Page 1of30 between thisversion andtheVersion record. Please citethisarticle asdoi:10.1002/oby.21653. through thecopyediting, typesetting, pagination andproofreading process,whichmay lead todifferences This istheauthor manuscriptaccepted forpublicationandhas undergonefullpeerreview buthasnotbeen body weight (US Patent Application No. 13/754,058; 13/754,058; No. Application Patent (US body weight National Institute of Diabetes & Digestive & Kidney & Digestive & Instituteof Diabetes National phone: 301 402 8248 301 402 8248 phone: of Health Institutes National Kidney & Digestive & Instituteof Diabetes National received funding from the Nutrition Science Initiat Science Nutrition the from funding received K.D.H. reports patent pending on a method of person a on method pending patent K.D.H.reports MD; MD; Nati Diseases, and Kidney andDigestive ofDiabetes Funding Count Word Date Revision [email protected] email: 301 402 0535 fax: 20892 5621 MD Bethesda, 4007 Drive, Room South 12A PhD Hall, D. Kevin beaddressed: should correspondence whom *To Disclosure: LLC. &Research Development, Janssen by sponsored Authors: Title: Running intake energy human of control Qua loss? appetite does counterweight strongly How Affiliations: 3 Department of Surgery, University of Michigan, Ann Ann of Michigan, University Departmentof Surgery, : This research was supported by the Intramural Res Intramural the research by wassupported This : Accepted ArticlePolidori David D.P. is a full time employee of Janssen Research & Research of employee Janssen a full time is D.P. 1 : 3526 3526 : Janssen Research & Development, LLC, San Diego, CA; LLC,Diego, San &Research Development, Janssen : August 4, 2016. 2016. 4, August :
Feedback control of human energy intake intake energy of human control Feedback This article isprotected by copyright. All rights reserved. 1 ; Arjun Sanghvi Arjun ; Obesity 2 ; Randy ; Seeley ive to investigate the effects of effects investigate the to ive Diseases, using data from a study afrom study data Diseases,using Diseases Diseases onal Institutes of Health, Bethesda, Bethesda, of Health, Institutes onal alized dynamic feedback control of control dynamic feedback alized assigned to the NIH) andhas assigned NIH) the to ntification of the of feedback ntification 3 ; Kevin D. HallD. Kevin ; Arbor, MI. Arbor,MI. earch Program of NIH, the Program earch Development, LLC. Development,
2 National Institute National 2*
1
Nordisk, Takeda, Daichii Sankyo, Novartis, Pfizer, Pfizer, Sankyo, Novartis, Daichii Takeda, Nordisk, ketogenic diets on human energy expenditure. R.S. i R.S. energy expenditure. human on diets ketogenic Accepted Article conflicts reports no A.S. Ingelheim. and Boehringer researchreceivedhas also support R.S., Ethicon. ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity from Novo Nordisk, Ethicon, Sanofi Sanofi Ethicon, Nordisk, from Novo Nestle, Circuit Therapeutics and Therapeutics Circuit Nestle, of interest. of interest. s a paid consultant for Janssen, Novo Novo Janssen, for aconsultant s paid 2
Page 2of30 Page 3of30 What this study adds study this What What is already known about this subject? subject? this about known already is What
• • • • •
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aac wtot iety nlecn epniue or expenditure influencing directly without balance food intake. intake. food SGLT2 inhibition provides a unique means of covertl of means unique a provides inhibition SGLT2 free living humans. free livinghumans. feedback the of quantification first the provide We known energy expenditure adaptations. adaptations. expenditure energy known lost weight of kg per intake energy in increase The to achieve and sustain large weight losses. losses. weight large andsustain achieve to pri the likely is intake energy of control Feedback energy intake and energy expenditure. expenditure. andenergy energy intake fe by regulated be to believed is weight body Human Accepted Articleyet be to has intake of energy feedback control the ha loss weight to expenditure energy of Adaptations ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. : Obesity quantified. quantified. mary reason why it is difficult is it why reason mary is several fold larger than the the than larger several fold is ve been well established, but but well established, been ve central pathways regulating regulating pathways central oto o eeg itk in intake energy of control y inducing negative energy negative inducing y edback control of both both of control edback 3
Objective Abstract Methods free livin in balance of energy covertmanipulation Results co engineering from using principles changes intake t weight between body the relationship analyzedthe being patients dir without loss weight resultingin increa that inhibitor glucose co transporter sodium pa 153 in trial placebo controlled week 52 duringa difficult. so is weight reduced body explain andhelps role larger aneven playsintake re and subsequent loss weight slowingof reasonfor Conclusions ener corresponding the than larger 3 fold morethan kcal/day ~100 by baseline above eating resultingin : We discovered that weight loss leads to a proport a leadsto loss weight discovered that We : : We used a validated mathematical method to calcul to method amathematical used validated We : Accepted Article intake of energy control feedback the quantify To : : While energy expenditure adaptations are oftenth energy : adaptations While expenditure ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity ectly aware of the energy deficit. We We deficit. energy the aware ectly of why long term maintenance of a maintenance whylong term ses urinary glucose excretion thereby excretion glucose urinary ses g humans. g humans. tients treated with canagliflozin, a canagliflozin, treated with tients gy expenditure adaptations. adaptations. gyexpenditure gain, feedback control of energy of control feedback gain, per kg of lost weight – an amount anamount – weight of lost kg per ime course and the calculated energy calculated course ime and the ntrol theory. theory. ntrol ional increase in appetite appetite in increase ional in response to long term long term to response in ate energy intake changes changes intake ateenergy ought to be the main main the be to ought 4
Page 4of30 Page 5of30 performed while subjects are housed in laboratory s laboratory in housed are subjects while performed e accurate While periods. time extended over people behavior (2). behavior(2). determi to system neurobiological complex a of part blt t acrtl maue hne i free livin in changes measure accurately to ability feedb w with intake changes expenditure energy energy of human quantification of assessment the has Why notntl, relvn sbet ae ooiu f notorious are subjects free living Unfortunately, impractical. studies based makinglaboratory lo over observations Therefore, (4). weight body or short te little exhibits and day to day from widely free liv Indeed, (3). world real the to results the env the of nature artificial the and duration short Accepted Articlecritical is intake energy of control feedback that ( loss in quantified accurately be to yet weight have adaptations resist to acting kcal/day of expendi hundreds energy found colleagues and Leibel example, en of alterations to response in h adapts expenditure humans in experiments Several expenditure. energy feedback by regulated be to believed is weight Body Introduction
ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity ing energy intake is known to fluctuate fluctuate to known is intake energy ing for body weight regulation and acts as acts and regulation weight body for rm correlation with energy expenditure expenditure energy with correlation rm translate to difficult it makes ironment humans despite the widespread belief belief widespread the despite humans r en ual t poie accurate provide to unable being or g energy intake in large numbers of of numbers large in intake energy g ng time scales are required thereby thereby required are scales time ng etting, such studies are typically of of typically are studies such etting, ergy intake and body weight. For For weight. body and intake ergy nergy intake measurements can be be can measurements intake nergy control of both energy intake and intake energy both of control eight loss? First, we lacked the the lacked we First, loss? eight 1). In contrast, energy intake intake energy contrast, In 1). e vrl hmn od intake food human overall ne ave quantified how energy energy how quantified ave ture adaptations of several several of adaptations ture ack control lagged the the lagged control ack 5
