Weight Loss Physiology: Emphasis on Metabolic AdaptationEric Ravussin, Ph.D

Minimally Invasive Surgery SymposiumFebruary 21-26, 2011; Salt Lake City, UT

Major Testing Wk 52Outpatient visits x x x x x x x x x x x x x

-6 to -1 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

* LCD subjects will have weekly outpatient visits from the beginning of the LCD diet until the inpatient assessment at week 7Weeks

Study Groups

SCRE

ENING

BASE

LINE

Roux-en-Y-Gastric Bypass (RYGB)

Sleeve Gastrectomy (SGx)

Gastric Banding (GBa)

Low calorie diet induced weight loss (LCD)

Surge

ry Wk 7

Funded by Ethicon Surgery

Goal: 48 subjects (12/group)

n=1

n=2

n=4

n=4

BARIA Study

• Energy Balance vs. Substrate Balance• Metabolic Adaptation• Bariatric Surgery: Energy Metabolism in Animal

Studies• Bariatric Surgery: Energy Metabolism in Human

Studies

Weight Loss Physiology: Emphasis on Metabolic Adaptation

Etiology of Overweight and ObesityThe Energy Balance Equation

Genes

Environment

Gain Stable Loss

Intake

Expenditure

Body Weight

Energy Intake (EI) = Energy Expenditure (EE) ± Body Energy Stores (S)

S ≈ body weight (W)

Energy Balance Equation in Response to Overfeeding or Caloric Restriction

Going from stable energy balance to 500 Kcal/d negative energy balance is not as simple as 1 pound of weight loss a week (¾ FM and ¼ FFM) because:

- The energy content of weight change is not constant- The fraction of weight loss as FFM is not constant- Energy expenditure changes in response to weight loss

Body Weight Simulatorshttp://www4.niddk.nih.gov/lbm/ (Kevin Hall; NIDDK)Web-based dynamic simulation model of adult human metabolism that predicts the time course of individual body weight change in response to a prescribed behavioral intervention.

http://pages.csam.montclair.edu/~thomasd/BodePlot.html (Thomas/Heymsfield)

Not to Do with Data from Energy BalanceAnd Energy Expenditure

• Energy Balance• Do not extrapolate an Energy Gap (kcal/d) over time• The rule of 1 pound of weight loss a week for

500kcal/day deficit is wrong

• Energy Expenditure• Do not divide VO2 (EE) by body weight• Such a division introduce a mathematical artifact

Body Size (Wt, FFM, BSA…)

VO2 (EE)

Range > 60,000 kcal

Energy Stores

Fat 125,000 kcal

Protein 40,000 kcal

Carbohydrate 2,000 kcal

Oxidation

as % stores

0.8

1.3

50

Intake

as Total Kcal

1,000

500

1,000

Daily Nutrient Balance (70kg Man; 20% Fat) on 2500 kcal/d Diet

(40% fat, 40% CHO , 20 % Protein) Range for up to 150-kg Man

Fat Intake = Fat Oxidation; Prot Intake = Prot OxidationCHO Intake = CHO Oxidation; Alcohol Intake = Alcohol Oxidation

Flatt JP, IJO July 1996

Regulation of Nutrients Balance: FQ/RQ Concept

Fat intake is poorly regulated because of the relatively small daily flux relative to the large pool size

Fat Balance vs. Energy Balance

Abbott WGH, et al. AJP 1988;255:E332-7

• Energy balance is buffered by fat balance

• Positive energy balance = fat gain

• Negative energy balance = fat loss

Variability in Respiratory Quotientand Impact on Weight Gain

Zurlo F, AJP 259:E650-E657, 1990

Cum

ulat

ive

Inci

denc

e of

a5

kg B

od

y W

eig

ht

Gai

n (

%)

Energy Bal% Body Fat

Sex

WithinSubject

Method

Per

cen

tag

e o

f E

xpla

ined

Var

ian

ce

40

20

0

Duration of Follow-up (years)

0 0.5 1 1.5 2 2.5 30

20

40

60

80

high RQ > 0.87

Low RQ < 0.82

Family

• Energy Balance vs. Substrate Balance• Metabolic Adaptation• Bariatric Surgery: Energy Metabolism in Animal

Studies• Bariatric Surgery: Energy Metabolism in Human

Studies

Weight Loss Physiology: Emphasis on Metabolic Adaptation

Extreme weight loss typically observed only after bariatric surgery

39.6%

Ciangura et al. Obesity 2010

3 6 12

-40

-30

-20

-10

0

Fat-free mass

Fat mass

Wei

gh

t L

oss

(kg

)

-20 kg

-30 kg

-37 kg

60%

40% 32% 30%

68%70%

Months following gastric bypass

60% loss of excess body weight

Buchwald et al. Am J Med. 2009

Loss of substantial lean mass considered detrimental

Does exercise attenuate fat-free mass loss and decrease metabolic

adaptation during weight loss?

Very-low calorie diets (including surgically-induced) result in rapid weight loss with substantial loss of FFM

Limited data suggests that exercise may preserve lean tissue during significant weight loss

QuestionWhat are the effects of large weight losses

(mediated through extreme exercise plus calorie restriction) on body composition and metabolic

adaptation?

