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  • No metabolic effects of mustard allyl-isothiocyanate compared withplacebo in men

    Mirjam Langeveld,1 Chong Yew Tan,1 Maarten R Soeters,1 Samuel Virtue,1 Laura PE Watson,2 Peter R Murgatroyd,2

    Graeme K Ambler,4 Santiago Vidal-Puig,3 Krishna V Chatterjee,1 and Antonio Vidal-Puig1

    1University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, and 2National

    Institute for Health Research/Wellcome Trust Clinical Research Facility, Addenbrookes Hospital, Cambridge, United Kingdom; 3Department of Applied

    Statistics and Operational Research and Quality, Technical University of Valencia, Valencia, Spain; and 4South East Wales Vascular Network, Aneurin Bevan

    University Health Board, Royal Gwent Hospital, Newport, United Kingdom

    ABSTRACTBackground: Induction of nonshivering thermogenesis can be usedto influence energy balance to prevent or even treat obesity. Thepungent component of mustard, allyl-isothiocyanate (AITC), acti-vates the extreme cold receptor transient receptor potential channel,subfamily A, member 1 and may thus induce energy expenditureand metabolic changes.Objective: The objective of our study was to evaluate the potentialof mustard AITC to induce thermogenesis (primary outcome) andalter body temperature, cold and hunger sensations, plasma meta-bolic parameters, and energy intake (secondary outcomes).Design: Energy expenditure in mice was measured after subcutaneousinjection with vehicle, 1 mg norepinephrine/kg, or 5 mg AITC/kg. Inour human crossover study, 11 healthy subjects were studied undertemperature-controlled conditions after an overnight fast. After in-gestion of 10 g of capsulated mustard or uncapsulated mustard or acapsulated placebo mixture, measurements of energy expenditure,substrate oxidation, core temperature, cold and hunger scores, andplasma parameters were repeated every 30 min during a 150-minperiod. Subjects were randomly selected for the placebo and capsu-lated mustard intervention; 9 of 11 subjects received the uncapsulatedmustard as the final intervention because this could not be blinded.After the experiments, energy intake was measured with the universaleating monitor in a test meal.Results: In mice, AITC administration induced a 32% increase inenergy expenditure compared with vehicle (17.5 6 4.9 J $ min21 $mouse21 compared with 12.56 1.2 J $ min21 $ mouse21, P = 0.03).Of the 11 randomly selected participants, 1 was excluded because ofintercurrent illness after the first visit and 1 withdrew after the secondvisit. Energy expenditure did not increase after ingestion of capsu-lated or uncapsulated mustard compared with placebo. No differencesin substrate oxidation, core temperature, cold and hunger scores, orplasma parameters were found, nor was the energy intake at the endof the experiment different between the 3 conditions.Conclusion: The highest tolerable dose of mustard we were able to usedid not elicit a relevant thermogenic response in humans. This trial wasregistered at www.controlled-trials.com as ISRCTN19147515. Am JClin Nutr 2017;106:1197205.

    Keywords: mustard, allyl-isothiocyanate, energy expenditure,thermogenesis, thermogenic food

    INTRODUCTION

    Mild cold exposure induces nonshivering thermogenesis(NST), which is at least partially mediated by the activation ofbrown adipose tissue (BAT). This specialized thermogenic organproduces heat from glucose and lipid oxidation by uncouplingthe electron transport chain from ATP production (13). Whenmaintained over a long period of time, this small increase in en-ergy expenditure can alter the energy balance to prevent the de-velopment of obesity or even mediate modest weight loss. Evenmild cold exposure is perceived as unpleasant (4), however, andthe achievement of continuous mild cold exposure has practicalissues. As such, alternative methods to induce NST are desirable.

    The concept of the use of thermogenic food components toincrease energy has long existed and has received renewed at-tention with the discovery of BAT-mediated NST in humans (5).Examples of thermogenic food components include caffeine,catechin, capsaicin, capsiate, and cinnamaldehyde (69).

    The cold-sensing receptors, which are present on the nerveendings of skin and in mucous membranes, have been charac-terized during the past 2 decades. They belong to the family oftransient receptor potential channels (TRPs). Different TRPs are

    The study was supported by the National Institute for Health Research and

    the British Retail Consortium Seed Fund. ML and MRS were supported by

    Marie Curie Fellowships; CYT was supported by the Wellcome Trust Fel-

    lowship; SV was supported by the Medical Research Council, the British

    Heart Foundation, and the Biotechnology and Biological Sciences Research

    Council; and AV-P was supported by the Biotechnology and Biological

    Sciences Research Council. This is an open access article distributed under the

    CC-BY license (http://creativecommons.org/licenses/by/3.0/).

