The role of gut hormones in energy homeostasis

• Main Author: McCullough, Katherine Anne
• Other Authors: Bloom, Steve ; Martin, Niamh
• Published: Imperial College London 2013
• Subjects: 612.3
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.693922

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.