and ketogenesis (lower levels of ketone bodies acetone, acetoacetate and β-hydroxybuturate), with an increased gluconeogenesis (higher levels of glucose) and lactate production through the Cahill cycle. Monitored metabolites are in bold. Pathway names are in gray.