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Calories, Carbs, or Quality? What Matters Most for Body Weight Kevin D. Hall, Ph.D. National Institute of Diabetes & Digestive & Kidney Diseases National Institutes of Health October 17, 2019 2 Erroneous Weight Loss Projections 3500

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Calories, Carbs, or Quality? What Matters Most for Body Weight

Kevin D. Hall, Ph.D. National Institute of Diabetes & Digestive & Kidney Diseases National Institutes of Health October 17, 2019

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2

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Erroneous Weight Loss Projections

3

3500 kcal per lb rule

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Calories In Calories Out

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Calories In & Out are NOT Independent

4

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Feedback Regulation of Body Weight

Calories In Calories Out

5

Leptin, etc.

5

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( )

{ }

( )

( )

( )

{ } ( )

( ) ( )

( )

min

ˆ ( ) 0, 1 ˆ ˆ 0, 1 exp

G G G C C b C F F F F P sig P P A A b b P sig PI P b sig

w D D w MAX S CI CI G G G f Z w D D f Z w MAX P D D S k f Z dP S PI PI P dt δ υ δ υ τ + + ∆ + = = + + − + + = = ∆ −  

( )

3 3 1

C P F F FFA TG d excr k P P

dG CI DNL GNG GNG G P CarbOx dt dF M FI M DNL KU KTG FatOx dt dP PI GNG ProtOx dt ρ ρ ε ε ρ = − + + − − = + − − − − = − − ˆ (1 ) (1 )

P G

FFM BM ECF ECP LCM BM ECF ECP ICW P G ICS BM ECF ECP ICW P h G h ICS = + + + = + + + + + + = + + + + + + + +

[ ] ( ) ( )

( )

( )

1 1

diet Na init CI b BW BW init

dECF Na ECF ECF CI CI ECF dt Na d ECF BW BW ECF dt ξ ξ τ ξ = ∆ − − − − + ∆ ∆ = − − ∆ TEE TEF PAE RMR = + + CI PI FI TEF

C P F

α α α + + =

( ) ( )

1 2

, if , else

b b T b

EI EI T EI EI dT EI EI T dt λ τ λ   ∆ − <   =   ∆ −    

( )

1 PAE T BW BW δ σ υ = + +

( ) (

) ( )

1 (1 ) (1 )( ) 1 ( )

c B B FFM B g init F d g F P K N excr P P P P F F F G G G

RMR E M FFM M G h ECF ECF F DNL GNG GNG KTG dP dF dG N D D D dt dt dt γ γ γ ε ε ε η η ε η η η η η   = + + − − ∆ + − − +   + − + − + + − + + + + + + + +

( )

ˆ 1 1

FFM FFM

T γ γ σ   = + −   ˆ

i FFM i i

dM dFFM γ γ =∑

[ ]

2 3

ˆ

F F diet PA Keys

F D D L L F   = +      

( ) ( )

( )

{ }

1 exp 0, 1

L L L

S L L L L b L diet L diet S S L Keys

K A B k CI CI B dL L dt K MAX F F τ   + − × − +   = − + − 1

PA init init

L δ υ ψ δ υ   + = −   +   ˆ exp exp ˆ

F F K F K P G b init K F F

D D PI G KTG D A k k PI G K D D ρ         = − −         +          

( ) ( )

max max

0, if , else

K thresh excr K K thresh thresh

KTG KTG KU KU KTG KTG KTG KTG ρ ρ ρ <     = −     −   ˆ

P P Keys b

P PI D D P PI χ       ∆ = +                 ˆ

G G init

G D D G   =    

C G G F F C F TG TG

M M GNG FI D M M ρ ρ ρ     = +        

( )

ˆ

P P C P Keys b b

P CI PI GNG GNG P CI PI χ         ∆ ∆ = − Γ + Γ +                    

( ) ( )

d init d d init DNL

CI G G DNL G G K × = + 3

f p C F P

CarbOx GNG GNG G P f TEE FatOx KetOx f TEE ProtOx f TEE = + − + × = + × = ×    6

Mathematical Modeling of Metabolism

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Mathematical Model

  • f Human Metabolism

Baseline Demographics & Anthropometrics Physical Activity Food Intake Body Weight Body Fat

Mathematical Modeling of Metabolism

7

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

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Corrected Weight Loss Projections

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3500 kcal per lb rule Dynamic Model

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

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Feedback Control of Appetite?

