the role of glucagon and glp-1 in the regulation of appetite

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The role of glucagon and GLP-1 in the regulation of appetite. Katherine Simpson, Jennifer Parker, Niamh Martin, Ben Field, James Minnion, Mohammad Ghatei and Steve Bloom Dept. Investigative Medicine Academic Trainees Annual Event 5 th May 2011

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The role of glucagon and GLP-1 in the regulation of appetite. Katherine Simpson , Jennifer Parker, Niamh Martin, Ben Field, James Minnion , Mohammad Ghatei and Steve Bloom Dept. Investigative Medicine Academic Trainees Annual Event 5 th May 2011. Obesity and type 2 diabetes mellitus. - PowerPoint PPT Presentation

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Page 1: The  role of glucagon and  GLP-1  in the regulation of appetite

The role of glucagon and GLP-1 in the regulation of appetite.

Katherine Simpson, Jennifer Parker, Niamh Martin, Ben Field, James Minnion, Mohammad Ghatei and Steve Bloom

Dept. Investigative Medicine

Academic Trainees Annual Event5th May 2011

Page 2: The  role of glucagon and  GLP-1  in the regulation of appetite

Obesity and type 2 diabetes mellitus

25% of adults in England are obese (BMI>30 kg/m2)

(Health and Social Care Information Centre, 2010)

Page 3: The  role of glucagon and  GLP-1  in the regulation of appetite

Type 2 diabetes

• Insulin resistance and high circulating glucagon• GLP-1 analogues: exenatide, liraglutide

GLP-1 and glucagon co-agonism:reduced body weightimproved glucose profilemarginal reduction in food intakeincreased energy expenditure

(Pocai A et al Oct 2009 and Day JW et al Oct 2009)

Page 4: The  role of glucagon and  GLP-1  in the regulation of appetite

Gut-brain axis

Page 5: The  role of glucagon and  GLP-1  in the regulation of appetite

GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2 COOHNH

Glucagon GLP-1 IP-2IP-1

major proglucagon fragment

PANCREAS

IP-1 GLP-2GLP-1 IP-2

INTESTINE AND BRAIN

glicentin

oxyntomodulin

Proglucagon

PC2 PC1/3

GLP-2GRPP GlucagonGRPP

Pre-proglucagon processing

Page 6: The  role of glucagon and  GLP-1  in the regulation of appetite

GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2 COOHNH

Glucagon GLP-1 IP-2IP-1

major proglucagon fragment

PANCREAS

IP-1 GLP-2GLP-1 IP-2

INTESTINE AND BRAIN

glicentin

oxyntomodulin

Proglucagon

PC2 PC1/3

GLP-2GRPP GlucagonGRPP

Pre-proglucagon processing

Page 7: The  role of glucagon and  GLP-1  in the regulation of appetite

GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2 COOHNH

Glucagon GLP-1 IP-2IP-1

major proglucagon fragment

PANCREAS

IP-1 GLP-2GLP-1 IP-2

INTESTINE AND BRAIN

glicentin

oxyntomodulin

Proglucagon

PC2 PC1/3

GLP-2GRPP GlucagonGRPP

Pre-proglucagon processing

Page 8: The  role of glucagon and  GLP-1  in the regulation of appetite

• Peripherally administered:decreases food intake in animals

• Peripheral effects prevented by:Vagotomy or lesions in the AP and NTS

• Human studies: Peripheral administration decreases meal size

• c-fos peripheral GLP-1: AP, NTS, amygdalaand PVN

Glucagon and GLP-1

Page 9: The  role of glucagon and  GLP-1  in the regulation of appetite

Aims: to answer the following questions

(1) What is the effect of co-administration of glucagon and GLP-1 on food intake?

(2) Which CNS areas are responsible for this effect?