biomarker method (6). (6). biomarkermethod energy intake changes were within 40 kcal/day of th of kcal/day 40 within were changes intake energy study restriction calorie year two a over subjects bo repeated using changes intake energy calculating in an validated recently we problem, important this limi severely methods biomarker objective employing method self report using intake energy of estimates were treated for one year with canagliflozin, an in an canagliflozin, with year one for treated were trial placebo controlled a from data used we Here, Accepted behavior. in changes conscious involve bo controlling mechanisms feedback to due be solely du intake energy in changes Therefore, quantify. to e total of components other in changes compensatory modulat in role complex have a has exercise doesn’t Furthermore, that behavior conscious a is exercise expenditu energy increase might program exercise an en of control feedback the on se per changes weight r cognitive evoke also expenditure energy or weight Rather, occurring. is this that knowing consciously k a by output energy increases that intervention an Article intake energy quantifying to impediment second The ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity hibitor of sodium glucose transporter 2 2 transporter glucose sodium of hibitor s (5) and the expense and difficulty of difficulty and expense the and (5) s ergy intake. For example, engaging in in engaging example, For ergyintake. esponses that may mask the effect of of effect the mask may that esponses in patients with type 2 diabetes who who diabetes 2 type with patients in and found that the mean calculated calculated mean the that found and expensive mathematical method for for method mathematical expensive most interventions that alter body body alter that interventions most control in humans is that we lacked lacked we that is humans in control ose determined using an expensive expensive an using determined ose ring an exercise program may not not may program exercise an ring on mut ihu participants without amount nown nergy expenditure that are difficult difficult are that expenditure nergy dy weight data in 140 free living free living 140 in data weight dy dy weight, but are likely to also also to likely are but weight, dy ing appetite (7) and may induce induce may and (7) appetite ing s hi apiaiiy T address To applicability. their ts re and lead to weight loss, but but loss, weight to lead and re an effective placebo control. control. placebo effective an 6
Page 6of30 Page 7of30 rvosy ulse paeocnrle tal f ca of trail placebo controlled published previously provides a novel way to covertly perturb human ener human perturb covertly to way novel a provides deficit energy the of aware directly being patients Calculating changes in energy intake during canagli energy during changesin intake Calculating Methods e sd esrd oy egt B, n bsln pati baseline and BW, weight, body measured used We controllin pathways central or 11) (10, expenditure (9) treatment of duration the throughout level same 90 approximately by UGE daily mean increases mg/day treat diabetes, 2 type with Inpatients (8). (UGE) fo the in output energy increasing thereby (SGLT2), Acceptede of energy control the strongerthan substantially the to was proportional humans in ofenergy intake (6) biomarkermethod expensive an against validated a mathema to asinputs g/day of 90 mean UGE assumed using the trial over aweek 52 mg/daycanagliflozin changes intake energy free living calculated the We system. control feedback activityof the Article inhibit SGLT2 by induced loss weight the countering A subjects. the of awareness conscious and volition ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity ment with canagliflozin at a dose of 300 300 of dose a at canagliflozin with ment xpenditure. xpenditure. measured body weight dataand an weight body measured amount of weight lost and was and lost of weight amount in 153 patients treated with 300 300 with treated patients 153 in flozin treatment flozin . In other words, SGLT2 inhibition inhibition SGLT2 words, other In . ny observed increased energy intake intake energy increased observed ny . We found that the feedback control control feedback the that found We . gy balance that largely bypasses the the bypasses largely that balance gy nagliflozin (8). We calculated the the calculated We (8). nagliflozin g energy intake and without the the without and intake energy g without directly altering energy energy altering directly without tical model that has recently been recently been has that model tical rm of urinary glucose excretion excretion glucose urinary of rm ion therefore likely reflects the the reflects likely therefore ion g/day which is sustained at the the at sustained is which g/day
ent characteristics in the the in characteristics ent 7
th with densityassociated energy waseffective the as well as both resting and total energy expenditur energy total and resting both as well as measureme longitudinal with humans adult in studies pri obtained data using validated and developed was mod mathematical a of linearization a is 1 Equation data. interpolat linear and point time one at data weight subjects 2 and canagliflozin treated subjects Three measurements per interval and interval per measurements equation: following (6)using the nevl egh was length interval interval, wei body of change the were model the to inputs The was used to calculate the rate of change of body we body of change of rate the calculate to used was changes in energy intake, intake, energy in changes
( Accepted Article BW BW + + − + = i − IB WB UGE BW BW BW EI ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 i i 0 ε ρ ) This article isprotected by copyright. All rights reserved. , and the moving average of the measured body weigh body measured the of average moving the and , dBW t = dt i Δ (N 1)*T ρ EI = , for each subject using a validated mathematical m mathematical validated a using subject each for , ) ( ηαρ αη ρ η T MF F FFM FFM FM FM = 52 was the number of days between measurements. measurements. between days of number the was 52 = , where where , + + + () )( ( 1 1 + − Obesity α β 0 0 N ) ( = 2 was the number of body weight weight body of number the was 2 = 1 − δ treated with placebo had missing body body missing had placebo with treated β e body weight change: change: weight e body e (12, 13, 14). The model parameter model The 14). 13, (12, e el of adult body weight dynamics that dynamics weight body adult of el ight over each interval, interval, each over ight ion was used to impute the missing missing the impute to used was ion nts of changes in body composition composition body in changes of nts marily from controlled feeding feeding controlled from marily ght versus baseline over each each over baseline versus ght (Equation 2) 2) (Equation (Equation 1) 1) (Equation dBW t time course course time t i / dt ethod ethod . The . ρ ρ 8
Page 8of30 Page 9of30 perturbation, perturbation,
The model parameters parameters Themodel activity changes are often assumed to be zero ( bezero to assumed often are activitychanges W available. if measurements, objective by informed activity parameter was activity parameter o andduration intensity given a bodyfor to weight and hav locomotion involve physicalactivities Most expenditure before and after achieving a period of of a period achieving andafter before expenditure bot as as well composition changes bodyin measured and The parameter indivi >100 whenstudying be<40likely kcal/day to st validation our previous group, but changeof the metabolic rate to fat free mass (FFM) and fat mass mass (FFM) and fat mass rate fat free metabolic to andρ individuals with the assumption that that assumption the with individuals thr can occur changes physicalactivity substantial e error, in changes be may energyintake calculated ε FFM defined how energy expenditure depends on bodyweig on depends expenditure energy how defined
Accepted Articlei changes associated with densities energy the are EI ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 β accounts for the adaptation of energy expenditure expenditure of energy for adaptation the accounts , and was determined using data from eight human st human eight from data using determined andwas , This article isprotected by copyright. All rights reserved. γ δ FFM 0 and δ δ and ε + + = ) ( δ 1 1 γ represents changes in physical activity that can b activity that physical in changes represents FM + − 1 α β
are the regression coefficients relating resting resting relating coefficients areregression the δ αγ γ ) ( =0 can also result in a biased mean energy intake a mean biased in result also =0can L F Obesity + δ =0) with the realization that the realization the =0)with oughout a study. Averaging over many many over Averaging oughouta study. udy demonstrated that this bias is is bias this that udydemonstrated long term stability at a lower weight. weight. aat lower stability long term f activity. The baseline physical physical baseline factivity. The 0 specially at the individual level where where level individual the at specially (FM), respectively. Parameters ρ Parameters (FM),respectively. e an energy cost that is proportional proportional is that cost energy ean duals (6). (6). duals ithout such measurements, physical physical measurements, such ithout h total and resting energyand resting total h (Equation 3). 3). (Equation n FM and FFM, respectively. FFM, FM n and ht: ht: during a diet adiet during udies that that udies e FM
