You are on page 1of 48

# 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

## 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
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

-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
p=0.0075
100 * *
0

-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
200

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

200

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

35

Metabolic

36

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)

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
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
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)
Bernard Miller B. Tim Walsh (Columbia)
Laura Musse