MISS 2011 Physiology of Weight Regulation: Implications for Bariatric Surgery Lee M. Kaplan, MD, PhD Gastrointestinal Unit MGH Weight Center [email protected] February 24, 2011
Jan 17, 2016
MISS 2011
Physiology of Weight Regulation: Implications for Bariatric Surgery
Lee M. Kaplan, MD, PhDGastrointestinal Unit
MGH Weight Center
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)
Stylopoulos et al., 2009
0
20
40
60
80
100N
utrie
nt A
bsor
ptio
n (
%)
Before RYGB
RYGB Does Not Alter Caloric Absorption
After RYGB
Stool Calorimetry
Stylopoulos et al., 2009
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
*
#
*
**
Time after start of meal (min)
0 20 40 60 80 100P
YY
(p
g/m
l)
0
50
100
150
200
250
300RYGBShamLean
5 min mixed meal
-10
*
**
**
**
Time after start of meal (min)
0 20 40 60 80 100P
YY
(p
g/m
l)
0
50
100
150
200
250
300RYGBShamLean
5 min mixed meal
-10
*
**
**
**
Time after start of meal (min)
0 20 40 60 80 100
GIP
(pg
/ml)
0
100
200
300
400
500
6005 min mixed meal
-10
Time after start of meal (min)
0 20 40 60 80 100
Act
ive
Am
ylin
(p
g/m
l)
0
50
100
150
200
2505 min mixed meal
-10
**
Time after start of meal (min)
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
Stylopoulos et al., 2009
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
** ***
** ***
Stylopoulos et al., 2009
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
Body Mass Index (kg/mBody Mass Index (kg/m22))
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
ExpenditureExpenditure
RYGB: Resolution of the “Overfed” StateRYGB: Resolution of the “Overfed” State
3030 3535 4040 4545
Body Mass Index (kg/mBody Mass Index (kg/m22))
kcal
/ 24
hou
rskc
al /
24 h
ours
20002000
25002500
30003000Post-op Post-op Energy Energy IntakeIntake
Post-op Post-op Energy Energy
ExpenditureExpenditure
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