9
Modeling feedback control of energy intake energy of intake control feedback Modeling previously described (14). The parameter (14). previouslydescribed The parameter associated water. its primari is of FFM change the that turnoverassuming initial value FM initial (16). diets calorie followingreduced in diabetes, 2 type including conditions, comorbid regar predictions loss weight accurate demonstrated food intake (2), general properties of the feedback the of properties general (2), intake food known are factors neuronal and hormonal many While Parameters weight changes,weight ethn across different beconsistent to demonstrated accurate change provides composition of bodymodel expenditure data from controlled feeding studies feeding studies data controlled from expenditure us model mathematical our validating to Inaddition values are given in are values canagli with of glucose excretion urinary increased α = ≡ Accepted Article FM C dFM dFFM η FM ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 α 0 and represents the relationship between changes of le betweenchanges relationship the represents α . The larger the initial fat mass, FM fat mass, initial the The . larger can be considered to be approximately constant wi constant beapproximately to considered can be Table 1 Table η This article isprotected by copyright. All rights reserved. FFM account for the biochemical cost of tissue deposit oftissue cost for biochemical the account . . where C = 10.4 kg is the Forbes parameter. This si This Forbes parameter. the is where kg = 10.4 C Obesity UGE represents the energy losses asof a result losses energy the represents (12, 13, 14), 14), 13, (12, ic groups and sexes (15). For modest For modest (15). andsexes groupsic free living individuals with obesity with free livingindividuals relationship between changes in body body in changes between relationship flozin treatment. Model parameter parameter Model treatment. flozin dless of medication usage or usage or of medication dless ing body composition and energy ingcomposition body 0 ly accounted for by body protein and protein for body by accounted ly , the smaller the parameter parameter the smaller the , predictions that have been have that predictions to be involved in the regulation of of regulation the in involved be to the model has also also has model the an and fat mass: mass: anand fat th FM fixed at its its at fixed ion and ion mple mple α , as , 10 Page 10of30 Page 11of30 proportional control of energy intake affects body body affects intake of energy control proportional profiles in response to sustained canagliflozin tre canagliflozin sustained response to in profiles proportional control of control proportional to capture the typical transient weight loss effect weight loss transient capture to typical the where the parameter where parameter the
calculated mean calculatedmean me and the outputs simulation the between residuals http://www.berkeleymadonna.c (version8.3; software impleme algorithm simplex a downhill by determined weight dynamics (14) and calculated the mean calculated mean the (14) and weightdynamics amathe validated to term UGE addeda we treatment, tested the ability of two potential feedback models feedback potential two of ability the tested w been not have intake energy in changes and weight the are by weightdescribed body signalsregulating th model, this In loss. weight of rate or duration weight body current the on only depend intake food co “proportional as to referred model, first the In Equation 4 was then added to the placebo energy int energy placebothe to added was 4 then Equation
Accepted Article ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 EI . . k This article isprotected by copyright. All rights reserved. P >0 EI
quantifies during canagliflozin treatment. The best fit param fit The best treatment. canagliflozin during × − = ItkB t BW k t EI ( the feedback strength. To simulate how how feedback strength.the simulate To ) Obesity P of being in the trial (see (see beingtrial the in of EI atment. atment. ntrol”, changes in the signals regulating regulating signals the in changes ntrol”, e aggregate effect of different feedback feedback different of effect aggregate e weight kinetics during canagliflozin canagliflozin during weight kinetics time course during placebo treatment treatment course placebo during time to describe the observed body weight weight body observed the describe to equation: equation: ake to simulate the mean the akesimulate to asured mean body weight and the and the weight body asuredmean ( matical model of adult human bodyhuman adult of model matical om) to minimize the sum of squares sum the minimize to om) nted using Berkeley Madonna Madonna Berkeley using nted ell characterized or quantified. We We quantified. or characterized ell ) (Equation 4) 4) (Equation and are not dependent on the the on dependent not are and Figure1 eter k ). P was 11
oe ht s oy egt elnd uig GT inhi SGLT2 during declined weight body as that Note by a parameter bya parameter ex is which from baseline, deviated bodyhas weight ener in changes that such (17) previouslysuggested baseline after 15 weeks ( weeks 15 after baseline previously reported (8). In response to the sustain the to response In (8). reported previously from Equation 4 and 4 Equation from
We also investigated another possible model for bod model possible another investigated also We The integral feedback control was simulated using E using simulated was control feedback integral The Table 2 Table Results o rninl dces b ~0 ka/a oe te fi the over kcal/day ~100 by decrease transiently to group, placebo the In (18). inhibitor SGLT2 another during changes intake energy mean the of estimates have increased by ~350 kcal/day at steady state ( state steady at kcal/day ~350 by increased have UG in increases estimated the given group treatment es hn k ( kg 1 than less group placebo the than more significantly and lower a reached and declined weight body mean treatment, 52 week study and had body weight measurements thro measurements weight body had and study week 52
Accepteddiabe 2 type the of characteristics the represents Article ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 k I
>0 iue 1A Figure : : k This article isprotected by copyright. All rights reserved. I − kcal/kg/d 1 = × − = ItkB Wd BW k t BW k t EI Figure1B ) ( ) ( ) ( . o xli te esrd oy egt hne i t in changes weight body measured the explain To ). I P ) ) 2 . Obesity ed increase in UGE with canagliflozin canagliflozin with UGE in increase ed iue 1B Figure ∫ 0 gy intake also depend on how long how on gydepend also intake t pressed as an integral term quantified quantified term pressedas an integral 90 weeks of empagliflozin treatment, empagliflozin of weeks 90 y weight regulation that was ythat regulation weight quation 5 with the best fit value of value fit best the with 5 quation mean energy intake was calculated calculated was intake energy mean whose mean body weight loss was was loss weight body mean whose E, energy intake was calculated to to calculated was intake energy E, new equilibrium several kilograms kilograms several equilibrium new ughout. The full study cohort was was cohort study full The ughout. rst several weeks and return to to return and weeks several rst bition, energy intake increased increased intake energy bition, tic subjects who completed the the completed who subjects tic τ τ ) which is similar to recent to similar is which ) (Equation 5) 5) (Equation 12 he he k P
Page 12of30 Page 13of30 baseline body weight) in response to a sustained pe sustained a to response in weight) body baseline patterns in humans receiving SGLT2 inhibitors. inhibitors. SGLT2 receiving humans in patterns perturbation (caloric loss via UGE) leads to a new new a to leads UGE) via loss (caloric perturbation parameter parameter n sfiin cniin o a ytm o rdc ze produce to system a for condition sufficient and theory control from result well known a is outcome of presence the in even values baseline to restored bo 5), (Equation control feedback integral included UGE in increase persistent the despite contrast, In In contrast, for any value of value any for contrast, In weight) body in reduction sustained a (i.e., error a will system feedback proportional a that and UGE) of a proportional feedback control system as shown shown as system control feedback proportional a of w to responding signals endocrine the that suggests using the proportional feedback model, our results results our model, feedback proportional the using obtai energyintake in changes mean the Bymodeling model feedback integral the for as shown treatment l weight transient only have would intake energy of qiiru ws ece. hs eea pten f r of pattern general This reached. was equilibrium of loss the for compensated it until baseline above lutaig ht rprinl edak oto (as control feedback proportional that illustrating