Calories In Calories Out

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Leptin, etc.

9

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Mathematical Model

  • f Human Metabolism

Baseline Demographics & Anthropometrics Calorie Intake Body Weight

Math Models to Calculate Calorie Intake?

Body Fat Calorie Expenditure

11

  • A. Sangvhi et al. Am J Clin Nutr.102:353-358 (2015)

11

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62 64 66 68 70 72 74 13 26 39 52 65 78 91 104 Body Weight (kg) Time (weeks)

DLW+DXA measurements

12

Validation: Caloric Restriction for 2 Years

N=140

  • A. Sangvhi et al. Am J Clin Nutr.102:353-358 (2015)

Mean ± 95% CI

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  • 600
  • 500
  • 400
  • 300
  • 200
  • 100

0-26 weeks 26-52 weeks 52-78 weeks 78-104 weeks Energy Intake Change (kcal/d) DLW/DXA Model

13

Mean CALERIE 2 Energy Intake Changes

13

N=135 N=125 N=117 N=115

Mean ± 95% CI

  • A. Sangvhi et al. Am J Clin Nutr.102:353-358 (2015)

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Model vs DLW/DXA within 40 kcal/d

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Leptin, etc.

??

Calories In Calories Out

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How to Increase Calorie Expenditure?

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Leptin, etc.

~90 g/d glucose

Calories In Calories Out

??

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How to Increase Calorie Expenditure?

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  • 5
  • 4
  • 3
  • 2
  • 1

6 12 18 24 30 36 42 48 54 Δ Body Weight (kg) Time (weeks)

Weight Changes during SGLT2 Inhibition

16

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

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

16

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  • 100

100 200 300 400 500 6 12 18 24 30 36 42 48 54 Δ Energy Intake (kcal/d) Time (weeks)

Intake Changes during SGLT2 Inhibition

~95 kcal/d per kg BW loss

17 17

  • D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016)
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Feedback Regulation of Body Weight

Calories In Calories Out Leptin, etc.

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~25 kcal/d per kg ~95 kcal/d per kg

  • D. Polidori, A. Sanghvi, R. Seeley, K.D. Hall. Obesity, 24:2289 (2016)
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Lifestyle Induced Weight & Fat Loss

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Mean ± 95% CI

19

J Guo et al. Am J Clin Nutr 107:558–65 (2018).

Body Weight Body Fat

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Corresponding Energy Balance Dynamics

20

Exponential decay

  • f diet adherence?

Intake Expenditure

20

Mean ± 95% CI

J Guo et al. Am J Clin Nutr 107:558–65 (2018).

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Perceived Effort Appetite increases ~95 kcal/d per kg weight lost Intake

Interpreting Lifestyle Weight Loss

21 21

Mean ± 95% CI

J Guo et al. Am J Clin Nutr 107:558–65 (2018).

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Large & Persistent Perceived Effort

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Intake Perceived Effort

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Mean ± 95% CI

J Guo et al. Am J Clin Nutr 107:558–65 (2018).

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The Promise of Low Carb Diets

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DS Ludwig & MI Friedman JAMA 311:2167-68 (2014).

Carbohydrate-Insulin Model of Obesity

“the metabolic effects of carbohydrate [to increase insulin] cause the adipocyte to take in, store, and trap too many

  • calories. Subsequently, energy expenditure declines and

hunger increases”

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“Any diet that succeeds does so because the dieter restricts fattening carbohydrates…Those who lose fat on a diet do so because of what they are not eating – the fattening carbohydrates” Gary Taubes, Why we get fat and what to do about it (2011).

Fat Loss Requires Carbohydrate Reduction?

