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 Health

@KevinH_PhD

July 20, 2018

2
Calories In & Out are NOT Independent

Calories Out Calories In

4
Feedback Regulation of Body Weight

Calories Out Calories In

Leptin, etc.
5
Feedback Regulation of Body Weight

Calories Out Calories In

Leptin, etc.
6
 Mathematical Modeling of Metabolism  P   PI 
dG DP = Dˆ P   +   
C = CI − DNL + GNGP + GNGF − G3P − CarbOx CI  ( G Ginit )
d
 G   PKeys   PI b  
dt DNL = DG = Dˆ G  
( G Ginit ) + K DNL
d d
 Ginit 
2
dF
F = 3M FFA FI M TG +  d DNL − KU excr − (1 −  k ) KTG − FatOx  F 3
dt DF = Dˆ F 
 FKeys   Ldiet + LPA 
dP  
P = PI − GNGP − ProtOx
dt dLdiet K L L 1 + ( AL − BL )  exp ( −k L CI CI b ) + BL 
S

L = − Ldiet
FFM = BM + ECF + ECP + LCM
= BM + ECF + ECP + ICW + P + G + ICS
dt

K LSL + MAX 0, ( F FKeys − 1)
SL

= BM + ECF + ECP + ICW ˆ + P(1 + h ) + G (1 + h ) + ICS   M  M    + 
P G
GNGF = FI  C G  + DF C  G  LPA =   − 1
  F M TG   M TG    init + init 
dECF
=
1
( Nadiet −  Na ( ECF − ECFinit ) − CI (1 − CI CIb ) ) + ECF
dt  Na     CI   PI  
ˆ  P
GNGP = GNG  − C   + (  +  )  
d ECF P 
=  BW ( BW − BWinit ) − ECF
P
 BW  PKeys   CI b   PI b  
dt
TEE = TEF + PAE + RMR   DF Dˆ F   PI   G 
KTG =  K DF  AK   exp  −k P  exp  −kG 
( )
RMR = Ec +  B M B +  FFM  FFM − M B − G 1 + hg − ( ECF − ECFinit )  +  F F   K K + DF Dˆ F   PI b   Ginit  
+(1 −  d ) DNL + (1 −  g )(GNGF + GNGP ) + (1 −  K ) KTG  0, if KTG  K  KTGthresh 
 
dP dF dG KU excr =   K KU max ( KTG  K − KTGthresh ) 
+ N N excr + ( P +  P ) DP +  P +  F DF +  F + G DG + G  , else 
dt dt dt  ( KTGmax − KTGthresh ) 

dT  1 ( EI EI b ) − T , if EI  EI b  wG ( DG Dˆ G ) + wC MAX 0, (1 + SC CI CI b ) G ( Gmin + G )

T =  fC =
dt 2 ( EI EI b ) − T , else  Z

dM i (
wF DF Dˆ F )
ˆFFM = i fF =
dFFM Z
i
CarbOx = GNG f + GNG p − G3P + fC  TEE
 FFM = ˆFFM 1 + (1 −  ) T 
FatOx = KetOx + f F  TEE fP =
  ( )
wP MAX 0, (1 + Psig ) + DP Dˆ P S A exp ( − k A ( +  ) ( b + b ) )

PAE =  (1 +  T ) BW +  BW Z
ProtOx = f P  TEE dPsig
 PI = S P PI PI b − Psig 7
TEF =  F FI +  P PI +  C CI
dt
Mathematical Modeling of Metabolism

Baseline
Demographics &
Anthropometrics

Physical Activity Mathematical Model Body Weight

Food Intake of Human Metabolism Body Fat

KD Hall et al. The Lancet 378:826-37 (2011) 8

Corrected Weight Loss Projections

Dynamic Model

3500 kcal per lb rule

KD Hall et al. The Lancet 378:826-37 (2011) 9

 BWplanner.niddk.nih.gov

KD Hall et al. The Lancet 378:826-37 (2011) 10

The Biggest Loser Competition

11
 Biggest Loser Body Weight and Fat Loss
Isolated on Ranch At Home
20

0
Mass Change (kg)

-20
Fat Mass
-40

-60 Body Weight

-80
-4 0 4 8 12 16 20 24 28 32
Time (weeks) Mean ± SD

12
KD Hall. Obesity 21(5):957-9 (2013)
Biggest Loser Energy Balance Dynamics
6000
Total Energy Expenditure
Energy Rate (kcal/d) 5000

