Why is it so Hard to Lose Weight and Keep it Off?

Transcription

1 Why is it so Hard to Lose Weight and Keep it Off? Kevin D. Hall, Ph.D. National Institute of Diabetes & Digestive & Kidney Diseases National Institutes of July 20, 2018

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4 Calories In & Out are NOT Independent Calories Out Calories In 4

5 Feedback Regulation of Body Weight Calories Out Calories In Leptin, etc. 5

6 Feedback Regulation of Body Weight Calories Out Calories In Leptin, etc. 6

7 dg C = CI DNL + GNG P + GNG F G 3 P CarbOx dt DNL = df F = 3M FFAFI MTG + d DNL KUexcr ( 1 k ) KTG FatOx dt dp PI GNG ProtOx P = P dt FFM = BM + ECF + ECP + LCM = BM + ECF + ECP + ICW + P + G + ICS = BM + ECF + ECP + ICW ˆ + P(1 + h ) + G(1 + h ) + ICS decf 1 = Na ECF ECF CI CI + ECF dt Na decf dt ( diet Na ( init ) CI ( 1 b )) ( ) = BW BW ECF BW BW init TEE = TEF + PAE + RMR RMR = Ec + BM B + FFM FFM M B G ( 1 hg ) ( ECF ECFinit ) + + F F + (1 ) DNL + (1 )( GNG + GNG ) + 1 KTG dt T dt TEF = FI + PI + CI F ( b) ( EI EI ) EI EI T, if EI EI 1 b = 2 b T, else ( ) ( 1 ) PAE = + T BW + BW P C P ( ) d g F P K dp df dg + N Nexcr + ( P + P ) DP + P + F DF + F + GDG + G dt dt dt ˆ FFM Mathematical Modeling of Metabolism dm i = i dffm i = ˆ 1+ 1 FFM FFM T G CarbOx = GNG + GNG G3P + f TEE f p C FatOx = KetOx + f TEE ProtOx = f TEE P F CI ( G Ginit ) d d ( G G ) + K f f init C F ( ˆ ) ( ) ( min ) w ( ˆ G DG DG ) + wcmax 0, 1+ SC CI CIb G G + G = Z w D D = Z F F F ˆ G DG = DG G init 0, ( 1+ ) + ( ˆ ) exp( ( + ) ( + )) w MAX P D D S k fp = Z dpsig PI = SP PI PIb Psig dt P sig P P A A b b 2 3 ˆ F D = D L + L F Keys F F diet PA ( ) ( ) SL dl KL 1 + AL BL exp k diet LCI CIb + BL L = L S SL dt L K + MAX 0, F F 1 CM G M G GNGF = FI + DF C FMTG MTG GNG d DNL L ˆ P PI = DP + P Keys PIb ( Keys ) L PA diet + = 1 init + init ˆ P CI PI = GNG + ( + ) P Keys CIb PIb P P C P D ˆ F D F PI G KTG = K DF AK exp kp exp kg K ˆ PI K + DF DF b Ginit 0, if KTG K KTGthresh KUexcr = K KUmax ( KTG K KTGthresh ), else ( KTGmax KTGthresh ) D P 7

8 Mathematical Modeling of Metabolism Baseline Demographics & Anthropometrics Physical Activity Food Intake Mathematical Model of Human Metabolism Body Weight Body Fat KD Hall et al. The Lancet 378: (2011) 8

9 Corrected Weight Loss Projections Dynamic Model 3500 kcal per lb rule KD Hall et al. The Lancet 378: (2011) 9

10 BWplanner.niddk.nih.gov KD Hall et al. The Lancet 378: (2011) 10

11 The Biggest Loser Competition 11

12 Mass Change (kg) Biggest Loser Body Weight and Fat Loss 20 Isolated on Ranch At Home Fat Mass Body Weight Time (weeks) Mean ± SD KD Hall. Obesity 21(5):957-9 (2013) 12

13 Energy Rate (kcal/d) Biggest Loser Energy Balance Dynamics Total Energy Expenditure Time (weeks) Mean ± SD KD Hall. Obesity 21(5):957-9 (2013) 13

14 Energy Rate (kcal/d) Biggest Loser Energy Balance Dynamics Total Energy Expenditure Exercise Time (weeks) Mean ± SD KD Hall. Obesity 21(5):957-9 (2013) 14

15 Energy Rate (kcal/d) Biggest Loser Energy Balance Dynamics Total Energy Expenditure Resting Metabolic Rate Exercise Time (weeks) Mean ± SD KD Hall. Obesity 21(5):957-9 (2013) 15

16 Resting Metabolic Rate (kcal/d) Metabolic Rate before the Biggest Loser R 2 = Fat-Free Mass (kg) DL Johannsen et al. JCEM 97(7): (2012) 16

17 Resting Metabolic Rate (kcal/d) Metabolic Rate after the Biggest Loser Metabolic Adaptation Fat-Free Mass (kg) DL Johannsen et al. JCEM 97(7): (2012) 17

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27 Body Weight Change (kg) Body Weight Regain p= * 0-20 * weeks 6 years *p <0.05 vs. baseline E Fothergill et al. Obesity 24: (2016) 27