25

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Isocaloric 30% Calorie Restricted Diets

Mean ± 95% CI

KD Hall et al. Cell Metabolism 22:427-436 (2015).

26

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  • 40
  • 30
  • 20
  • 10

10 20 24 hr C-peptide (% change) RC RF

Only RC Diet Decreased Insulin Secretion

*

Mean ± 95% CI

KD Hall et al. Cell Metabolism 22:427-436 (2015).

N=19 men & women with obesity

p = 0.001

* p<0.01

vs baseline

NS

27

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Only RC Diet Increased Fat Oxidation

** ** ** ** p<0.001

Burning Fat Burning Carbs

Mean ± 95% CI

KD Hall et al. Cell Metabolism 22:427-436 (2015).

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N=19 men & women with obesity

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  • 600
  • 500
  • 400
  • 300
  • 200
  • 100

1 2 3 4 5 6 Cumulative Fat Change (g) Time (days) RC data RC model RF data RF model

More Cumulative Body Fat Loss with RF

** ** **

Mean ± 95% CI

** p<0.001

KD Hall et al. Cell Metabolism 22:427-436 (2015).

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N=19 men & women with obesity

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Only RC Decreases Energy Expenditure

Mean ± SE

KD Hall et al. Cell Metabolism 22:427-436 (2015).

  • 140
  • 120
  • 100
  • 80
  • 60
  • 40
  • 20

20 40 Δ Energy Expenditure (kcal/d) RC data RF data

Sleep 24 hour

Mean ± SE p = 0.0024

* p<0.005

vs baseline

* *

p = 0.099 NS NS

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Recently, a study in Cell Metabolism by Kevin Hall from the National Institutes of Health attracted a lot of buzz in the news and online…[but] there were some real problems with the study

  • The low-carb diet wasn’t low at all,

actually, with 29 percent of calories coming from carbs, including refined

  • carbs. A true low-carb diet would have

less than 10 percent of calories from carbs.

  • It was a very short-duration study

(only six days) conducted on only nineteen people who were contained in a metabolic ward where all the food was provided…It showed what happened in a vacuum but not in real life.

Mark Hyman, MD Eat Fat, Get Thin (2016)

The Low Carb Community Responds

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0.75 0.8 0.85 0.9 0.95

  • 3 -2 -1 0

1 2 3 4 5 6 24hr Respiratory Qotient Time (days) RC data RC model RF data RF model

Hypothetical Extended Duration Study

Fat Adaptation?

32

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2 Month Isocaloric Ketogenic Diet Study

DXA 2 days residing in metabolic chamber DLW dose

4 weeks inpatient Baseline Diet 4 weeks inpatient Low Carb Ketogenic Diet

Energy Intake Adjustment Energy Intake Clamped

Day 0 Day -15 Day 15 Day 28 Day -28

KD Hall et al. AJCN 104:324–33 (2016).

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  • 80
  • 60
  • 40
  • 20

20 40

  • 10

10 20 30 24 hr C-peptide (% change) Time (days)

Rapid & Persistent Decrease in Insulin Secretion

Mean ± 95% CI

** ** ** *****

*p<0.0033

KD Hall et al. AJCN 104:324–33 (2016).

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N=17 men with overweight and class I obesity

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Rapid & Persistent Increase in Ketosis

Mean ± SEM

KD Hall et al. AJCN 104:324–33 (2016).

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N=17 men with overweight and class I obesity

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  • 0.15
  • 0.1
  • 0.05

0.05

  • 10

10 20 30 Δ 24hr RQ Time (days)

Rapid & Persistent Shift to Fat Oxidation

Mean ± 95% CI

*p<0.0045

** ** ** **

KD Hall et al. AJCN 104:324–33 (2016).

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Burning Fat Burning Carbs

N=17 men with overweight and class I obesity

Fat Adaptation?

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No Significant Effect on Daily Expenditure

Mean ± 95% CI

37

KD Hall et al. AJCN 104:1488-90 (2016).