Participant Characteristics

Baseline Week 6 bl to wk 6 Week 30 bl to

wk 30

Weight (kg) 145 (110-215) 130 (95-194) <.001 87 (60-138) <.001

BMI 48.7 (40.7-72.8) 43.6 (37.2-65.7) <.001 29.3 (22.2-46.8) <.001

Fat (%) 49 (36-57) 46 (33-54) NS 27 (13-43) <.001

FM (kg) 71 (52-122) 59 (42-104) <.001 24 (11-60) <.001

FFM (kg) 74 (50-104) 71 (48-98) NS 62 (47-84) <.001

Age: 36 years (20-56 y old)4 males, 7 females

Johannsen et al, in review, 2011

-100

-80

-60

-40

-20

0

Exce

ss w

eigh

t Los

s (%

)Intensive “Lifestyle Intervention”

Resulted in Conservation of Lean Mass

Week 6 Week 30

-19 ± 3 %

-73 ± 16 % -60

-50

-40

-30

-20

-10

0

Fat massFat-free mass

Wei

ght l

oss

(kg) -15 ± 5 kg

-58 ± 25 kg

80% 19%

81%

Week 30Week 6

Johannsen et al, in review, 2011

1500

2000

2500

3000

Resti

ng

meta

bo

lic r

ate

(kcal/d

ay)

Predicted RMR = 1,241 + 19.2 FFM + 1.8 FM – 9.8 age + 405 (male)

Metabolic Adaptation Occurs despite Lean Mass Preservation

Baseline Week 6 Week 30

p<0.001p=0.006

-244 ± 231 -504 ± 171

Johannsen et al, in review, 2011

The Metabolic Adaptation Occurred Early in the Intervention

40 60 80 1001000

2000

3000

4000Week 6

Week 30

Baseline regression line

Fat-free Mass (kg)

Res

tin

g m

etab

olic

rat

e (k

cal/d

ay)

Johannsen et al, in review, 2011

Determinants of the Metabolic Adaptation

CR

↓ leptin

↓ Gonadal axis ↓ SNS ↓ Thyroid hormones

↓ Energy metabolism = metabolic adaptation

Correlation between change in leptin and RMR residual in BL (7 mo) and GB (12 mo) participants

Johannsen et al, in review, 2011

Summary and Question

• An intensive lifestyle intervention (vigorous daily exercise and self-selected calorie restriction) results in extreme weight loss with preservation of lean mass

• Despite the preservation in lean mass, significant metabolic adaptation occurred

Does a similar “Metabolic Adaptation” happen after bariatric surgery?

• Energy Balance vs. Substrate Balance• Metabolic Adaptation• Bariatric Surgery: Energy Metabolism in Animal

Studies• Bariatric Surgery: Energy Metabolism in Human

Studies

Weight Loss Physiology: Emphasis on Metabolic Adaptation

RYGB induces substantial increase in EE in rats

RYGB rats have:

1) Decreased body weight

2) Increased total and resting oxygen consumption

3) Lower RQ

Stylopoulos, Obesity, 2009

RYGB-stimulated increases in EE are dependent on food ingestion

RYGB rats have:

• Higher resting V02 during ad lib refeeding and not during fasting

• Higher core body temperature

Stylopoulos, Obesity, 2009

Zheng, Am J Physiol Regul Integr Comp Physiol, 2009

RYGB rats have higher RER

Energy Balance:Emphasis on Metabolic Adaptation

with Bariatric Surgery

• Energy Balance vs. Substrate Balance• Metabolic Adaptation• Bariatric Surgery: Energy Metabolism in Animal

Studies• Bariatric Surgery: Energy Metabolism in Human

Studies

Decreased measured and predicted REE after RYGB in 20 obese women

Bobbioni-Harsch, JCEM, 2000

Increased fat oxidation after RYGB in 20 obese women

Bobbioni-Harsch, JCEM, 2000

Metabolic adaptation occurs with surgically-induced weight loss

0

500

1000

1500

2000

2500

RM

R (

kcal

/day

)

20

25

30

35

40

RM

R/F

FM

(kc

al/k

g)

Baseline Month 6

-396 ± 157 kcal/dp<0.001

-3.3 ± 3.6 kcal/kg FFMp<0.05

Fat-free mass (kg)

RM

R (

kcal

/day

)

Values of RMR relative to FFM at baseline (regression line) and month 6 post-surgery

Carrasco et al. Obes Surg. 2007

Ratio of REE/FFM was reduced from 33.4 to 30.1 kcal/kg (P<0.05)

RQ decreased from 0.86 to 082 (P<0.05)

Van Gemert, IJO, 2000

TEE and SMR are decreased after vertical banded gastroplasty (8 obese)

Lipid oxidation is increased after vertical banded gastroplasty in 8 obese subjects

Van Gemert, IJO, 2000

Conclusions from Human Energy Metabolism Data after Bariatric Surgery

(Bypass)

• Generally, gastric bypass seems to decrease the magnitude of the metabolic adaptation

• Gastric bypass seems to increase lipid oxidation

Question?What are the mechanisms underlying the favorable energy metabolism profile after

gastric bypass?