Metabolic Effects Of Intermittent Fasting

Metabolic Effects ofIntermittent FastingByRona AntoniDepartment of Nutritional SciencesFaculty of Health and Medical SciencesUniversity of SurreyA thesis submitted in accordance with the requirements of theUniversity of Surrey for the Degree of Doctor of Philosophy2017 Rona Antoni 20171

AbstractIntermittent fasting describes dietary strategies in which the pattern of energy restriction(intermittent energy restriction, IER) or timing of food intake (time-restricted feeding, TRF) arealtered such that individuals undergo repeated periods of “fasting”. The overarching aim of thisPhD project was to investigate the metabolic health impacts of these intermittent fasting variants.Intermittent energy restrictionStudy one assessed the acute metabolic effects of substantial energy restriction (ER) in healthy,overweight/obese participants using a cross-over design. Six-hour postprandial responses wereassessed the morning following one day of total 100% ER, partial 75% ER and isoenergetic intake(0% ER) via serial blood sampling and indirect calorimetry. Postprandial substrate oxidation wasshifted towards fat oxidation (p 0.080) and ketogenesis (p 0.001) in an apparent dose responsemanner following 75-100% ER, translating to a reduction in postprandial lipaemia (p 0.001).Conversely, glucose tolerance was impaired (p 0.002).Study two utilised similar methods to investigate the chronic effect of IER (75% ER for twodays/week) on postprandial metabolism following 5% weight-loss. This was compared tomatched weight-loss achieved via a “standard treatment” control of continuous ER (2510kJ/daydeficit). Rates of weight-loss were similar between groups (p 0.446), despite greater reportedreductions in energy intake during IER (p 0.012), which might be explained in part by an adaptivedecline in resting energy expenditure (p 0.067). Both interventions comparatively (p 0.903)improved postprandial insulinaemia, whereas the relative reduction in postprandial lipaemia wasgreater following IER (p 0.042).Time-restricted feedingStudy three examined the effects of a 10-week, three-hour daily shortening of the eating windowon fasting metabolism and adiposity utilising a parallel-armed controlled design. In a small groupof lean and overweight/obese participants, TRF led to modest reductions in adiposity (p 0.047)2

and fasting glycaemia (p 0.073), possibly explained by the spontaneous reduction in energyintake observed.Combined, these data provide novel insights into the metabolic effects of intermittent fasting.Replication and mechanistic evaluation in diverse population groups, including those withestablished metabolic disorders, is warranted.3

Published worksResearch articles Antoni R, Johnston KL, Collins AL and Robertson MD (2016) Effects of intermittent fastingon glucose and lipid metabolism. Proc Nutr Soc. (in press) Antoni R, Johnston KL, Collins AL and Robertson MD (2016) Investigation into the acuteeffects of total and partial energy restriction on postprandial metabolism amongstoverweight/obese participants. Br J Nutr. 115 (6), Pg 951-959 Antoni R, Johnston KL, Collins AL and Robertson, MD (2014) The effects of intermittentenergy restriction on indices of cardiometabolic health. Res Endocrinol. 2014, Article ID459119Conference abstracts Antoni R, Johnston KL, Collins AL and Robertson MD (2016) Intermittent versuscontinuous energy restriction on postprandial metabolism following matched 5% weight-loss.Proc Nutr Soc. 75 (OCE3), E105 Antoni R, Johnston KL, Collins AL and Robertson MD (2015) Investigation into the acuteeffects of intermittent energy restriction on postprandial substrate metabolism Proc Nutr Soc.75 (OCE1), E29 Antoni R, Johnston KL, Collins AL and Robertson MD (2015) Acute effects of intermittentenergy restriction on energy compensation: a pilot study T3:PO.023. Obes Facts. 8(1), doi:10.1159/0003821404

DeclarationThis thesis and the work to which it refers are the results of my own efforts. Any ideas, data,images or text resulting from the work of others (whether published or unpublished) are fullyidentified as such within the work and attributed to their originator in the text, bibliography or infootnotes. This thesis has not been submitted in whole or in part for any other academic degreeor professional qualification. I agree that the University has the right to submit my work to theplagiarism detection service TurnitinUK for originality checks. Whether or not drafts have beenso-assessed, the University reserves the right to require an electronic version of the final document(as submitted) for assessment as above. The thesis is available for Library use on theunderstanding that it is copyright material and that no quotation from the thesis may be publishedwithout proper acknowledgement or consent.5