Accepted Articlek P
= 95 kcal/day per kg) mimics the observed body weig body observed the mimics kg) per kcal/day 95 = ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. k I
> 0, a system including integral feedback in the re the in feedback integral including system a 0, > Obesity in response to a sustained perturbation. perturbation. sustained a to response in , if the system regulating body weight weight body regulating system the if , calories via UGE, after which, a new a which, after UGE, via calories dy weight would ultimately have been been have ultimately would weight dy quantify the strength of energy intake intake energy of strength the quantify in Figure 2. Figure in 2. oss during sustained SGLT2 inhibitor inhibitor SGLT2 sustained during oss rturbation (i.e., persistently increased increased persistently (i.e., rturbation eight loss (such as leptin) act as part part as act leptin) as (such loss eight equilibrium at a lower body weight, weight, body lower a at equilibrium that integral feedback is a necessary necessary a is feedback integral that defined by Equation 4 with the the with 4 Equation by defined ro steady state error (i.e., return to to return (i.e., error steady state ro ned with SGLT2 inhibitor treatment SGLT2inhibitor with ned sustained increases in UGE. This This UGE. in increases sustained in the curves depicted in in depicted curves the in lways have a non zero steady state steady state non zero a have lways esponse, in which a sustained sustained a which in esponse, ht and energy intake intake energy and ht iue 2 Figure gulation 13
imre mtos uig n nesv 2 er calori year 2 intensive an during methods biomarker Note that at the point of maximum weight loss occur loss weight maximum of point the at that Note baseline followed by an exponential relaxation towa relaxation exponential an by followed baseline g A iia pten f easn de ahrne h adherence diet relapsing of pattern similar A kg. wh levels at baseline practically was energyintake kcal/day 100 within to returned already had intake (6, 21). had plateaued we of period early the during lower much was intake energy in intake. c minor relatively indicates and 3B Figure in shown correspond expenditure energy estimated The months. trajectory depicted in in depicted trajectory obe for results our of importance the illustrate To l weight 20% to 10 with observed energyexpenditure t greater substantially effect lost—an weight of kg inta energy average, On humans. in control feedback Accepted in illustrated is trajectory Articleco intake energy calculated The (20). regain weight plat a loss, weight initial by characterized course illustrates and (19) program loss weight commercial ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Figure 3A Figure Figure 3B Figure that resulted from long term participation in a st a in participation long term from resulted that showing an initial reduction of ~700 kcal/day from from kcal/day ~700 of reduction initial an showing Obesity sity treatment, consider the body weight weight body the consider treatment, sity eau after 6 8 months, followed by slow slow by followed months, 6 8 after eau ile body weight was still reduced by ~5 ~5 by reduced was still weight bodyile rresponding to this mean body weight weight body mean this to rresponding of baseline. After 1 year, the average average the year, 1 After baseline. of hanges in comparison to the changes changes the to comparison in hanges han the ~30 kcal/kg/day changes in in changes kcal/kg/day ~30 the han ring at the ~8 month plateau, energy energy plateau, month ~8 the at ring rds baseline intake over the ensuing ensuing the over intake baseline rds oss in subjects with obesity (1). obesity with subjects (1). in oss ight loss than after the body weight weight body the after than loss ight ke increased by ~100 kcal/day per per kcal/day ~100 by increased ke as been observed using objective objective using observed been as the ubiquitous body weight time time weight body ubiquitous the e restriction study where calorie calorie where study restriction e ing to this intervention is also also is intervention this to ing ructured 14 Page 14of30 Page 15of30 baseline levels. levels. baseline esset fot s eurd o vi oeetn a overeating avoid to required is effort persistent nefeig 2, 5 2) Hprhga n hs stu these in Hyperphagia 26). 25, semi st (24, underfeeding experimental following men lean in observed (22) regained was weight lost the until hyperphagia models when a return to to return a when models be has behavior Such regain. weight of acceleration abov eating in result will intake energy of control food restrain to efforts ongoing of absence the In Discussion peie uig h itreto dsie h averag the despite intervention the during appetite Accepted ov to signals biological continuing the of face the ongoin the of index quantitative a is and 3C Figure Article a the and appetite increased the between difference c weight body the from arising signals feedback the corresponding pattern intake energy the illustrates system control feedback proportional the of context th consider to enlightening is it intervention, the rap participants the that indicating as interpreted slow by followed plateau weight corresponding a and retu subjects with early very lapsed adherence diet the during course time intake energy calculated The ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. d libitum ad feeding following diet restriction resulted in in resulted restriction diet following feeding Obesity idly decreased their efforts to adhere to to adhere to efforts their decreased idly e baseline levels with an accompanying accompanying an with levels baseline e to the increased appetite in response to to response in appetite increased the to intake following weight loss, feedback loss, weight following intake bove baseline to satisfy the increased increased the satisfy to baseline bove rning to their previous caloric intake intake caloric previous their to rning eir food intake behavior within the the within behavior intake food eir g effort to sustain the intervention in in intervention the sustain to effort g ereat. In this context, a substantial substantial a context, this In ereat. lifestyle intervention suggests that that suggests intervention lifestyle e energy intake returning to near near to returning intake energy e weight regain. While this might be be might this While regain. weight ctual energy intake is depicted in in depicted is intake energy ctual . This phenomenon has been also also been has phenomenon This . . The dashed curve in Figure 3B 3B Figure in curve dashed The . hanges shown in Figure 3A. The The 3A. Figure in shown hanges en previously observed in rodent rodent in observed previously en is a blee t rsl from result to believed was dies arvation (23) or short term short term or (23) arvation 15
pleiotropic effects and their impact on energy expe energy on impact and their effects pleiotropic We do not yet know whether the simple proportional proportional simple the whether know yet not do We further increase as weight loss is sustained (as wo (as sustained is loss weight as increase further in rapidly occur that hormones appetite regulating with consistent is feedback integral without system energy controlling signals the that suggestion The Accepteddeli exogenous or (7) exercise as such expenditure, inter other contrast, In intake. food of regulation dir to unlikely is intervention the and consistent, clear, is action of mechanism the since homeostasis pro unique a provides SGLT2 of inhibition Long term cha weight how about information provide not anddo Articlewit associated scales time long the to intake, extrapolated energy of modulation short term on signals t about information useful provide can studies such en in changes compensatory measure to manipulations hum in regulation intake energy of studies Previous intake. food increased ru be cannot weight lost regain to desire conscious body both of loss from arising signals homeostatic ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity ectly affect central pathways involved in involved pathways central affect ectly uld occur with integral feedback)integral with occur uld nditure can be highly variable. highlyvariable. can nditure be h regulation of human energy balance balance energy human of regulation h ventions aimed at increasing energy energy increasing at aimed ventions intake act as a proportional feedback feedback proportional a as act intake the roughly proportional changes in in changes proportional roughly the led out and may have contributed to contributed have may and out led epne o egt os n d not do and loss weight to response very of thyroid hormone (33), have have (33), hormone thyroid of very nges influence energy intake. energy intake. influence nges a ad en ise (7 2) bt a but 28), (27, tissues lean and fat ans have employed short term diet diet short term employed have ans be for assessment of human energy energy human of assessment for be controller represented by Equation Equation by represented controller ergy intake (29, 30, 31, 32). While While 32). 31, 30, (29, intake ergy he influence of episodic appetite appetite episodic of influence he its effect on energy output is is output energy on effect its the results cannot be readily readily be cannot results the