28 % Change after 6years What Determines Weight Regain? P = Physical Activity Energy Intake 0-50 P = 0.83 > 13% Weight Loss < 13% Weight Loss (-24.9% ± 3.8%) (+1.1% ± 4.0%) J Kerns et al. Obesity 25(11): (2017) 28

29 Weight Regain & Energy Intake r = p = 0.61 J Kerns et al. Obesity 25(11): (2017) 29

30 Weight Regain & Physical Activity r = p = J Kerns et al. Obesity 25(11): (2017) 30

31 RMR Change (kcal/day) Resting Metabolic Rate Remained Low 0 *-200 * p=0.35 * * 30 weeks 6 years E Fothergill et al. Obesity 24: (2016) *p <0.05 vs. baseline 31

32 Metabolic Adaptation (kcal/d) Metabolic Adaptation Persisted p= * * 30 weeks 6 years E Fothergill et al. Obesity 24: (2016) *p <0.05 vs. baseline 32

33 30 wk Metabolic Adaptation (kcal/d) Weight Regain & Metabolic Adaptation r=-0.1 p= % Weight Gained at 6 years E Fothergill et al. Obesity 24: (2016) 33

34 6 yr Metabolic Adaptation (kcal/d) Weight Regain & Metabolic Adaptation r=0.59 p= % Weight Gained at 6 years E Fothergill et al. Obesity 24: (2016) 34

35 Spring Model of Metabolic Adaptation 35

36 Spring Model of Metabolic Adaptation Metabolic Adaptation 36

37 Spring Model of Metabolic Adaptation Metabolic Adaptation 37

38 Feedback Control of Appetite Calories Out?? Calories In ~90 g/d glucose Leptin, etc. 39

39 Δ Body Weight (kg) Weight Changes during SGLT2 Inhibition N=153 adults with Obesity & Type 2 diabetes treated with canagliflozin Time (weeks) D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 40

40 Δ Energy Intake (kcal/d) Intake Changes during SGLT2 Inhibition ~100 kcal/d per kg BW loss Time (weeks) D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 41

41 Feedback Regulation of Body Weight ~20-30 kcal/d per kg Calories Out ~100 kcal/d per kg Calories In Leptin, etc. 42

42 Body Weight (kg) Typical Weight Loss with Lifestyle Change N=211 clients of Weight Watchers Months Mean ± SE Data from S. Heshka et al. JAMA 289: (2003) 43

43 Intake and Expenditure (kcal/d) Corresponding Calorie Balance Dynamics Calorie Expenditure Exponential decay of diet adherence! Calorie Intake Months D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 44

44 Intake and Expenditure (kcal/d) Interpreting Lifestyle Weight Loss Calorie Expenditure Calorie Intake Months D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 45

45 Intake and Expenditure (kcal/d) Interpreting Lifestyle Weight Loss Increased Appetite Perceived Effort Calorie Expenditure Calorie Intake Months D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 46

46 kcal/d Interpreting Lifestyle Weight Loss Perceived Effort Calorie Intake Change Months D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 47

47 Summary The body resists weight loss and promotes weight regain via slowing metabolism and increased appetite Long-term maintenance of lost weight requires ongoing support and persistent effort Increased physical activity may be especially beneficial for maintaining lost weight, in addition to overall health benefits Reengineering your local environment may help facilitate maintenance of lost weight Drugs may help, but they need to be sustained to have lasting effects 52

48 Intramural NIH Amber Courville (CC) Peter Herscovitch (CC) John Ingeholm (NIMH) Seth Kallman (NIMH) Alex Martin (NIMH) Lydia Milbury (NIMH) Kristina Rapuano (NIMH) Nancy Sebring (CC) W. Kyle Simmons (NIMH) Nora Volkow Intramural NIDDK Alison Baskin Robert Brychta Thomas Bemis Dhruva Chandramohan Kong Chen Stephanie Chung Valerie Darcey Courtney Duckworth Erin Fothergill Stephanie Goodwin Juen Guo Gail Hall Lilian Howard Rebecca Howard Darcy Johannsen Peter Jordan Nick Knuth Lex Kravitz Brooks Leitner Luke Maisuradze Bernard Miller Laura Musse Carla Prado Emma Preuschl Marc Reitman Arjun Sanghvi Mario Siervo Monica Skarulis Wayne Staton Terri Wakefield Mary Walter Peter Walter Laura Yannai Megan Zhou Extramural Collaborators Naji Abumrad (Vanderbilt) CALERIE Study Group Britta Göbel (Sanofi) Brian Gilmore (PBRC) Robert Huizenga (UCLA) Jennifer Kerns (DC VA Med Center) Rudy Leibel (Columbia) Pamela Marks-Shulman (Vanderbilt) Corby Martin (PBRC) Laurel Mayer (Columbia) Eric Ravussin (PBRC) David Polidori (J&J) Leanne Redman (PBRC) Jennifer Rood (PBRC) Michael Rosenbaum (Columbia) Robyn Tamboli (Vanderbilt) Randy Seeley (U Michigan) Steven R. Smith (TRI) Jon Moon (MEI) B. Tim Walsh (Columbia) Special Thanks Nursing Staff at the NIH MCRU Volunteer Study Subjects Nutrition Science Initiative