4000

3000

2000

1000

0
-4 0 4 8 12 16 20 24 28 32
Time (weeks)
Mean ± SD

13
KD Hall. Obesity 21(5):957-9 (2013)
Biggest Loser Energy Balance Dynamics
6000
Total Energy Expenditure
Energy Rate (kcal/d) 5000

4000

3000

2000

1000 Exercise
0
-4 0 4 8 12 16 20 24 28 32
Time (weeks)
Mean ± SD

14
KD Hall. Obesity 21(5):957-9 (2013)
Biggest Loser Energy Balance Dynamics
6000
Total Energy Expenditure
Energy Rate (kcal/d) 5000

4000

3000
Resting Metabolic Rate
2000

1000 Exercise
0
-4 0 4 8 12 16 20 24 28 32
Time (weeks)
Mean ± SD

15
KD Hall. Obesity 21(5):957-9 (2013)
Metabolic Rate before the Biggest Loser
4000

Resting Metabolic Rate (kcal/d)

3500

R2 =0.85
3000

2500

2000

1500
40 60 80 100 120
Fat-Free Mass (kg)

DL Johannsen et al. JCEM 97(7):2489–2496 (2012) 16

Metabolic Rate after the Biggest Loser
4000

Resting Metabolic Rate (kcal/d)

3500

3000
Metabolic
Adaptation
2500

2000

1500
40 60 80 100 120
Fat-Free Mass (kg)

DL Johannsen et al. JCEM 97(7):2489–2496 (2012) 17

18
 Body Weight Regain
p=0.0002
40
*
20

Body Weight Change (kg)

0
-20 *
-40
-60
-80
-100
-120
30 weeks 6 years
*p <0.05 vs. baseline
E Fothergill et al. Obesity 24:1612-1619 (2016) 27
 What Determines Weight Regain?
P = 0.003
200
Physical

% Change after 6years

150 Activity

100 Energy
Intake
50

0
P = 0.83
-50
> 13% Weight Loss < 13% Weight Loss
(-24.9% ± 3.8%) (+1.1% ± 4.0%)

J Kerns et al. Obesity 25(11):1838-1843 (2017) 28

Weight Regain & Energy Intake

r = -0.15
p = 0.61

J Kerns et al. Obesity 25(11):1838-1843 (2017) 29

Weight Regain & Physical Activity

r = -0.82
p = 0.0003

J Kerns et al. Obesity 25(11):1838-1843 (2017) 30

Resting Metabolic Rate Remained Low
p=0.35
0 * *
*-200 *
-400

RMR Change (kcal/day)

-600
-800
-1000
-1200
-1400
-1600
-1800
-2000
30 weeks 6 years

*p <0.05 vs. baseline

E Fothergill et al. Obesity 24:1612-1619 (2016) 31
Metabolic Adaptation Persisted
p=0.0075
100 * *
0

Metabolic Adaptation (kcal/d)

-100
-200
-300
-400
-500
-600
-700
-800
-900
30 weeks 6 years

*p <0.05 vs. baseline

E Fothergill et al. Obesity 24:1612-1619 (2016) 32
Weight Regain & Metabolic Adaptation
200

30 wk Metabolic Adaptation
0 r=-0.1
p=0.75
-200
(kcal/d) -400

-600

-800

-1000
-50 0 50 100 150
% Weight Gained at 6 years

E Fothergill et al. Obesity 24:1612-1619 (2016) 33

Weight Regain & Metabolic Adaptation
200

6 yr Metabolic Adaptation
0 r=0.59
p=0.025
-200
(kcal/d) -400

-600

-800

-1000
-50 0 50 100 150
% Weight Gained at 6 years

E Fothergill et al. Obesity 24:1612-1619 (2016) 34

Spring Model of Metabolic Adaptation

35
Spring Model of Metabolic Adaptation

Metabolic
Adaptation

36
Spring Model of Metabolic Adaptation

Metabolic Adaptation

37
 Feedback Control of Appetite

??
Calories Out Calories In

~90 g/d
glucose

Leptin, etc.
39
Weight Changes during SGLT2 Inhibition
0

Δ Body Weight (kg)

