Developing a novel model to assess the specificity of appetite-reducing agents

Aims

This research aims to develop a single in vivo model for investigation of anti-obesity drugs, which could replace the multiple animal studies currently required to determine whether an agent is worth pursuing as an anti-obesity target.

Background

Obesity is a major public health issue. Over 1.5 billion adults are overweight worldwide, and these rates are increasing. Current anti-obesity agents are ineffective. There is, therefore, great interest in identifying appetite-regulating pathways as targets for anti-obesity drugs.

Energy homeostasis relies on complex systems that are currently impossible to reproduce in vitro. At present numerous in vivo experiments are required to determine if an agent that reduces appetite does so by targeting an appetite-regulating pathway, or whether the reduction in appetite is due to toxicity or other behavioural effects interfering with eating patterns.

Establishing a single experimental model to identify specific inhibitors of appetite will significantly reduce animal use across industry and academia, and could facilitate more rapid development of agents to treat obesity.

Research details and methods

Recognised physiological and non-physiological appetite inhibitors will be administered to Wistar rats implanted with telemetry devices. These telemetry devices, in combination with the Comprehensive Laboratory Animals monitoring System (CLAMS), will be used to measure physiological parameters, such as blood pressure, heart rate and body temperature.

The data generated will be analysed and a mathematical model will be devised that can robustly distinguish between physiological and non-physiological factors suppressing appetite.

Obesity is a major public health issue. Current anti-obesity agents are ineffective. There is thus great interest in identifying novel targets for anti-obesity drugs. Energy homeostasis relies on complex systems impossible to reproduce in vitro. In vivo studies allow the analysis of these systems. However, it is difficult to determine whether an agent that reduces appetite is doing so specifically. The rat is a widely used experimental model for the study of energy homeostasis. Many agents can reduce food intake in the rat following peripheral or central administration. However, it can be difficult to establish whether such an effect represents a specific effect on physiological appetite-regulating pathways, or whether it is due to toxic or other non-specific effects. Currently it is necessary to carry out a number of in vivo protocols to establish whether an agent is specifically influencing appetite, and thus whether it represents a good target for anti-obesity drug development. Non-specific appetite-inhibitors often result in side effects such as alterations in blood pressure and locomotor activity, and may result in disrupted eating patterns. However, there is currently no single protocol or model that can be used to determine whether an appetite inhibitor is specific.

This aim of this studentship is to develop a novel model to assess the specificity of appetite-inhibiting agents. The student will centrally and peripherally administer recognised physiological and non-physiological appetite inhibitors to animals implanted with telemetry devices, and will then use the Comprehensive Laboratory Animals Monitoring System to measure parameters including food intake, oxygen consumption, behaviour, blood pressure and body temperature. In collaboration with the mathematics department at Imperial, the student will use this data to establish a mathematical model that can robustly distinguish between physiological and non-physiological anorectic factors. Establishing a single experimental model to identify specific inhibitors of appetite will significantly reduce animal use across industry and academia, and will facilitate more rapid development of agents to treat obesity.

Alamshah A, McGavigan AK, Spreckley E, Kinsey-Jones JS, Amin A, Tough IR, O'Hara HC, Moolla A, Banks K, France R, Hyberg G, Norton M,Cheong W, Lehmann A, Bloom SR, Cox HM, Murphy KG (2016).  L-Arginine promotes gut hormone release and reduces food intake in rodents.  Diabetes, Obesity and Metabolism 18(5):508-518. doi: 10.1111/dom.12644

Kinsey-Jones JS, Alamshah A, McGavigan AK, Spreckley E, Banks K, Cereceda Monteoliva N, Norton M, Bewick GA, Murphy KG (2015).  GPRC6a is not required for the effects of a high-protein diet on body weight in mice.  Obesity 23(6):1194-200. doi: 10.1002/oby.21083

Spreckley E, Murphy KG (2015).  The L-cell in nutritional sensing and the regulation of appetite.  Frontiers in Nutrition 2:23. doi: 10.3389/fnut.2015.00023

McGavigan AK, O'Hara HC, Amin A, Kinsey-Jones J, Spreckley E, Alamshah A, Agahi A, Banks K, France R, Hyberg G, Wong C, Bewick GA, Gardiner JV, Lehmann A, Martin NM, Ghatei MA, Bloom SR, Murphy KG (2014).  L-cysteine suppresses ghrelin and reduces appetite in rodents and humans.  International Journal of Obesity 39(3):447-55. doi: 10.1038/ijo.2014.172

Back to top
PhD Studentship

Status:

Closed

Principal investigator

Dr Kevin Murphy

Institution

Imperial College London

Grant reference number

NC/K500379/1

Award date:

Oct 2012 - Sep 2015

Grant amount

£90,000