(34). (34). 16 Page 16of30 Page 17of30 engages only after sufficient weight loss to cross cross to loss weight sufficient after only engages inta energy in changes by uncompensated are changes exampl For losses. weight of range a for valid is 4 n motn lmtto o or td i ta w did we that is study our of limitation important An energyintake. actual their than Accepted diet the of effort perceived the reflect accurately self r Therefore, levels. baseline above at overeat the resist to effort persistent calculated the with over intake energy self reported constancy relative quantitativ are measurements intake energy reported ot suggest results Our adherence. diet of loss than d entirely be may plateau weight month 6 8 the that platea has weight when time later the with compared betw consumption caloric in differences significant persi indicate that measurements self reported with l weight during adherence diet of decay exponential Article may intake energy of control feedback Proportional p and identify its individuals, variability between feedb intake energy the characterize fully more and is research Future change. weight body of function ad intake energy in result may losses weight larger ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity hysiological mediators in humans. humans. in mediators hysiological eported measurements of diet may more may diet of measurements eported er to adhere to the intervention rather rather intervention the to adhere to er herwise and further illustrate that self that illustrate further and herwise e, it may be possible that small weight small that possible be may it e, aptations corresponding to a nonlinear nonlinear a to corresponding aptations increased appetite and the drive to to drive the and appetite increased ue to slowing of metabolic rate rather rather rate metabolic of slowing to ue the first 6 months corresponds well well corresponds months 6 first the oss interventions markedly contrasts contrasts markedly interventions oss een the period of early weight loss loss weight early of period the een ued (36). This has led to speculation to led has This (36). ued ely unreliable (5). Nevertheless, the the Nevertheless, (5). unreliable ely oe threshold some ack control system, characterize its its characterize system, control ack required to address these questions questions these address to required o hv drc maueet of measurements direct have not stence of diet adherence and no no and adherence diet of stence help explain why the calculated calculated the why explain help e uh ht h cnrl system control the that such ke
(35). Furthermore, Furthermore, (35). 17
the compensatory energy intake responses to be char be responsesto intake energy compensatory the s enable individual the would SGLT2 inhibitors with in in UGE daily Measuring level. group the at lost) (~1 intake energy of control proportional calculated correspondingly a is there Therefore, assumed. was t unlikely is study this in UGE daily mean the that measu was UGE 24h mean where studies other in meals simi is this (39); g 14.7 was test meal 3h the over measu was UGE where test tolerance meal a underwent 38). 37, (9, canagliflozin mg/day 300 with treated measuremen previous on based g/day ~90 be to assumed mea directly not was UGE rather since responses mean individual group the to analysis our restricted We (11). canagliflozin with treated rodents treatment significant no showing of data and (10) empagliflozin weeks 4 after expenditure energy meal no showing humans in study week 4 a from data with en influence directly not did inhibition SGLT2 that Accepted Article intake energy in chang weight to response the simulate accurately to m mathematical our using changes expenditure energy Rath inhibition. SGLT2 following expenditure energy ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 1, 3 14). 13, (12, This article isprotected by copyright. All rights reserved. Therefore, the calculated energy intake changes ass changes intake energy calculated the Therefore, Obesity o be substantially different than what what than different substantially be o ergy expenditure which is consistent consistent is which expenditure ergy acterized. acterized. ubject variability in the magnitude of magnitude of the variability in ubject es resulting from controlled changes changes controlled from resulting es lar to the value observed following following observed value the to lar 00 kcal/day per kg of body weight weight body of kg per kcal/day 00 hne i oye cnupin in consumption oxygen in changes sbe o sbet i ti study this in subjects of subset A dividuals during long term studies studies long term during dividuals significant changes in pre or post or pre in changes significant odel that was previously validated validated previously was that odel red to be ~90 g/day and suggests suggests and g/day ~90 be to red red; their mean increase in UGE UGE in increase mean their red; small uncertainty in the mean mean the in uncertainty small diabetes 2 type with people in ts er, we calculated the expected expected the calculated we er, ue i ec sbet u was but subject each in sured than attempt to characterize characterize to attempt than with the SGLT2 inhibitor inhibitor SGLT2 the with umed umed 18 Page 18of30 Page 19of30
oges n bst o My , 06 n acue, Ca Vancouver, in 2016 2, May on Obesity on Congress a in part, in presented, previously were data These Accepted manuscript. the anddrafted DP, analyses; the performed KDH and DP, AS, study; data the of accuracy the and data the of integrity s the in data the all to access full had KDH and DP the on comments helpful fortheir andAaron Cypess Corpora Pharma Tanabe Mitsubishi with collaboration Researc Janssen by developed been has Canagliflozin Acknowledgements therapies. obesity effective Articlemaj a poses system control feedback this countering envir obesogenic omnipresent an in (40) expenditure wit along appetite increased of face the in changes and heroic by so do term long the over loss weight f The adaptations. expenditure energy eff corresponding an – weight lost of kilogram per baseline above that found We humans. free living in system control quantific first the provide results our summary, In ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity analysis. DP, KDH and RS designed the the designed RS and KDH DP, analysis. to o te nry nae feedback intake energy the of ation appetite increased by ~100 kcal/day ~100 by increased appetite manuscript. manuscript. vigilant efforts to maintain behavior behavior maintain to efforts vigilant or challenge for the development of of development the for challenge or tudy and take responsibility for the the for responsibility take and tudy onment. Permanently subverting or or subverting Permanently onment. pritn sprsin f energy of suppression persistent h bstract form at the International International the at form bstract KDH, and RS interpreted the data the interpreted RS and KDH, tion. We thank Marc L. Reitman Reitman L. Marc thank We tion. ect several fold larger than the the than larger several fold ect ew who successfully maintain maintain successfully who ew h & Development, LLC, in in LLC, Development, & h nada and at the 50th Annual Annual 50th the at and nada 19
8. Stenlof K, Cefalu WT, Kim KA, Jodar E, Alba M, E M, Alba E, KA, Jodar Kim WT, CefaluK, Stenlof 8. 5. Schoeller DA. How accurate is self reported diet self reported is accurate DA. How Schoeller 5. 9. Devineni D, Polidori D. Clinical Pharmacokinetic Clinical D. Polidori D, Devineni 9. 4. Edholm OG, Adam JM, Healy MJ, Wolff HS, Goldsmit HS, Wolff HealyMJ, JM, OG, Adam Edholm 4. 3. Gibbons C, Finlayson G, Dalton M, Caudwell P, Bl P, Caudwell M, Dalton Finlayson C, G, Gibbons 3. 6. Sanghvi A, Redman LA, Martin CK, Ravussin E, Hal E, Ravussin CK, Martin LA, SanghviRedman A, 6. 1. Leibel RL, Rosenbaum M, Hirsch J. Changes in ene Changes in HirschJ. M, RL, Leibel Rosenbaum 1. References Vienna, Austria. in 2014 o Study the for Association European the of Meeting 10. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Baldi Frascerra S, E, Muscelli E, Ferrannini 10. 2. Berthoud HR. The neurobiology of food intake in in intake of food neurobiology The Berthoud HR. 2.