Page 10: The  role of glucagon and  GLP-1  in the regulation of appetite

Effects of glucagon on food intake

0-30 mins

Saline 3 10 30 100 300 500 7500.00.10.20.30.40.50.60.70.80.9

**

**

****

A

Food

inta

ke (g

)

Glucagon nmol/kg

30-90 mins

Saline 3 10 30 100 300 500 7500.00.10.20.30.40.50.60.70.80.91.0

B

Food

inta

ke (g

)

Glucagon nmol/kg

Page 11: The  role of glucagon and  GLP-1  in the regulation of appetite

Effects of GLP-1 on food intake

0-30 mins

Saline 3 10 30 50 100 300 6000.0

0.1

0.2

0.3

0.4

0.5

0.6

**

******

GLP-1 nmol/kg

Food

inta

ke (g

)

A30-90 mins

Saline 3 10 30 50 100 300 6000.00.10.20.30.40.50.60.70.8

**

B

Food

inta

ke (g

)GLP-1 nmol/kg

Page 12: The  role of glucagon and  GLP-1  in the regulation of appetite

‘Subthreshold doses’ of glucagon and GLP-1

0-30 mins

Saline 3 10 30 100 300 500 7500.00.10.20.30.40.50.60.70.80.9

**

**

****

A

Food

inta

ke (g

)

Glucagon nmol/kg

0-30 mins

Saline 3 10 30 50 100 300 6000.0

0.1

0.2

0.3

0.4

0.5

0.6

**

******

GLP-1 nmol/kg

Food

inta

ke (g

)

A

Page 13: The  role of glucagon and  GLP-1  in the regulation of appetite

Co-administration of glucagon and GLP-1

Page 14: The  role of glucagon and  GLP-1  in the regulation of appetite

Question 2:

Which CNS areas are responsible for these effects on food intake?

Page 15: The  role of glucagon and  GLP-1  in the regulation of appetite

AP NTSNTS

vagal afferents

Brainstem

Hypothalamus

Page 16: The  role of glucagon and  GLP-1  in the regulation of appetite

Glucagon 750 nmol/kg s/c

GLP-1 600 nmol/kg s/c

Saline s/c250 uM

250 uM

250 uM

Page 17: The  role of glucagon and  GLP-1  in the regulation of appetite

Dose response c-fos activation in the brainstem following glucagon administration

AP

Saline 30 100 300 500 7500

25

50

75

100

125

150

175

*

Glucagon nmol/kg

c-fli

cou

nts

NTS

Saline 30 100 300 500 7500

100

200

300

400

*

**

Glucagon nmol/kg

c-fli

cou

nts

0-30 mins

Saline 3 10 30 100 300 500 7500.00.10.20.30.40.50.60.70.80.9

**

**

****

A

Food

inta

ke (g

)

Glucagon nmol/kg

Page 18: The  role of glucagon and  GLP-1  in the regulation of appetite

Dose response c-fos activation in the brainstem following GLP-1 administration

AP

Saline 3 30 50 100 6000

50

100

150 ***

GLP-1 nmol/kg

c-fli

cou

nts

NTS

Saline 3 30 50 100 6000

100

200

300

400 *

GLP-1 nmol/kg

c-fli

cou

nts

0-30 mins

Saline 3 10 30 50 100 300 6000.0

0.1

0.2

0.3

0.4

0.5

0.6

**

******

GLP-1 nmol/kg

Food

inta

ke (g

)

A

Page 19: The  role of glucagon and  GLP-1  in the regulation of appetite

c-fos activation in the brainstem following co-administration of glucagon and GLP-1

Page 20: The  role of glucagon and  GLP-1  in the regulation of appetite

Central nuclei of the amygdala

saline GLP-1 GlucagonGLP-1/Glucagon0

100

200

300

400

500 #

**

c-fo

s im

mun

orea

ctiv

ity

• No significant differences in hypothalamus• Central nucleus of amygdala and reward

Page 21: The  role of glucagon and  GLP-1  in the regulation of appetite

Summary

Co-administration of glucagon and GLP-1:

– decreases food intake to a greater degree than either peptide alone

– Increases c-fos expression in similar brainstem areas: AP and NTS

Page 22: The  role of glucagon and  GLP-1  in the regulation of appetite

Future work(1)Food intake and CNS pathways:

- which neuronal population(2)Chronic effects of dual receptor agonism:

- chronic feeding studies in rodents(3) Effects in humans:

- glucagon/GLP-1 co-infusion and the effect on food intake

Page 23: The  role of glucagon and  GLP-1  in the regulation of appetite

(4) Glucose homeostasis:- glucose tolerance tests(5) Energy expenditure:- calorimetry

- BAT mass and UCP-1 mRNA

Page 24: The  role of glucagon and  GLP-1  in the regulation of appetite

AcknowledgementsProfessor Steve BloomDr Niamh Martin

Jenny Parker, Klara Hostomska, Jamie PlumerDr James Minnion, Dr Ben Field and Dr Tricia TanProfessor Mohammad Ghatei

Wellcome Trust