    ML, CYT, and MRS share first authorship.

    Address correspondence to ML (e-mail: m.langeveld@amc.nl).

    Abbreviations used: AITC, allyl-isothiocyanate; BAT, brown adipose

    tissue; NST, nonshivering thermogenesis; RER, respiratory exchange ratio;

    TRP, transient receptor potential channel; TRPA1, transient receptor poten-

    tial channel subfamily A, member 1; TRPM8, transient receptor potential

    channel subfamily M, member 8; UEM, universal eating monitor.

    Received November 4, 2016. Accepted for publication September 11,

    2017.

    First published online October 25, 2017; doi: https://doi.org/10.3945/ajcn.

    116.148395.

    Am J Clin Nutr 2017;106:1197205. Printed in USA. 1197

    Downloaded from https://academic.oup.com/ajcn/article-abstract/106/5/1197/4822311by gueston 05 June 2018

    http://www.controlled-trials.comhttp://creativecommons.org/licenses/by/3.0/https://doi.org/10.3945/ajcn.116.148395https://doi.org/10.3945/ajcn.116.148395

  • sensitive to different temperature ranges: 18248C is sensed byTRP subfamily M, member 8 (TRPM8) and temperatures,188C are sensed by TRP subfamily A, member 1 (TRPA1) (10,11). Cold sensing via these receptors initiates a cascade of re-sponses resulting in changes in behavior, insulation, and meta-bolic rate. Allyl-isothiocyanate (AITC), the pungent componentof mustard, activates TRPA1. In mice, AITC activates BAT andat the same time causes vasoconstriction in the tail, which isconsistent with a response to cold exposure (12). AITC mixedin a high-fat diet also reduces weight gain and improves insulinsensitivity (13). In addition, the inhibition of lipogenesis byAITC metabolites may have antiobesity effects (14).

    Little is known about the metabolic response to cold receptoractivating food components in humans. A study of the effectsof different food components on postprandial metabolic rateshowed that mustard tends to increase metabolic rate (15);however, the thermogenic food components were mixed in ameal, which in itself has a thermogenic effect (16).

    The objective of the present study was to evaluate the potentialof mustard AITC to induce thermogenesis (primary outcome) andalter body temperature, cold and hunger sensations, plasmametabolic parameters, and energy intake (secondary outcomes).We conducted a proof-of-principle study in mice, measuringenergy expenditure in response to AITC treatment. Next, westudied the effect of mustard on energy expenditure, substrateoxidation patterns, temperature, and sensations of cold and hungerin humans. We hypothesized that AITC would increase energyexpenditure. A study arm in which the mustard was capsulated wasincluded to determine whether any metabolic response was elicitedby the stimulation of cold receptors in the mouth or further downthe gastrointestinal tract, and to correct for the potential stress effectof the strong taste.

    METHODS

    Ethics

    All of the animal protocols used in this study were approved bythe Home Office (United Kingdom) and the University ofCambridge. All of the human subjects provided written informedconsent, and the study conformed to the standards set by the latestrevision of the Declaration of Helsinki. The study received ap-proval from the Cambridge Central East of England ResearchEthics Committee. The trial was registered at www.controlled-trials.com as ISRCTN19147515.

    Measurement of thermogenic response in mice

    The thermogenic response to subcutaneous injection withvehicle, norepinephrine, or AITC was assessed by indirect cal-orimetry under anesthesia. Indirect calorimetry was performed inan Oxymax calorimetry chamber (Columbus Instruments), whichhad a 2.7-L capacity and was housed within a large temperature-controlled cabinet. Room air to the chamber was passed through aheat exchanger to warm it to 308C. The temperature within thecalorimetric chambers was continuously monitored and fixed at308C. Oxygen consumption (VO2), carbon dioxide production(VCO2), and respiratory exchange ratio (RER) (VCO2/VO2)were measured with the use of a custom-built oxygen and carbondioxide monitoring system. Energy expenditure was calculated

    from VO2 and VCO2 with a modified Weir equation. Airflow rateswere set at 400 mL/min. Measurements of oxygen and carbondioxide concentrations in the room air and the air leaving each cagewere taken every 4 min. Mice were placed in the calorimetricchamber following intraperitoneal injection of sodium pentobarbi-tal (90 mg/kg). Baseline gas exchange was recorded once steadystate was achieved ($3 consecutive stable measurements). Micewere then injected with either 1 mg norepinephrine/kg (Sigma),5 mg AITC/kg, or vehicle phosphate-buffered saline, and returnedto the calorimetry chamber. Maximal VO2rates were achievedtypically within 1216 min postinjection and wer

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