The regulation of appetite Randy J. Seeley Department of Psychiatry University of Cincinnati.

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.

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


Adiposity SignalsAdiposity SignalsCaloric IntakeCaloric Intake

Energy BalanceStored Calories


Humoral Regulation



Leptin, InsulinLeptin, InsulinCaloric IntakeCaloric Intake



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



Leptin, InsulinLeptin, InsulinCaloric IntakeCaloric Intake



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


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


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) * **


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

)


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


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)


0

1

2

3

4

5

p<0.05

ns

p<0.01


p<0.05

2-h

Fo

od

In

tak

e (

g)

b


0

1

2

3

4

5

p<0.05

ns

p<0.01


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

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 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

Orexin-A

MCH

NPYAgRP

Opioids

Arcuate

LHA

Food Intake

Food Choice

The regulation of appetite Randy J. Seeley Department of Psychiatry University of Cincinnati.

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