the regulation of appetite randy j. seeley department of psychiatry university of cincinnati
TRANSCRIPT
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The regulation of appetite
Randy J. Seeley
Department of Psychiatry
University of Cincinnati
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Obesity Trends* Among U.S. AdultsBRFSS, 1985
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1986
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1987
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1988
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1989
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1990
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1991
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1992
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1993
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1994
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1995
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1996
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1997
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1998
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 1999
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 2000
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Obesity Trends* Among U.S. AdultsBRFSS, 2001
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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Accuracy!
Energy Intake in a Year
912500 calories
Gaining 1 pound (0.45 kg) in a year
4050 calories
Error of 0.4%
Or
11 calories/day
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1985
2001
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Humoral Regulation
CNS Regulatory Mechanisms
CNS Regulatory Mechanisms
Adiposity SignalsAdiposity SignalsCaloric IntakeCaloric Intake
Energy BalanceStored Calories
Energy BalanceStored Calories
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Humoral Regulation
CNS Regulatory Mechanisms
CNS Regulatory Mechanisms
Leptin, InsulinLeptin, InsulinCaloric IntakeCaloric Intake
Energy BalanceStored Calories
Energy BalanceStored Calories
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Alphabet Soup• Leptin• Insulin• Amylin• NPY• CRH• UCN• UCN II• Galanin• Neurotensin• CART• Oxytocin -MSH
• Corticosterone• Serotonin• Dopamine• MCH• Orexins• Histamine• Ghrelin• GLP-1• GLP-2• AgRP• Beacon• Cannabinoids
• TNFα• Beta-Endorphin• Dynorphin• BDNF• PYY• IL-6• IL-1• IL-1RA• Norepinephrine• Amino Acids• PRL-RL• GAL-LP
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Partial List of Systems Involved in Hypothalamic Control of Food Intake
• Leptin• Insulin• Amylin• NPY• CRH• Urocortin• Urocortin II• Galanin• Neurotensin• CART• Oxytocin -MSH
• Corticosterone• Serotonin• Dopamine• MCH• Orexins• Histamine• Ghrelin• GLP-1• GLP-2• AgRP• Beacon• Cannabinoids
• TNFalpha• Beta-Endorphin• Dynorphin• IL-6• IL-1• IL-1RA• Norepinephrine• Amino Acids• PRL-RL
“Abandon all hope, ye who enter here.”
Dante’s Inferno
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Humoral Regulation
CNS Regulatory Mechanisms
CNS Regulatory Mechanisms
Leptin, InsulinLeptin, InsulinCaloric IntakeCaloric Intake
Energy BalanceStored Calories
Energy BalanceStored Calories
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Leptin Receptor mRNA
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Melanocortin System
LigandsACTH
-MSHPOMC
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Melanocortin System
LigandsACTH
-MSH
ReceptorsMC1 (skin and hair)
MC2 (adrenal)
MC3 (hypothalamus)
MC4 (CNS)
POMC
Crawford et al., 1996
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Melanocortin System
LigandsACTH
-MSH
AgRP
ReceptorsMC1 (skin and hair)
MC2 (adrenal)
MC3 (hypothalamus)
MC4 (CNS)
POMC
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Negative Energy Balance
0 25 50 75 100 125 150 175 200200
250
300
350
ControlFood Restricted
Days
Bod
y W
eigh
t (g
)
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Energy Balance
Low Leptin, Insulin
Negative
AgRP
Increased FoodIntake and
Weight Gain
+-
A “Simple” Model
POMC
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Melanocortins
α-MSH AgRP
Fasting
Leptin Deficiency
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Positive Energy Balance
0 25 50 75 100 125 150 175 200200
250
300
350 Overfed
ControlFood Restricted
Days
Bod
y W
eigh
t (g
)
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Energy Balance
Low Leptin, Insulin High Leptin, Insulin
Negative
POMC AgRP
Positive
AgRP
Increased FoodIntake and
Weight Gain
Decreased FoodIntake and
Weight Loss
+ +- -
A “Simple” Model
POMC
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Involuntary Overfeeding--POMC
Control Overfed
100
200
300
400
AR
C P
OM
C m
RN
A(%
of c
ontr
ol)
**
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Involuntary Overfeeding
0
10
20
30
40 CSF 0.1 nm SHU
CONTROLS OVERFED
***
Food
Inta
ke (g
)
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POMC/-MSH/MC4
Critical to the response to positive energy balance
Integrates many inputs including feedback hormones such as leptin and insulin
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Melanocortin System
LigandsACTH
-MSH
AgRP
ReceptorsMC1 (skin and hair)
MC2 (adrenal)
MC3 (hypothalamus)
MC4 (CNS)
POMC
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Agouti Related Peptide (AgRP)
0 0.001 0.005 0.01 0.1 1 50.0
2.5
5.0
7.5
10.0
Dose (nmol)
2-h
Food
Inta
ke (
g) * **
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Agouti Related Peptide (AgRP)
Saline 0.001 0.005 0.01 0.1 1.0 5.00
5
10
15
20
25
30
35
40
45
50
* ** *
* p<0.001
Dose (nmoles)
24 H
our
Food
Inta
ke (g
)
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Agouti Related Peptide (AgRP)
24 48 72 120 1440
10
20
30
40
50
60
70
Saline1nm AgRP
***
*
***
***
Hours
24-h
Fo
od
In
take
(g
)
***
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Agouti Related Peptide (AgRP)
24 48 72 120 1440
10
20
30
40
50
60
70
Saline1nm AgRP
***
*
***
***
Hours
24-h
Fo
od
In
take
(g
)
***
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Agouti Related Peptide (AgRP)
24 48 72 120 1440
10
20
30
40
50
60
70
Saline1nm AgRP
***
*
***
***
Hours
24-h
Fo
od
In
take
(g
)
***
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Agouti Related Peptide (AgRP)
24 48 72 120 1440
10
20
30
40
50
60
70
Saline1nm AgRP
***
*
***
***
Hours
24-h
Fo
od
In
take
(g
)
***
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Agouti Related Peptide (AgRP)
24 48 72 120 1440
10
20
30
40
50
60
70
Saline1nm AgRP
***
*
***
***
Hours
24-h
Fo
od
In
take
(g
)
***
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Mechanisms of AgRP Action
Irreversible MC receptor antagonism?