7. Blundell JE, Gibbons C, Caudwell P, Finlayson G, Finlayson P, C, Caudwell Gibbons JE, Blundell 7. Proc Nutr Soc Nutr Proc Inhibitor. a Sodium ofCanagliflozin, InteractionProfile Drug Clin Invest Clin response to sodium glucose cotransporter 2 inhibiti 2 cotransporter sodium glucose responseto 1990; intake and energy expenditure of army recruits. of armyrecruits. expenditure and energy intake Phenotyping Guidelines: studying eating behaviour i behaviour eating studying Guidelines: Phenotyping free living energy intake. intake. free livingenergy mea to method mathematical and accurate inexpensive from altered body weight. weight. alteredfrom body endocrinology CANTATA M study. study. CANTATA M fin and exercise: diet with controlled inadequately in monotherapy canagliflozin of efficacyand safety Accepted of exercise. impact andenergy balance: Article
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20 J J Page 20of30 Page 21of30 15. Broyles ST, Bouchard C, Bray GA, Greenway FL, J FL, GA,BrayGreenway C, Bouchard BroylesST, 15. 17. Tam J, Fukumura D, Jain RK. A mathematical mode Amathematical RK. Fukumura Jain D, J, Tam 17. 22. Maclean PS, Bergouignan A, Cornier MA, Jackman Jackman MA, Cornier A, Bergouignan MacleanPS, 22. 16. Brady I, Hall KD. Dispatch from the field: is m is field: the from Dispatch I,KD. BradyHall 16. 12. Hall KD, Guo J, Dore M, Chow CC. The progressiv CC. Chow Dore M, J, KD, Guo Hall 12. 20. Franz MJ, VanWormer JJ, Crain AL, Boucher JL, H AL, Crain BoucherJL, JJ, VanWormer FranzMJ, 20. 11. Liang Y, Arakawa K, Ueta K, Matsushita Y, Kuriy Y, Matsushita K, Ueta K, Arakawa LiangY, 11. 19. Heshka S, Anderson JW, Atkinson RL, Greenway FL RL, Greenway Atkinson AndersonJW, HeshkaS, 19.
13. Hall KD, Jordan PN. Modeling weight loss mainte Modeling weight loss PN. KD, Jordan Hall 13. 21. Ravussin E, Redman LM, Rochon J, Das SK, Fontan Das SK, LM,J, Rochon Redman E, Ravussin 21. 14. Hall KD, Sacks G, Chandramohan D, Chow CC, Wang CC, Chow D, Chandramohan G, KD, Sacks Hall 14. 18. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall Sanghvi Hall A, S, Crowe T, Hach G, Ferrannini 18. Metabolism dieting: the impetus for weight regain. weightregain. for impetus the dieting: effects on predictors of health span and longevity. span health of predictors on effects r caloric of human trial controlled yearrandomized 2011; groups. regulation by leptin: energy balance and defense of anddefense energy balance byregulation leptin: Care normal and diabetic animal models. models. animal and diabetic normal glglucose,for threshold renal on ofcanagliflozin obesity treatment in the real world? world? real the in obesitytreatment clinical trials with a minimum 1 year follow up. a minimum with trials clinical andmeta systematicreview a outcomes: Weight loss America and its environmental impact. impact. environmental andits America al. Quantification of the effect of energy imbalance on imbalance of energy effect of the Quantification 2011; randomized trial. trial. randomized a compared structur with self help with loss Weight weight regain. weightregain. 1755 1767. 1755 1767. Balance After Sodium Glucose Cotransporter 2 (SGLT2 2 GlucoseCotransporter Sodium BalanceAfter
Accepted Articlerelationshi mass mass fat free of fat Consistency 2015. 2015. 378: 301: ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 Br J Nutr J Br 826 837. 826 837. R581 600. R581 600. 2009; This article isprotected by copyright. All rights reserved. Am J Clin Nutr Clin J Am 2011; JAMA 9: 52 63. 52 63. 105: 2003; 1272 1276. 1272 1276. 2008; 289: Obesity 1792 1798. 1792 1798. Obesity (Silver Spring) (Silver Obesity PLoS One PLoS 88: Am J Physiol Regul Integr Comp Physiol Comp Integr Regul Physiol J Am PLoS One PLoS 1495 1503. 1495 1503. 2012; athematical modeling applicable to to applicable modeling athematical J Am Diet Assoc Diet Am J ycemia, and body weight in in ycemia,weight and body KD, Ferrannini E. Energy E. KD,Ferrannini 2009;
Journal of Gerontology of Journal nance to help prevent body prevent help to nance ama C, Martin T Martin C, ama estriction: feasibility and and feasibility estriction: a stable body weight. weight. a body stable bodyweight. ed commercial program: a program: edcommercial e increase of food waste in in waste food eof increase ohnson RL Newton ohnson WD, iston T, Caplan W Caplan T, iston MR. Biology's response to to response Biology's MR. p across ethnicity and sex sex and across p ethnicity l of murine metabolic metabolic of murine l 7: a L,WE aKraus , Hill JO, Phinney SD JO, Hill , analysis of weight loss weight loss of analysis e30555. e30555. YC, Gortmaker SL Gortmaker YC, 4: ) Inhibition. Inhibition. ) e7940. e7940. 2014; Lancet 2007; 22: , et al. et , , et al. et , 1939 1941. 1939 1941. Diabetes Diabetes , et al. et , 107:
Cell Cell Effect 2015. 2015. Atwo , et al. et , , et al. et ,
, et et , 21
32. Stubbs RJ, Ritz P, Coward WA, Prentice AM. Cove AM. Prentice WA, Coward Ritz P, RJ, Stubbs 32. 33. Lovejoy JC, Smith SR, Bray GA, DeLany JP, Rood BraySR, JP, GA, DeLany Smith LovejoyJC, 33. 30. Bellisle F, Perez C. Low energy substitutes for Low energysubstitutes C. F, Bellisle Perez 30. 25. Roberts SB, Fuss P, Heyman MB, Evans WJ, Tsay R MB, WJ, Evans Heyman FussSB, P, Roberts 25. 24. Heyman MB, Young VR, Fuss P, Tsay R, Joseph L, Tsay Joseph Fuss P, R, VR, Young HeymanMB, 24. 3 KeysA. 23. 29. Almiron Roig E, Palla L, Guest K, Ricchiuti C, C, Ricchiuti K, Guest L, Palla E, Almiron Roig 29. 28. Dulloo AG, Jacquet J, Girardier L.Girardier Poststarvati J, AG, Jacquet Dulloo 28.
