Ghrelin and the long-term regulation of energy balance

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Obesity is the major cause of early death in the UK and the number of obese individuals is rising dramatically. As yet, there are no effective treatments. The factors which regulate appetite and body weight are largely unknown.

The recently identified hormone, ghrelin, is the only hormone which when given into the blood increases appetite. However, the long-term effects of ghrelin are unknown. I propose that ghrelin is a long-term regulator of appetite and therefore body weight. Therefore I will examine the effects of long-term increases in ghrelin and long-term ghrelin deficiency on appetite and weight in rodents.

I will examine the effects of long-term increases in circulating ghrelin, either by giving ghrelin continuously for 14 days using a minipump or by incorporating the ghrelin gene into muscle cells which then release ghrelin into the circulation for up to 6 months. I will examine the effects of reducing circulating ghrelin in adult mice by removing ghrelin-producing cells.

These studies aim to determine if ghrelin plays an important role in controlling appetite and body weight. Therapies which prevent the action of ghrelin may then prove to be effective treatments for obesity.

Technical Summary

Obesity is the primary cause of premature death in the UK and its prevalence is rising dramatically. Identification of the mechanisms regulating energy balance and thus adiposity is essential for development of effective treatments. Although the central neuropeptide pathways modulating appetite have been extensively studied, the peripheral regulators of appetite are only now being determined. Ghrelin, a product of gastric endocrine cells, is the only circulating hormone which potently stimulates appetite when given acutely and at physiological levels. Its actions appear to be the opposite of those of leptin.

There is now evidence that circulating ghrelin may play an important role in long-term appetite regulation and therefore body weight control. High circulating ghrelin is found in obesity associated with Prader-Willi syndrome and food intake fails to suppress circulating active ghrelin in obese individuals. Conversely, gastric bypass reduces circulating ghrelin and may prevent weight gain. I propose that peripheral ghrelin is an important long-term regulator of energy intake and expenditure. Therefore I will examine

A) The effects of chronically elevated circulating ghrelin, produced either by minipump infusion or by adeno-associated virus-mediated preproghrelin over expression, on energy intake, expenditure and hypothalamic neuropeptide gene expression.

B) The effects of chronic ghrelin deficiency produced in adult transgenic mice on energy intake, energy expenditure and hypothalamic neuropeptide gene expression.

These studies will establish whether ghrelin is an important physiological regulator of body weight and may provide the physiological basis for therapeutic interventions in the treatment of obesity.

Publications

10 25 50
 
Description Rockefeller University 
Organisation Rockefeller University
Country United States 
Sector Academic/University 
PI Contribution Overseas training period in Dept of Molecular Genetics at Rockefeller University. Commenced projects using neuronal tracers to identify common neurons in output to metabolically active peripheral organs
Collaborator Contribution Intellectual contributions and provision of materials and animals
Impact Two manuscripts in preparation and further research underway
 
Description School visit -NYC 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Hosting high school students for lab project Presenting to high school students about research project

High school students gained entry to university for undergraduate science studies
Year(s) Of Engagement Activity 2007,2009