-1 N=153 adults with
Obesity & Type 2 diabetes
-2 treated with canagliflozin

-3

-4

-5
0 6 12 18 24 30 36 42 48 54
Time (weeks)

D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 40

 Intake Changes during SGLT2 Inhibition
500

Δ Energy Intake (kcal/d) 400

300
200
~100 kcal/d
100 per kg BW loss
0
-100
0 6 12 18 24 30 36 42 48 54
Time (weeks)

D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 41

Feedback Regulation of Body Weight

~20-30 kcal/d ~100 kcal/d

per kg per kg
Calories Out Calories In

Leptin, etc.
42
Typical Weight Loss with Lifestyle Change
97
95 N=211 clients of Weight Watchers

Body Weight (kg) 93

91
89
87
85
0 3 6 9 12 15 18 21 24
Months
Mean ± SE

43
Data from S. Heshka et al. JAMA 289:1792-1798 (2003)
Corresponding Calorie Balance Dynamics
2700

Intake and Expenditure 2500 Calorie Expenditure

(kcal/d)
2300 Exponential decay
of diet adherence!
2100
Calorie Intake
1900
0 3 6 9 12 15 18 21 24
Months

D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 44

 Interpreting Lifestyle Weight Loss
3500

Intake and Expenditure 3100

(kcal/d)
2700
Calorie Expenditure
2300
Calorie Intake
1900
0 3 6 9 12 15 18 21 24
Months

D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 45

 Interpreting Lifestyle Weight Loss
3500

Intake and Expenditure

Increased Appetite
3100
(kcal/d) Perceived Effort
2700
Calorie Expenditure
2300
Calorie Intake
1900
0 3 6 9 12 15 18 21 24
Months

D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 46

 Interpreting Lifestyle Weight Loss

800
600 Perceived Effort
400
200
kcal/d

0
-200
-400
Calorie Intake Change
-600
-800
0 3 6 9 12 15 18 21 24
Months

D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016) 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
Intramural NIH Intramural NIDDK Extramural Collaborators
Amber Courville (CC) Alison Baskin Naji Abumrad (Vanderbilt)
Peter Herscovitch (CC) Robert Brychta CALERIE Study Group
Thomas Bemis Britta Göbel (Sanofi)
John Ingeholm (NIMH) Dhruva Chandramohan Brian Gilmore (PBRC)
Seth Kallman (NIMH) Kong Chen Robert Huizenga (UCLA)
Alex Martin (NIMH) Stephanie Chung Jennifer Kerns (DC VA Med Center)
Lydia Milbury (NIMH) Valerie Darcey Rudy Leibel (Columbia)
Courtney Duckworth Pamela Marks-Shulman (Vanderbilt)
Kristina Rapuano (NIMH)
Erin Fothergill Corby Martin (PBRC)
Nancy Sebring (CC) Stephanie Goodwin
Laurel Mayer (Columbia)
W. Kyle Simmons (NIMH) Juen Guo
Eric Ravussin (PBRC)
Nora Volkow (NIDA) Gail Hall
David Polidori (J&J)
Lilian Howard
Leanne Redman (PBRC)
Rebecca Howard
@KevinH_PhD Darcy Johannsen
Jennifer Rood (PBRC)
Michael Rosenbaum (Columbia)
Peter Jordan
Nick Knuth Robyn Tamboli (Vanderbilt)
Lex Kravitz Randy Seeley (U Michigan)
Brooks Leitner Steven R. Smith (TRI)
Luke Maisuradze Jon Moon (MEI)
Bernard Miller B. Tim Walsh (Columbia)
Laura Musse
Carla Prado
Emma Preuschl Special Thanks
Marc Reitman
Arjun Sanghvi
Mario Siervo Nursing Staff at the NIH MCRU
Monica Skarulis Volunteer Study Subjects
Wayne Staton
Terri Wakefield
Nutrition Science Initiative
Mary Walter
Peter Walter
Laura Yannai
Megan Zhou