MISS 2011 Physiology of Weight Regulation: Implications for Bariatric Surgery Lee M. Kaplan, MD, PhD...

MISS 2011

Physiology of Weight Regulation: Implications for Bariatric Surgery

Lee M. Kaplan, MD, PhDGastrointestinal Unit

MGH Weight Center

[email protected]

February 24, 2011

Obesity

Historical view• Lifestyle choice

• Characterological flaw (willpower, psychology)

Current perspective

• Complex physiology

• Epidemic from changes in modern environment

• Widely recognized as a disease

• Huge burden of associated illness – a cause of more than 60 medical disorders (incl. 12 types of cancer)

• Devastating effect on efficacy and quality of life

Feedback Regulation of Energy MetabolismFeedback Regulation of Energy Metabolism

AdiposeAdiposetissuetissue

AdipocytokinesAdipocytokines(esp. leptin)(esp. leptin)

CNS

Food intakeFood intakeNutrient handlingNutrient handling

Energy expenditureEnergy expenditure

LiverLiverMuscleMuscleBoneBone

Metabolic Metabolic needsneeds

Sensory OrgansSensory OrgansGI TractGI Tract

EnvironmentalEnvironmentalsensingsensing

EnergyEnergystoresstores

Interaction of Weight and Satiety Pathways

Defense of a Body Fat “Set Point”

0 25 50 75 100 125 150 175 200200

250

300

350 Overfed

ControlFood Restricted

Days

Bod

y W

eigh

t (g

)Forced dietary manipulation Ad libitum fed

Adapted from S. Woods

Obesity: A Failure of Weight Regulation

Genetics

Developmentalprogramming

EnvironmentAdipose tissue

LeptinLeptin

HT

Food intakeEnergy expenditure

Nutrient handling

CortexCortex

GI TractGI Tract

Defense of a Body Fat “Set Point”Defense of a Body Fat “Set Point”

2020 2525 3030 3535

Body Mass Index (kg/mBody Mass Index (kg/m22))

kcal

/ 2

4 ho

urs

kcal

/ 2

4 ho

urs

20002000

25002500

30003000

EnergyEnergyExpenditureExpenditure

EnergyEnergyIntakeIntake

(–) Energy Balance(–) Energy Balance(+) Energy Balance(+) Energy Balance

Adapted from Weigle, 1995Adapted from Weigle, 1995

Weight Loss Surgery

Combination

Roux-en-Y Gastric Bypass

Adjustable Gastric Banding

Vertical SleeveGastrectomy

Gastric

Why is gastric bypass so effective?

Mechanisms of Bariatric Surgery

Restricted food intake

Malabsorption

Classical model:

Mechanical

Altered GI signals to brain

• Endocrine• Neuronal

Altered GI signals to other tissues (pancreas, liver)

Current model:

Physiological

Signaling Changes after Gastric Bypass

Distal signals• Exposure of distal small

bowel to undigested food• Elevated PYY

• Elevated GLP-1

Proximal signals• Proximal gastric distension

• Diminished ghrelin

• Distal gastric exclusion

• Duodenal exclusion• Altered portal venous sensing

Roux-en-Y Gastric Bypass in Mice

Roux: 10-15% of totalintestinal length

BP: 10-15% of totalintestinal length

Common : >70% of totalintestinal length

GP

DS

RYGB Induces Weight Loss in Mice

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10 11

Time after Surgery (Weeks)

% P

reo

per

ativ

e B

od

y W

eig

ht

Sham

RYGB

Stylopoulos et al., 2009

Potential Physiologic Mechanisms

Appetitive drive/food intake

Nutrient absorption

Energy expenditure

0

2000

4000

6000

8000

10000

12000

14000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Time (Weeks)

RYGB

Sham

RYGB Reduces Nutrient Intake

Cu

mu

lati

ve F

oo

d In

take

(k

cal)


0

20

40

60

80

100N

utrie

nt A

bsor

ptio

n (

%)

Before RYGB

RYGB Does Not Alter Caloric Absorption

After RYGB

Stool Calorimetry


RYGB Alters Diet Preferences

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Sham RYGB

% D

aily

Co

nsu

mp

tion

LFDHFD

GI Endocrine Responses to RYGB

Time after start of meal (min)

0 20 40 60 80 100

Act

ive

GL

P-1

(pg

/ml)

0

50

100

150

200

250

300RYGB Sham Lean

5 min mixed meal

-10

*

#

*

**


0 20 40 60 80 100P

YY

(p

g/m

l)

0

50

100

150

200

250

300RYGBShamLean

5 min mixed meal

-10

*

**

**

**


0 20 40 60 80 100P

YY

(p

g/m

l)

0

50

100

150

200

250

300RYGBShamLean

5 min mixed meal

-10

*

**

**

**


0 20 40 60 80 100

GIP

(pg

/ml)

0

100

200

300

400

500

6005 min mixed meal

-10


0 20 40 60 80 100

Act

ive

Am

ylin

(p

g/m

l)

