The role of gut hormones in energy homeostasis
File(s)
Author(s)
McCullough, Katherine Anne
Type
Thesis
Abstract
Obesity is an increasing worldwide problem and yet current pharmaceutical treatments
only produce modest weight loss which is rarely sustained. Glucagon and glucagon-like
peptide-1 (GLP-1) are members of the secretin family of peptide hormones. Both
hormones are products of the preproglucagon gene, and are produced in the pancreas
and gut respectively. GLP-1 is an incretin hormone that enhances glucose-mediated
insulin release and inhibits glucagon secretion. In contrast, glucagon counter-regulates
insulin and stimulates gluconeogenesis in response to low circulating levels of glucose.
Despite their opposing roles in glucose homeostasis, both hormones reduce food intake
in rodents and humans. In addition, glucagon increases energy expenditure.
In this thesis, I have investigated for the first time the effects of co-administration of
glucagon and GLP-1 in energy balance. Co-administration of glucagon and GLP-1 in mice
significantly reduced food intake compared to controls and appeared to do so in an
additive manner. Glucagon and GLP-1 alone and in combination activated similar areas
within the brainstem and amygdala. Prolonged co-administration of novel, protease-
resistant analogues of glucagon and GLP-1 reduced body weight in diet-induced obese
(DIO) mice, despite similar food intake compared to saline controls. Furthermore,
glucagon and GLP-
1
analogue
co
-administration improved glucose homeostasis
compared to saline controls in DIO mice.
Intravenous infusion of glucagon alone and in combination with GLP-1 increased energy
expenditure in overweight humans whilst GLP-1 alone had no effect. This represents a
first in man study of the effects of co-administration of glucagon and GLP-1 on energy
homeostasis
. Sub-anorectic doses of glucagon and GLP-1 in combination reduced food
intake whilst alone they had no effect.
Co
-administration of both hormones ameliorated
the rise in plasma glucose seen following glucagon infusion alone, demonstrating an
additional benefit of GLP-1 and glucagon in combination.
These findings suggest that the combination of GLP-1 and glucagon represents an
exciting therapeutic target for development of a novel anti-obesity agent.
only produce modest weight loss which is rarely sustained. Glucagon and glucagon-like
peptide-1 (GLP-1) are members of the secretin family of peptide hormones. Both
hormones are products of the preproglucagon gene, and are produced in the pancreas
and gut respectively. GLP-1 is an incretin hormone that enhances glucose-mediated
insulin release and inhibits glucagon secretion. In contrast, glucagon counter-regulates
insulin and stimulates gluconeogenesis in response to low circulating levels of glucose.
Despite their opposing roles in glucose homeostasis, both hormones reduce food intake
in rodents and humans. In addition, glucagon increases energy expenditure.
In this thesis, I have investigated for the first time the effects of co-administration of
glucagon and GLP-1 in energy balance. Co-administration of glucagon and GLP-1 in mice
significantly reduced food intake compared to controls and appeared to do so in an
additive manner. Glucagon and GLP-1 alone and in combination activated similar areas
within the brainstem and amygdala. Prolonged co-administration of novel, protease-
resistant analogues of glucagon and GLP-1 reduced body weight in diet-induced obese
(DIO) mice, despite similar food intake compared to saline controls. Furthermore,
glucagon and GLP-
1
analogue
co
-administration improved glucose homeostasis
compared to saline controls in DIO mice.
Intravenous infusion of glucagon alone and in combination with GLP-1 increased energy
expenditure in overweight humans whilst GLP-1 alone had no effect. This represents a
first in man study of the effects of co-administration of glucagon and GLP-1 on energy
homeostasis
. Sub-anorectic doses of glucagon and GLP-1 in combination reduced food
intake whilst alone they had no effect.
Co
-administration of both hormones ameliorated
the rise in plasma glucose seen following glucagon infusion alone, demonstrating an
additional benefit of GLP-1 and glucagon in combination.
These findings suggest that the combination of GLP-1 and glucagon represents an
exciting therapeutic target for development of a novel anti-obesity agent.
Version
Open Access
Date Issued
2013-04
Date Awarded
2013-07
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Bloom, Steve
Martin, Niamh
Sponsor
Wellcome Trust (London, England)
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)