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

Obesity and type 2 diabetes mellitus

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

(Health and Social Care Information Centre, 2010)

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)

Gut-brain axis

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

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

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

• 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

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?

Effects of glucagon on food intake

0-30 mins

Saline 3 10 30 100 300 500 7500.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

**

**

****

A

Fo

od

in

take

(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

Fo

od

in

take

(g

)

Glucagon nmol/kg

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

Fo

od

in

take

(g

)

A30-90 mins

Saline 3 10 30 50 100 300 6000.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

**

B

Fo

od

in

take

(g

)GLP-1 nmol/kg

‘Subthreshold doses’ of glucagon and GLP-1

0-30 mins

Saline 3 10 30 100 300 500 7500.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

**

**

****

A

Fo

od

in

take

(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

Fo

od

in

take

(g

)

A

Co-administration of glucagon and GLP-1

Question 2:

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

AP NTSNTS

vagal afferents

Brainstem

Hypothalamus

Glucagon 750 nmol/kg s/c

GLP-1 600 nmol/kg s/c

Saline s/c250 uM

250 uM

250 uM

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

co

un

ts

NTS

Saline 30 100 300 500 7500

100

200

300

400

*

**

Glucagon nmol/kg

c-fli

co

un

ts

0-30 mins

Saline 3 10 30 100 300 500 7500.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

**

**

****

A

Fo

od

in

take

(g

)

Glucagon nmol/kg

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

co

un

ts

NTS

Saline 3 30 50 100 6000

100

200

300

400*

GLP-1 nmol/kg

c-fli

co

un

ts

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

Fo

od

in

take

(g

)

A

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

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

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

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

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

- BAT mass and UCP-1 mRNA

AcknowledgementsProfessor Steve BloomDr Niamh Martin

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

Wellcome Trust