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
5th 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 weight
improved glucose profile
marginal reduction in food intake
increased energy expenditure
(Pocai A et al Oct 2009 and Day JW et al Oct 2009)
Gut-brain axis
Pre-proglucagon processing
Proglucagon
NH
GRPP
Glucagon
IP-1
IP-2
GLP-1
PC2
GLP-2
PC1/3
PANCREAS
INTESTINE AND BRAIN
glicentin
major proglucagon fragment
GRPP
Glucagon
COOH
IP-1
GLP-1
IP-2
GLP-2
GRPP
Glucagon
IP-1
oxyntomodulin
GLP-1
IP-2
GLP-2
Pre-proglucagon processing
Proglucagon
NH
GRPP
Glucagon
IP-1
IP-2
GLP-1
PC2
GLP-2
PC1/3
PANCREAS
INTESTINE AND BRAIN
glicentin
major proglucagon fragment
GRPP
Glucagon
COOH
IP-1
GLP-1
IP-2
GLP-2
GRPP
Glucagon
IP-1
oxyntomodulin
GLP-1
IP-2
GLP-2
Pre-proglucagon processing
Proglucagon
NH
GRPP
Glucagon
IP-1
IP-2
GLP-1
PC2
GLP-2
PC1/3
PANCREAS
INTESTINE AND BRAIN
glicentin
major proglucagon fragment
GRPP
Glucagon
COOH
IP-1
GLP-1
IP-2
GLP-2
GRPP
Glucagon
IP-1
oxyntomodulin
GLP-1
IP-2
GLP-2
Glucagon and GLP-1
• 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
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
A
B
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
**
30-90 mins
**
Food intake (g)
Food intake (g)
0-30 mins
**
**
Saline
3
10
30
100
300
Glucagon nmol/kg
500
750
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Saline
3
10
30
100
300
500
Glucagon nmol/kg
750
Effects of GLP-1 on food intake
B
0-30 mins
30-90 mins
0.6
0.8
0.5
0.7
0.4
0.3
**
**
0.2
**
0.1
**
0.0
Saline
3
10
30
50
100
GLP-1 nmol/kg
300
600
Food intake (g)
Food intake (g)
A
0.6
0.5
0.4
0.3
0.2
**
0.1
0.0
Saline
3
10
30
50
100
GLP-1 nmol/kg
300
600
‘Subthreshold doses’ of glucagon and GLP-1
A
A
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0-30 mins
0.6
**
**
Food intake (g)
Food intake (g)
0-30 mins
**
**
0.5
0.4
0.3
**
**
0.2
0.1
**
**
300
600
0.0
Saline
3
10
30
100
300
Glucagon nmol/kg
500
750
Saline
3
10
30
50
100
GLP-1 nmol/kg
Co-administration of glucagon and GLP-1
Question 2:
Which CNS areas are responsible for
these effects on food intake?
Hypothalamus
NTS
AP
NTS
vagal afferents
Brainstem
Saline s/c
250 uM
Glucagon 750 nmol/kg s/c
250 uM
GLP-1 600 nmol/kg s/c
250 uM
Dose response c-fos activation in the brainstem
following glucagon administration
A
Food intake (g)
0-30 mins
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
**
**
**
**
Saline
3
10
30
100
300
500
750
Glucagon nmol/kg
AP
NTS
400
175
*
125
100
75
50
c-fli counts
c-fli counts
150
**
300
*
200
100
25
0
0
Saline
30
100
300
500
Glucagon nmol/kg
750
Saline
30
100
300
500
Glucagon nmol/kg
750
Dose response c-fos activation in the brainstem
following GLP-1 administration
A
0-30 mins
Food intake (g)
0.6
0.5
0.4
0.3
**
**
0.2
0.1
**
**
300
600
0.0
Saline
3
10
30
50
100
GLP-1 nmol/kg
NTS
AP
150
400
**
c-fli counts
c-fli counts
*
100
50
*
300
200
100
0
0
Saline
3
30
50
100
GLP-1 nmol/kg
600
Saline
3
30
50
100
GLP-1 nmol/kg
600
c-fos activation in the brainstem following
co-administration of glucagon and GLP-1
• No significant differences in hypothalamus
• Central nucleus of amygdala and reward
Central nuclei of the amygdala
#
c-fos immunoreactivity
500
**
400
300
200
100
0
saline
GLP-1
GlucagonGLP-1/Glucagon
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
Acknowledgements
Professor Steve Bloom
Dr Niamh Martin
Jenny Parker, Klara Hostomska, Jamie Plumer
Dr James Minnion, Dr Ben Field and Dr Tricia Tan
Professor Mohammad Ghatei
Wellcome Trust