-1 0 24 h 48 h
Food Off
2
Food On
AgRP MTII
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Mechanisms of AgRP Action
0
1
2
3
4
5
6
7
8
9
Saline Saline AgRP AgRP + + + + Saline MTII Saline MTII
p<0.01
ns ns
p<0.001
2-h
Fo
od
In
tak
e (
g)
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Mechanisms of AgRP Action
0
1
2
3
4
5
6
7
8
9
Saline Saline AgRP AgRP + + + + Saline MTII Saline MTII
p<0.01
ns ns
p<0.001
2-h
Fo
od
In
tak
e (
g)
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Mechanisms of AgRP Action
0
1
2
3
4
5
p<0.05
ns
p<0.01
Saline Saline AgRP AgRP + + + + Saline MTII Saline MTII
p<0.05
2-h
Fo
od
In
tak
e (
g)
b
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Mechanisms of AgRP Action
0
1
2
3
4
5
p<0.05
ns
p<0.01
Saline Saline AgRP AgRP + + + + Saline MTII Saline MTII
p<0.05
2-h
Fo
od
In
tak
e (
g)
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Mechanisms of AgRP Action
0
1
2
3
4
5
p<0.05
ns
p<0.01
Saline Saline AgRP AgRP + + + + Saline MTII Saline MTII
p<0.05
2-h
Fo
od
In
tak
e (
g)
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Model
POMC
Increased Weight
Decreased Weight
Leptin/Insulin R
Leptin/Insulin R
MC4 Receptor
Y1 or Y5 Receptor
Leptin Insulin
WHITEFAT
Arcuate PVN
AgRP
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Model
AgRP
POMC
Increased Weight
Decreased Weight
MC4 Receptor
Y1 or Y5 Receptor
Leptin WHITEFAT
Arcuate PVN
Leptin Insulin
Leptin/Insulin R
Leptin/Insulin R
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Model
POMC
Increased Weight
Decreased Weight
MC4 Receptor
Y1 or Y5 Receptor
Leptin WHITEFAT
Arcuate PVN
AgRP
Leptin Insulin
Leptin/Insulin R
Leptin/Insulin R
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Partial List of Systems Involved in Hypothalamic Control of Food Intake
• Leptin• Insulin• Amylin• NPY• CRH• CHRL• Urocortin• Urocortin II• Galanin• Neurotensin• CART• Oxytocin -MSH
• Corticosterone• Serotonin• Dopamine• MCH• Orexins• Histamine• Ghrelin• GLP-1• GLP-2• AgRP• Beacon• Cannabinoids• PRL-RL
• TNFalpha• Beta-Endorphin• Dynorphin• BDNF• IL-6• IL-1• IL-1RA• NA-OMI• Norepinephrine• Amino Acids
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Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
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Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
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AgRP and Opioids
Sal + Sal Nalx + Sal Sal + AgRP Nalx+ AgRP0
1
2
3
4
5
6 **
Fo
od
Inta
ke (
g)
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AgRP and Opioids
Sal + Sal Nalx + Sal Sal + AgRP Nalx+ AgRP0
1
2
3
4
5
6 **
Fo
od
Inta
ke (
g)
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Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
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Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
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Orexin and Opioids
1-hr food intake (g)
0
1
2
3
4saline0.3 mg/kg Nal
saline Orexin-A
*
#
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Orexin and Opioids
1-hr food intake (g)
0
1
2
3
4saline0.3 mg/kg Nal
saline Orexin-A
*
#
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Orexin and Opioids
1-hr food intake (g)
0
1
2
3
4saline0.3 mg/kg Nal
saline Orexin-A
*
#
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MCH and Opioids
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Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Food Choice
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0 1 2 3 40
1
2
3
4
5
6
7
8
Saline
AgRP
Hours
Inta
ke o
f L
ow
Fat
Die
t (k
cals
)
AgRP & Low Fat Diet
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0 1 2 3 40
10
20
30
40
50
60
70
Saline
AgRP
***
***
***
Hours
Inta
ke o
f H
igh
Fat
Die
t (k
cals
)
AgRP & High Fat Diet
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Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Food Choice
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Orexin and Food Choice
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MCH and Food Choice
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AgRP, Orexin and MCH
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AgRP, Orexin and MCH
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AgRP, Orexin and MCH
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Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Food Choice
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