27. Blundell JE, Finlayson G, Gibbons C, Caudwell P Caudwell C, Gibbons Finlayson G, JE, Blundell 27. 26. Winkels RM, Jolink Stoppelenburg A, de Graaf K, Graaf de A, RM, Jolink Stoppelenburg Winkels 26. 31. Stubbs RJ, Harbron CG, Murgatroyd PR, Prentice Prentice PR, Harbron Murgatroyd CG, RJ, Stubbs 31. balance in free living men eating ad libitum. adlibitum. eating men balancefree living in Physiol Behav Physiol J Clin Nutr Clin J Endocrinol Metab Endocrinol balance, body composition, and energy expenditure i expenditure and energy composition, balance, body hyperthyroi mild induced of experimentally paradigm Rev Control of food intake in older men. oldermen. in intake of food Control dietary fat to carbohydrate and energy density: eff density: and energy carbohydrate dietaryfat to R250 257. R250 257. impact on nutritional regulation. regulation. nutritional on impact Minneapolis, 1950. 1950. Minneapolis, and body weight regulation in normal weight youngm normal weight in regulation weight and body that determine energy compensation: a systematic re a systematic compensation: energy determine that 2011; overshooting in humans: a role for feedbacksignals arole for humans: overshootingin appetite control: Do resting metabolic rate andfat rate metabolic resting Do control: appetite young and elderly men. elderlymen. youngand o after weeks 3 compensation L.Energyintake Groot 1994; eating ad libitum. adlibitum. eating substrate effecton density: andenergy dietaryfat
Accepted2013; Article 12: 18: ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 The biology of human starvation human of biology The 277 286. 277 286. 197 205. 197 205. 71: 1997; 458 473. 458 473. This article isprotected by copyright. All rights reserved. 2015; 65: Am J Clin Nutr Clin J Am 1997; 152: 717 723. Journal of the American Medical Directors Associati Directors Medical American the of Journal 82: 473 478. 473 478. 765 770. 765 770. Neuroscience and biobehavioral reviews biobehavioral and Neuroscience 1995; Obesity JAMA 62: . University of Minnesota Press: Press: University . of Minnesota 1994; 316 329. Am J Clin Nutr Clin J Am sugars and fats in the human diet: diet: human the in and fats sugars on hyperphagia and body fat fat and body hyperphagia on Vint N, Jebb SA Jebb N, Vint flux and food intake in men men in intake and food flux 272: free mass drive energy intake? energyintake? drive freemass ect on food intake and energy andenergy intake ectfood on , Hopkins M. The biology of The biology M. Hopkins , AM. Covert manipulation of manipulation Covert AM. Siebelink E, Mars M, de Mars M, E, Siebelink from lean and fat tissues. fattissues. leanfrom and rt manipulation of the ratio of ratio of the manipulation rt JC, GouvierD JC, view of preload studies. studies. ofview preload Roberts SB. Underfeeding Underfeeding SB. Roberts n healthy young men. healthy n , Rasmussen H Rasmussen , f restricted energy intake in in energyintake f restricted dism: effects on nitrogen nitrogen on effects dism: 1601 1606. 1601 1606. en. Am J Physiol J Am 1995; , et al. et , 62: , et al. et , , et al. et , 330 337. 330 337. Factors 1992; A
J Clin Clin J Nutr Nutr on 263: Am Am 22
Page 22of30 Page 23of30 38. Sha S, Polidori D, Heise T, Natarajan J, Farrel J, HeiseD, Natarajan T, Polidori S, Sha 38. 39. Polidori D, Mari A, Ferrannini E. Canagliflozin E. Ferrannini A, Mari D, Polidori 39. 37. Devineni D, Curtin CR, Polidori D, Gutierrez MJ Gutierrez D, Polidori CR, Curtin D, Devineni 37. 35. Speakman JR, Levitsky DA, Allison DB, Bray MS, BrayDB, MS, Levitsky DA,Allison JR, Speakman 35. 40. Fothergill E, Guo J, Howard L, Kerns JC, Knuth Knuth L,JC, Howard Kerns J, Guo E, Fothergill 40. 34. Sumithran P, Prendergast LA,Purce Prendergast DelbridgeE, P, Sumithran 34.
36. Greenberg I, Stampfer MJ, Schwarzfuchs D, Shai Shai D, Schwarzfuchs MJ, I, Greenberg Stampfer 36. patients with type 2 diabetes mellitus. mellitus. type with diabetes 2 patients Disease models &mechanisms models Disease (Silver Spring) (Silver sodium glucose co transporter 2 inhibitor canaglifl inhibitor 2 glucose co transporter sodium clinical pharmacology clinical metabolic adaptation 6 years after "The Biggest Los years Biggest "The after 6 adaptation metabolic al. type 2 diabetes. typediabetes. 2 c of beta model based improves indices inhibitor, 2 2011; transporter 2 inhibitor, in subjects with type with di 2 subjects in transporterinhibitor, 2 of canagliflo and pharmacodynamics Pharmacokinetics understand how genes and environments combine to re to combine environments genesand how understand mo alternative and some points settling points, Set (DIRECT). (DIRECT). dietary the diets: interventi loss weight long term
Accepted Article w to adaptations Long termof hormonal persistence 365: ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 1597 1604. 1597 1604. J Am Coll Nutr Coll Am J This article isprotected by copyright. All rights reserved. 2016; Diabetologia 24: 2013; 1612 1619. 1612 1619. 2009; 53: 2014; 2011; 601 610. 601 610. 28: Obesity 57: 159 168. 159 168. 4: Diabetes Obes Metab Obes Diabetes 891 901. 891 901. 733 745. 733 745. l K, WangK, SS l , a sodium glucose co transporter glucose co transporter a , sodium abetes mellitus. mellitus. abetes ND, Brychta R ND,Brychta on randomized controlled trial trial controlled randomized on , Murphy J, Rusch S Rusch Murphy , J, ll K, Shulkes A, Kriketos A Kriketos A, Shulkes K, ll I. Adherence and success in in andsuccess I.Adherence dels: theoretical options to to theoretical options dels: ozin on plasma volume in volume plasma on ozin ell function in patients with with patients in function ell er" competition. er"competition. de Castro JM, Clegg DJ JM, deCastro gulate body adiposity. adiposity. body gulate zin, a sodium glucose co glucose a sodium zin, eight loss. eightloss. 2014; , et al. et , , et al. et , Journal of of Journal N Engl J Med J Engl N 16: Effect of the the Effect of Obesity Obesity 1087 1095. 1087 1095. , et al. et , Persistent Persistent
, et al. et , , et et , 23
1 Table Parameter η UGE UGE ρ γ η ρ γ δ FFM δ FFM β FFM FM FM FM 0
. Mathematical model parameters. parameters. model Mathematical .
