# Presentation: 380046

## The regulation of appetite

- Randy J. Seeley
- Department of Psychiatry
- University of Cincinnati

## Obesity Trends* Among U.S. AdultsBRFSS, 1985

- Source: Mokdad A H, et al.* J Am Med Assoc* 1999;282:16, 2001;286:10.

## Obesity Trends* Among U.S. AdultsBRFSS, 1986

- 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. AdultsBRFSS, 1987

- 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. AdultsBRFSS, 1988

- 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. AdultsBRFSS, 1989

- 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. AdultsBRFSS, 1990

- 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. AdultsBRFSS, 1991

- 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. AdultsBRFSS, 1992

- 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. AdultsBRFSS, 1993

- 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. AdultsBRFSS, 1994

- 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. AdultsBRFSS, 1995

- 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. AdultsBRFSS, 1996

- 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. AdultsBRFSS, 1997

- 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. AdultsBRFSS, 1998

- 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. AdultsBRFSS, 1999

- 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. AdultsBRFSS, 2000

- 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. AdultsBRFSS, 2001

- 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

**1985**

**2001**

## Humoral Regulation

**CNS Regulatory **
**Mechanisms**

**Adiposity Signals**

**Caloric Intake**

**Energy Balance**
**Stored Calories**

## Humoral Regulation

**CNS Regulatory **
**Mechanisms**

**Leptin, Insulin**

**Caloric Intake**

**Energy Balance**
**Stored 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**

**Leptin, Insulin**

**Caloric Intake**

**Energy Balance**
**Stored Calories**

## Leptin Receptor mRNA

## Melanocortin System

_**Ligands**_
- ACTH
- -MSH

## Melanocortin System

_**Ligands**_
- ACTH
- -MSH

_**Receptors**_
- MC1 (skin and hair)
- MC2 (adrenal)
- MC3 (hypothalamus)
- MC4 (CNS)

- Crawford et al., 1996

## Melanocortin System

_**Ligands**_
- ACTH
- -MSH
- AgRP

_**Receptors**_
- MC1 (skin and hair)
- MC2 (adrenal)
- MC3 (hypothalamus)
- MC4 (CNS)

## Negative Energy Balance

## AgRP

- Low Leptin, Insulin

**Negative**

**AgRP**

- Increased Food
- Intake and
- Weight Gain

**+**

**-**

**A “Simple” Model**

**POMC**

## Melanocortins

## Positive Energy Balance

## A “Simple” Model

- Low Leptin, Insulin

- High Leptin, Insulin

**Negative**

- POMC

**AgRP**

**Positive**

- AgRP

- Increased Food
- Intake and
- Weight Gain

- Decreased Food
- Intake and
- Weight Loss

**+**

**+**

**-**

**-**

**A “Simple” Model**

**POMC**

## Involuntary Overfeeding--POMC

## Involuntary Overfeeding

## POMC/-MSH/MC4

- Critical to the response to positive energy balance
- Integrates many inputs including feedback hormones such as leptin and insulin

## Melanocortin System

_**Ligands**_
- ACTH
- -MSH
- AgRP

_**Receptors**_
- MC1 (skin and hair)
- MC2 (adrenal)
- MC3 (hypothalamus)
- MC4 (CNS)

## Agouti Related Peptide (AgRP)

## Agouti Related Peptide (AgRP)

## Agouti Related Peptide (AgRP)

## Agouti Related Peptide (AgRP)

## Agouti Related Peptide (AgRP)

## Agouti Related Peptide (AgRP)

## Agouti Related Peptide (AgRP)

## 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

## Mechanisms of AgRP Action

## Mechanisms of AgRP Action

- b

## Mechanisms of AgRP Action

## Mechanisms of AgRP Action

## Model

**POMC**

**Increased Weight**

**Decreased Weight**

- Leptin/Insulin R

- Leptin/Insulin R

- MC4 Receptor

- Y1 or Y5 Receptor

**Leptin Insulin**

**WHITE**
**FAT**

**Arcuate**

**PVN**

**AgRP**

## Model

**AgRP**

**POMC**

**Increased Weight**

**Decreased Weight**

- MC4 Receptor

- Y1 or Y5 Receptor

**Leptin**

**WHITE**
**FAT**

**Arcuate**

**PVN**

**Leptin Insulin**

- Leptin/Insulin R

- Leptin/Insulin R

## Model

**POMC**

**Increased Weight**

**Decreased Weight**

- MC4 Receptor

- Y1 or Y5 Receptor

**Leptin**

**WHITE**
**FAT**

**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

**NPY**
**AgRP**

**Opioids**

- Arcuate

- LHA

**Food Intake**

## Orexin-A

- MCH

**NPY**
**AgRP**

**Opioids**

- Arcuate

- LHA

**Food Intake**

## AgRP and Opioids

## AgRP and Opioids

## Orexin-A

- MCH

**NPY**
**AgRP**

**Opioids**

- Arcuate

- LHA

**Food Intake**

## Slide 61

## Slide 62

## Orexin-A

- MCH

**NPY**
**AgRP**

**Opioids**

- Arcuate

- LHA

**Food Intake**

## Orexin and Opioids

## Orexin and Opioids

## Orexin and Opioids

## MCH and Opioids

## Orexin-A

- MCH

**NPY**
**AgRP**

**Opioids**

- Arcuate

- LHA

**Food Intake**

## AgRP & Low Fat Diet

**AgRP & Low Fat Diet**

## AgRP & High Fat Diet

**AgRP & High Fat Diet**

## Orexin-A

- MCH

**NPY**
**AgRP**

**Opioids**

- Arcuate

- LHA

**Food Intake**

## Orexin and Food Choice

## MCH and Food Choice

## AgRP, Orexin and MCH

## AgRP, Orexin and MCH

## AgRP, Orexin and MCH

## Orexin-A

- MCH

**NPY**
**AgRP**

**Opioids**

- Arcuate

- LHA

**Food Intake**