P = 0.21

N=17 men with overweight and class I obesity

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Weighted Mean Difference in Energy Expenditure (kcal/d) P < 0.0001

Hall & Guo Gastroenterology 152:1718–27 (2017)

Energy Expenditure: Isocaloric Carb vs. Fat

38

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Body Fat: Isocaloric Carb vs. Fat

Weighted Mean Difference in Body Fat (g/d)

39

P < 0.0001

Hall & Guo Gastroenterology 152:1718–27 (2017)

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Low Carb Low Fat

Can We Transcend the Diet Wars?

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In the case of nutritionism, the widely shared but unexamined assumption is that the key to understanding food is indeed the nutrient. Put another way: Foods are essentially the sum of their nutrient parts.

42

Diet Quality & “Nutritionism”

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Diet Quality & Ultra-processed Food

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Ultra-processed vs Unprocessed Diets

The meals had similar amounts of: Calories, Carbs, Fat, Protein, Sugar, Sodium, Fiber 20 Adults were instructed to eat as much or as little as desired Primary Outcome: Energy Intake Differences

KD Hall et al. Cell Metabolism 30:1-11 (2019).

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Ultra-processed Diets Cause Increased Intake

Mean ± SE

KD Hall et al. Cell Metabolism 30:1-11 (2019).

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More Carbs & Fat with Ultra-processed Diets

Mean ± SE

490±34 1102±75 1387±105 872±60 492±31 1106±82

P=0.0001

KD Hall et al. Cell Metabolism 30:1-11 (2019).

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Larger Meals with Ultra-processed Diets

Mean ± SE

490±34 1102±75 1387±105 872±60 492±31 1106±82 KD Hall et al. Cell Metabolism 30:1-11 (2019).

P=0.008 P=0.003

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No Differences in Self-Reported Appetite

Mean ± SE

490±34 1102±75 1387±105 872±60 492±31 1106±82 KD Hall et al. Cell Metabolism 30:1-11 (2019).

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No Differences in Pleasantness or Familiarity

Mean ± SE

490±34 1102±75 1387±105 872±60 492±31 1106±82 KD Hall et al. Cell Metabolism 30:1-11 (2019).

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Faster Eating Rate for Ultra-processed Meals

Mean ± SE

490±34 1102±75 1387±105 492±31 1106±82 KD Hall et al. Cell Metabolism 30:1-11 (2019).

P<0.0001 P<0.0001

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Ultra-processed Diets Cause Weight Gain

Mean ± SE

KD Hall et al. Cell Metabolism 30:1-11 (2019).

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Ultra-processed Diets Cause Fat Gain

Mean ± SE

KD Hall et al. Cell Metabolism 30:1-11 (2019).

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Substantial Individual Variability

r=0.8 P<0.0001 KD Hall et al. Cell Metabolism 30:1-11 (2019).

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Mechanisms?

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Intramural NIDDK

Alexis Ayuketah Robert Brychta Thomas Bemis Hongyi Cai Thomas Cassimatis Dhruva Chandramohan Kong Chen Stephanie Chung Elise Costa Valerie Darcey Laura Fletcher Ahmed Gharib Stephanie Goodwin Juen Guo Lilian Howard Rebecca Howard Nick Knuth Suzanne McGehee Laura Musse Ronald Ouwerkerk Carla Prado Emma Preuschl Marc Reitman Irene Rozga Michael Stagliano Mary Walter Peter Walter Laura Yannai Megan Zhou

Intramural NIH

Amber Courville (CC) Paule Joseph (NINR) Merel Kozlosky (CC) Klaudia Raisinger (CC) Shanna Yang (CC)

Special Thanks

Nursing Staff at the NIH MCRU Metabolic Kitchen Staff Volunteer Study Subjects Nutrition Science Initiative

Extramural Collaborators

Ciaran Forde (Singapore) Christopher Gardner (Stanford) Rudy Leibel (Columbia) Laurel Mayer (Columbia) Eric Ravussin (PBRC) Jennifer Rood (PBRC) Michael Rosenbaum (Columbia) Steven R. Smith (TRI) Jon Moon (MEI)

  • B. Tim Walsh (Columbia)