AcknowledgementsI am indebted to Dr Denise Robertson and Dr Adam Collins, for believing in me enough to supportme with my initial PhD application. In addition, I would also like to thank them for all of thesupport and encouragement they have given me during my PhD.My thanks also go to Lighterlife, who part-funded my studentship and provided additionalfunding for research consumables. In particular, I would like to thank Dr Kelly Johnston for allof the guidance she has given to me throughout my PhD, as well as for her time and the helpfulcomments given during manuscript revisions.This PhD would not have happened without the guidance of Dr Laura Tripkovic and Dr LouiseWilson, who gave me a glimpse into the research world, and who actively encouraged me topursue a career in research.Thank you also to my friends and colleagues at the Faculty of Health and Medical Sciences,especially Dr Tracey Robertson who was always there with a cup of coffee in hand during themost difficult moments.This PhD would not have been possible without my participants, who selflessly gave up their timeto take part in my research. Thank you also to the staff at the Surrey Clinical Research Centre, fortheir medical assistance during my study days, I could not have done it without you.The biggest thanks goes to my family: to my parents, for the enormous sacrifices they made whichultimately enabled me to do a PhD. Stewart, my partner, thank you for supporting andencouraging me throughout this journey.6

Statement of ContributionsPersonnelDr Denise RobertsonSenior lecturer in NutritionalPhysiology, University of SurreyContributionsPrincipal PhD supervisorDr Adam CollinsProgramme Director ofNutrition, University of SurreyDr Kelly JohnstonCo-supervisorCo-supervisorHead of Nutrition, LighterlifeDr Johnathan JohnstonReader in Chronobiology,University of SurreyPrincipal investigator on time-restricted feedingprojectMr Peter WilliamsStatistician,University of SurreyDr Fariba Shojaee-MoradieDiabetes Research Fellow,University of SurreyDr Tracey Robertson,Postdoctoral Research Fellow,University of SurreyProvided assistance with statistical analysesPerformed one RIA assay on behalf of PhDresearcherPerformed ELISA assay in conjunction withPhD researcher. Assisted with study days ontime-restricted feeding project.Research nursesSurrey Clinical ResearchCentreAssisted with blood samplingLeila FinikaridesBritish BroadcastingCompanyConducted participant recruitment for timerestricted feeding project7

Table of ContentsABSTRACT. 2DECLARATION . 5ACKNOWLEDGEMENTS . 6STATEMENT OF CONTRIBUTIONS. 7TABLE OF CONTENTS . 8LIST OF FIGURES . 13LIST OF TABLES . 14LIST OF ABBREVIATIONS . 15CHAPTER 1 : INTRODUCTION . 181.1 BRIEF INTRODUCTION . 181.2 DEVELOPMENT OF OBESITY ASSOCIATED CARDIOMETABOLIC DISORDERS . 201.2.1 Adipose tissue response to positive energy imbalance . 201.2.2 Insulin resistance: a common aetiological factor underlying cardiometabolic risk . 231.2.3 Subcutaneous and visceral adipose tissue depots . 231.2.4 Non-lipid mediators of insulin resistance . 241.3 THE POSTPRANDIAL STATE AND RELEVANCE TO DISEASE . 241.3.1 Transport and tissue uptake of glucose and lipids . 251.3.2 Post absorptive state . 281.3.3 Meal ingestion . 281.3.4 Postprandial metabolism as a marker of cardiometabolic disease risk . 301.4 INTERMITTENT ENERGY RESTRICTION . 331.4.1 Weight-loss benefits and current guidelines . 331.4.2 Intermittent energy restriction: an alternative weight-loss approach . 331.4.3 Acceptability of intermittent energy restriction and effects on body weight . 341.4.4 Acute effects of substantial energy restriction . 388