Accepted Article 360 kcal/d kcal/d 360 0.24 kcal/kg 1100 kcal/kg 9300 Description kcal/kg 230 kcal/kg 180 kcal/kg/d 0 kcal/kg/d 10 kcal/kg/d 22 kcal/kg/d 3.2 Value ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity Dietary and adaptive thermogenesis adaptivethermogenesis Dietaryand mass free of fat Energydensity mass of fat Energydensity turnover of Energy protein cost fatturnover of Energy cost changes Physicalactivity at baseline Physicalactivity offat freemass rate Energyexpenditure offat mass rate Energyexpenditure (300 mg/d) mg/d) (300 canagliflozin with excretion glucose urinary increased due to Energyloss 24 Page 24of30 Page 25of30 Table 2. Table eGFR(mL/min/1.73m (y) Diabetesduration (mmol/L) glucose plasma Fasting HbA1c(%) Other Asian American African Blackor White Race,(%) n circumference (cm) Waist BMI(kg/m (kg) BW Age(years) Female Male (%) n Sex, Characteristic repo otheror not Islander,multiple, otherPacific otherwise indicated. indicated. otherwise
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Baseline characteristics of the study subjects. Da studyof the subjects. Baseline characteristics
Accepted Article2
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ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901
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Includes American Indian or Alaska Native, Native Native IndianAlaska Native, or IncludesAmerican This article isprotected by copyright. All rights reserved. 2 )
8.2 ± 2.1 ± 8.2 0.6 ± 7.5 13 ± 106 Placebo (n = 89) = (n 88 ± 18 ± 88 10 ± 57 85 ± 21 ± 85 10 (11) 10 (17) 15 (70) 62 (47) 42 (53) 47 32 ± 6 ± 32 3 ± 4 ± 3 2 (2) 2 Obesity
rted rted Canagliflozin (n = 153) = (n 9.3 ± 2.4 ± 9.3 0.8 ± 7.9 15 ± 105 106 (69) 106 87 ± 21 ± 87 11 ± 55 88 ± 19 ± 88 16 (10) 16 (16) 24 (57) 87 (43) 66 ta are mean ± SD unless unless SD ± aremean ta 32 ± 6 ± 32 3 ± 4 ± 3 7 (5) 7
Hawaiian or Hawaiian 25
baseline (thin horizontal gray line). The feedback gray The line). horizontal (thin baseline Figure2 CI. 95% Mean± diabetes treated with canagliflozin (8). (A) Observ (8). (A) canagliflozin with treated diabetes curve) of energy intake. (B) Calculated changes in in changes Calculated (B) intake. energy curve)of (solid control proportional changes with simulated (A) Average body weight ( weight body (A)Average Figure3 CI. 95% ± energyMean intake. curve) (solid control or proportional changeswith the SGLT2 inhibitor group ( group SGLT2 the inhibitor (A) Average body weight measurements in the placebo the in measurements weight body (A)Average group (group curves, respectively. (B). Calculated energy intake energy Calculated (B). curves,respectively. Figure 1. FIGURELEGENDS (solid curve) initially drops by a large amount fol amount by a large curve) drops (solid initially ( during intervention the little changesrelatively weight slow by followed intervention ofa lifestyle intervention. (C) The average effort during the int the during effort The(C) average intervention. r is (dashedthat curve) appetite largein increase . Characterization of feedback control of energyin of control of feedback Characterization . . Energy balance dynamics during a lifestyle interv a lifestyle during dynamics balance Energy . ) along with mathematical model simulations depicte simulations model mathematical with )along Accepted Article during placeb changes energy intake and Bodyweight ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved.
■ ) typically decreases and reaches a plateau after 6 after a plateau and reaches )typically decreases ) along with the mathematical model simulations (cu simulations model mathematical the with )along Obesity dotted curve) whereas energy intake intake energy whereas curve) dotted esisted by the attempt to sustain the the sustain to byattempt the esisted lowed by an exponential return towards towards return an exponential by lowed ervention was defined as the difference the as was ervention defined from the body weight loss signals a loss weight body the from ed changes in body weight ( weight bodyin edchanges integral control (dashed curve) of curve)of (dashed control integral changes in the placebo group ( group placebo the changes in regain. (B) Energy expenditure expenditure regain. Energy (B) energy intake ( energy intake curve) or integral control (dashed control integral curve)or group( take in subjects with type with 2 subjects takein ention for weight loss (19). loss for weight ention d as dashed and solid solid and as dashed d o and SGLT2 inhibition. inhibition. and SGLT2 o ) and SGLT2 inhibition inhibition )and SGLT2 ) and the simulated simulated andthe ) ■ 8 months 8months ) and the andthe ) rves). rves). )and 26 Page 26of30 Page 27of30 between the increased appetite and the actual energ actual and the appetite betweenincreased the
Accepted Article ba a near return to despite duringintervention the ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 This article isprotected by copyright. All rights reserved. Obesity seline energy intake. Mean ± 95% CI. CI. 95% ± Mean energy seline intake. y intake. A substantial effort persists persists effort yAsubstantial intake. 27 60 59 B A
Δ Energy Intake (kcal/d) -200 -100 100 200 300 400 500 Δ Body Weight (kg) -5 -4 -3 -2 -1 ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 0 0 0
Accepted0 Article 6 6 This article isprotected by copyright. All rights reserved. 12 12 Figure1 18 18 Time (weeks) Time (weeks) Obesity Placebo 24 24 Placebo
30 Canagliflozin 30 Canagliflozin
36
36 42 42
48 48
54 54 Page 28of30 60 59 Page 29of30
Δ Energy Intake (kcal/d) B A
-100 100 200 300 400 500 600 Δ Body Weight (kg) -5 -4 -3 -2 -1 0 0 ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 0 Accepted0 Article ProportionalControl Integral Control 6 6 This article isprotected by copyright. All rights reserved. 12 12 18 18 ProportionalControl Time (weeks) Time (weeks) Obesity Figure2 Integral Control 24 24
30 30
36 36 42 42
48 48
54 54 60 59 C B A
Energy Rate (kcal/d) Effort (kcal/d) 1900 2300 2700 3100 Body Weight (lbs) ScholarOne, 375GreenbrierDrive,Charlottesville, VA,22901 190 195 200 205 210 200 400 600 800
0 Accepted Article 0 0 0 EnergyIntake 3 3 3 This article isprotected by copyright. All rights reserved. Appetite 6 6 6 Obesity Figure3 9 9 9 Months Months Months
EnergyExpenditure 12 12 12
15 15 15 18 18 18 21 21 21 24 24 24
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