Post on 12-Jan-2016
The regulation of appetite
Randy J. Seeley
Department of Psychiatry
University of Cincinnati
Obesity Trends* Among U.S. AdultsBRFSS, 1985
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1986
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1987
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1988
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1989
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1990
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1991
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1992
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1993
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1994
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1995
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1996
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1997
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1998
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 1999
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 2000
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
Obesity Trends* Among U.S. AdultsBRFSS, 2001
Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.
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
1985
2001
Humoral Regulation
CNS Regulatory Mechanisms
CNS Regulatory Mechanisms
Adiposity SignalsAdiposity SignalsCaloric IntakeCaloric Intake
Energy BalanceStored Calories
Energy BalanceStored Calories
Humoral Regulation
CNS Regulatory Mechanisms
CNS Regulatory Mechanisms
Leptin, InsulinLeptin, InsulinCaloric IntakeCaloric Intake
Energy BalanceStored Calories
Energy BalanceStored Calories
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
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
Humoral Regulation
CNS Regulatory Mechanisms
CNS Regulatory Mechanisms
Leptin, InsulinLeptin, InsulinCaloric IntakeCaloric Intake
Energy BalanceStored Calories
Energy BalanceStored Calories
Leptin Receptor mRNA
Melanocortin System
LigandsACTH
-MSHPOMC
Melanocortin System
LigandsACTH
-MSH
ReceptorsMC1 (skin and hair)
MC2 (adrenal)
MC3 (hypothalamus)
MC4 (CNS)
POMC
Crawford et al., 1996
Melanocortin System
LigandsACTH
-MSH
AgRP
ReceptorsMC1 (skin and hair)
MC2 (adrenal)
MC3 (hypothalamus)
MC4 (CNS)
POMC
Negative Energy Balance
0 25 50 75 100 125 150 175 200200
250
300
350
ControlFood Restricted
Days
Bod
y W
eigh
t (g
)
Energy Balance
Low Leptin, Insulin
Negative
AgRP
Increased FoodIntake and
Weight Gain
+-
A “Simple” Model
POMC
Melanocortins
α-MSH AgRP
Fasting
Leptin Deficiency
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
)
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
Involuntary Overfeeding--POMC
Control Overfed
100
200
300
400
AR
C P
OM
C m
RN
A(%
of c
ontr
ol)
**
Involuntary Overfeeding
0
10
20
30
40 CSF 0.1 nm SHU
CONTROLS OVERFED
***
Food
Inta
ke (g
)
POMC/-MSH/MC4
Critical to the response to positive energy balance
Integrates many inputs including feedback hormones such as leptin and insulin
Melanocortin System
LigandsACTH
-MSH
AgRP
ReceptorsMC1 (skin and hair)
MC2 (adrenal)
MC3 (hypothalamus)
MC4 (CNS)
POMC
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) * **
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
)
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
)
***
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
)
***
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
)
***
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
)
***
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
)
***
Mechanisms of AgRP Action
Irreversible MC receptor antagonism?
-1 0 24 h 48 h
Food Off
2
Food On
AgRP MTII
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)
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)
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
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)
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)
Model
POMC
Increased Weight
Decreased Weight
Leptin/Insulin R
Leptin/Insulin R
MC4 Receptor
Y1 or Y5 Receptor
Leptin Insulin
WHITEFAT
Arcuate PVN
AgRP
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
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
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
Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
AgRP and Opioids
Sal + Sal Nalx + Sal Sal + AgRP Nalx+ AgRP0
1
2
3
4
5
6 **
Fo
od
Inta
ke (
g)
AgRP and Opioids
Sal + Sal Nalx + Sal Sal + AgRP Nalx+ AgRP0
1
2
3
4
5
6 **
Fo
od
Inta
ke (
g)
Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Orexin and Opioids
1-hr food intake (g)
0
1
2
3
4saline0.3 mg/kg Nal
saline Orexin-A
*
#
Orexin and Opioids
1-hr food intake (g)
0
1
2
3
4saline0.3 mg/kg Nal
saline Orexin-A
*
#
Orexin and Opioids
1-hr food intake (g)
0
1
2
3
4saline0.3 mg/kg Nal
saline Orexin-A
*
#
MCH and Opioids
Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Food Choice
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
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
Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Food Choice
Orexin and Food Choice
MCH and Food Choice
AgRP, Orexin and MCH
AgRP, Orexin and MCH
AgRP, Orexin and MCH
Orexin-A
MCH
NPYAgRP
Opioids
Arcuate
LHA
Food Intake
Food Choice