0

50

100

150

200

2505 min mixed meal

-10

**


0 20 40 60 80 100

Acy

late

d G

hre

lin (

pg

/ml)

0

50

100

150

200

250

300 RYGBShamLean

5 min mixed meal

-10

**

GLP-1GLP-1 PYY Amylin

Ghrelin GIP

Shin et al., 2010

GLP-1 Signaling Is Not Required for Improved Insulin Sensitivity after RYGB

0

1

2

3

4

5

Vehicle Exe 9-39

RYGBSham

HO

MA

-IR

Munoz and Kaplan, unpublished

GLP-1 Signaling Required for Improved OGT

0

20

40

60

80

100

120

SO RYGB SO + Ex9 RYGB + Ex9

Ora

l GT

T G

luco

se A

UC

C57BL/6 DIO Mice6 week GLP-1 receptor antagonism

Munoz and Kaplan, unpublished

GBP Increases Energy Expenditure

50

60

70

80

90

100

110

0 1 2 3

Time after GBP (months)

Per

cent

age

of In

itial

Wei

ght

Sham

Pair Feeding

GBP


RYGB Increases Energy Expenditure

400

500

600

700

800

900

1000

1100

1200

400

450

500

550

600

650

700

750

800

850

900

TE

E -

VO

2 (m

l/hr/

kg.7

5 )

RE

E -

VO

2 (m

l/hr/

kg.7

5 )ShamRYGB Weight-matched

* p<0.05** p<0.001

** ***

** ***


Surgery is the Un-DietSurgery is the Un-Diet

DietDiet SurgerySurgery

AppetiteAppetite

HungerHunger

SatietySatiety

Reward-based eatingReward-based eating

Energy expenditureEnergy expenditure

Stress responseStress response

AppetiteEnergy balance

Glucose metabolism

RYGB - Physiologic Model

Central Mechanisms

Gastric Bypass

Guthormones

Efferentneurons Improved Diabetes

Weight Loss

LiverPancreas

Altering the “Set Point” with Gastric SurgeryAltering the “Set Point” with Gastric Surgery

3030 3535 4040 4545


kcal

/ 24

hou

rskc

al /

24 h

ours

20002000

25002500

30003000

Baseline Baseline Energy Energy

ExpenditureExpenditure

Baseline Baseline Energy Energy IntakeIntake

Post-op Post-op Energy Energy IntakeIntake

Post-op Post-op Energy Energy


RYGB: Resolution of the “Overfed” StateRYGB: Resolution of the “Overfed” State

3030 3535 4040 4545


kcal

/ 24

hou

rskc

al /

24 h

ours

20002000

25002500

30003000Post-op Post-op Energy Energy IntakeIntake

Post-op Post-op Energy Energy


Overfed stateOverfed state

Set Point and Weight RegainF

at M

ass

Se

t Po

int

Time (years)

Aging and environmental influences

SurgeryEnvironmental influencesand aging

Summary

• RYGB works by influencing the normal physiological regulation of energy balance and glucose homeostasis

• alters appetitive drives and decreases food intake

• Increases diet-induced thermogenesis

• There are multiple types of surgery with distinct and overlapping mechanisms of action

• RYGB influences glucose homeostasis through decreased food intake, decreased body fat and direct effects independent of the other two

• Alters regulation of both insulin sensitivity and pancreatic -cell function

• Effects of gastric banding mediated by weight loss alone

Summary

• There are GI anatomic correlates of outcome• stomach for food intake regulation

• small bowel for regulation of energy expenditure, glucose homeostasis

• GLP-1 and MC4R have essential roles in the signaling mechanisms underlying response to surgery

• GLP-1 role appears limited to glucose homeostasis

• Roles of PYY, CCK, ghrelin, amylin, glucagon, OXM not clear

• The widespread physiological effects of surgery suggest many undiscovered molecular mechanisms

SmallAnimalMetabolicSurgery

Core Resource

PROGRAM ANNOUNCEMENT

The Physiology of Metabolic Surgery:

Lessons from Animal Models

The Second International Workshop on Animal Models of Weight Loss Surgery

April 3-5, 2011 ● Boston, Massachusetts

Register at: www . amw11 . orgHARVARDMEDICAL SCHOOL

BOSTON NUTRITION / BOSTON NUTRITION / OBESITYOBESITYRESEARCH CENTERRESEARCH CENTER

SmallAnimalMetabolicSurgery

Core Resource

The Physiology of Metabolic Surgery:Lessons from Animal Models

April 3-5, 2011 ● Boston, Massachusetts

Register at: www . amw11 . org

ProgramSurgical overview

Physiological effects of weight loss surgery

Effects on food intake and appetitive behavior

Effects on energy expenditure

Effects on glucose homeostasis

GI mechanisms

CNS mechanisms

Medical device solutions and physiology

Genetic contributions and systems biology

Live surgical demonstrations

MISS 2011 Physiology of Weight Regulation: Implications for Bariatric Surgery Lee M. Kaplan, MD, PhD...

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