1.4.5 Chronic effects of intermittent energy restriction . 411.4.6 Does the mode of energy restriction (intermittent versus continuous) influencemetabolic responses during weight-loss? . 491.4.7 Summary and knowledge gaps relevant to PhD . 511.5 MEAL TIMINGS AND HEALTH: AN OVERVIEW . 541.5.1 Time-restricted feeding . 541.5.2 Summary and knowledge gaps relevant to PhD . 601.6 AIMS AND OBJECTIVES OF PHD PROJECT . 61CHAPTER 2 : GENERAL METHODS . 622.1 BODY WEIGHT AND COMPOSITION . 622.2 ASSESSMENT OF ENERGY REQUIREMENTS . 622.3 ASSESSMENT OF ENERGY INTAKE . 632.3.1 Diet diaries . 632.3.2 Dietary analyses . 632.4 ASSESSMENT OF POSTPRANDIAL SUBSTRATE METABOLISM AND THERMOGENESIS . 642.5 BLOOD SAMPLE COLLECTION AND ANALYSES . 662.5.1 Blood sample collection . 662.5.2 Biochemical analyses and calculations . 672.6 INDIRECT CALORIMETRY . 712.6.1 Calculation of energy expenditure . 712.6.2 Postprandial substrate oxidation. 722.7 STATISTICAL ANALYSES . 72CHAPTER 3 : INVESTIGATION INTO THE ACUTE EFFECTS OF TOTAL AND PARTIALENERGY RESTRICTION ON POSTPRANDIAL METABOLISM . 733.1 INTRODUCTION . 733.2 STUDY AIMS, OUTCOMES AND HYPOTHESIS . 743.2.1 Aims . 743.2.2 Outcomes. 749

3.2.3 Hypothesis . 743.3 PARTICIPANTS AND METHODS . 743.3.1 Participants . 743.3.2 Study protocol . 753.3.3 Experimental techniques and analyses . 793.3.4 Statistical analyses. 813.3.5 Data omissions . 813.4 RESULTS . 813.4.1 Participant characteristics . 813.4.2 Day one: Controlled energy intake day - dietary intakes and appetite . 823.4.3 Day two: Assessments conducted the day after each controlled intake day . 833.4.4 Days one, two and three: Cumulative dietary intakes . 893.5 DISCUSSION . 91CHAPTER 4 : INTERMITTENT VERSUS CONTINUOUS ENERGY RESTRICTION ONPOSTPRANDIAL METABOLISM FOLLOWING MATCHED WEIGHT-LOSS . 984.1 INTRODUCTION . 984.2 STUDY AIMS, OUTCOMES AND HYPOTHESIS . 994.2.1 Aims . 994.2.2 Outcomes. 994.2.3 Hypothesis . 994.3 PARTICIPANTS AND METHODS . 994.3.1 Participants . 994.3.2 Study protocol . 1004.3.3 Experimental techniques and analyses . 1034.3.4 Statistical analyses. 1064.3.5 Data omissions . 1074.4 RESULTS . 1084.4.1 Participant baseline characteristics and attrition . 10810

4.4.2 Body weight and body composition . 1094.4.3 Dietary intakes and physical activity . 1104.4.4 Fasting biochemistry and physiological markers . 1134.4.5 Postprandial glucose metabolism . 1144.4.6 Postprandial lipid metabolism . 1174.4.7 Questionnaires . 1194.5 DISCUSSION . 120CHAPTER 5 : INVESTIGATION INTO THE EFFECTS OF TIME-RESTRICTED FEEDINGON HUMAN DIETARY INTAKE, BODY FAT AND METABOLIC PHYSIOLOGY . 1315.1 INTRODUCTION . 1315.2 AIMS, OUTCOMES AND HYPOTHESIS. 1325.2.1 Aims . 1325.2.2 Outcomes. 1325.2.3 Hypothesis . 1325.3 PARTICIPANTS AND METHODS . 1325.3.1 Participants . 1325.3.2 Study design and protocol overview . 1335.3.3 Experimental techniques and analyses . 1355.3.4 Statistical analyses. 1365.3.5 Data omissions . 1375.4 RESULTS . 1375.4.1 Eating window and dietary intakes . 1385.4.2 Body weight and body composition . 1395.4.3 Fasting cardiometabolic risk markers.

and fasting glycaemia (p 0.073), possibly explained by the spontaneous reduction in energy intake observed. Combined, these data provide novel insights into the metabolic effects of intermittent fasting. Replication and mechanistic evaluation in diverse population groups, including those with established metabolic disorders, is warranted.