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Characterisation of the actions of leptin mimetics on hypothalamic neurons.

Reference	BB/I015663/1
Principal Investigator / Supervisor	Professor Michael Ashford
Co-Investigators / Co-Supervisors	Dr Anudharan Balendran
Institution	University of Dundee
Department	Cardiovascular and Diabetes Medicine
Funding type	Skills
Value (£)	91,932
Status	Completed
Type	Training Grants
Start date	03/10/2011
End date	02/10/2015
Duration	48 months

Abstract

unavailable

Summary

The hormone, leptin, plays an important role in the maintenance of whole body energy homeostasis in animals and humans, by acting in the brain to decrease feeding and increase energy expenditure. Age-related obesity and subsequent associated metabolic dysfunction significantly increase the risk of a number of chronic disease states, including diabetes, cardiovascular disease, certain cancers and Alzheimer's disease. However, leptin's anorexigenic effects are diminished in aged and obese individuals, despite increased plasma levels of the hormone. This phenomenon is known as leptin resistance and is associated with a combination of reduced transport of circulating leptin into the brain and a loss of direct leptin receptor mediated signalling in the hypothalamus. Leptin acts on specific populations of neurons in the hypothalamus, notably those of the arcuate nucleus, which is thought to be the key centre associated with leptin resistance. Leptin normally mediates alterations in the levels of specific neuropeptides, through changes in transcription, and in the release of these neuropeptides through modification of neuronal electrical activity and synaptic efficacy. These actions are lost or diminished through diet induced obesity and subsequent induction of leptin resistance. Recently, small molecule non-peptide leptin mimetics have been developed that are orally active and reduce food intake and body weight in leptin resistant obese rodents. The mechanism by which these molecules overcome leptin resistance is presently unknown, and this lack of knowledge is hindering the development of further studies. It is intended to examine leptin mimetic actions, in comparison to the native hormone, on previously well-defined neuronal cell models (e.g beta cells and hypothalamic cell lines) and diet-induced obese rodents, in order to determine the molecular basis for this effect. This will be achieved using a combination of biochemical signalling, neuropeptide expression and electrophysiological analyses. Thus, we will assess leptin and leptin-mimetic signalling mechanisms using leptin-sensitive and leptin-resistant cells and tissues. Our aim is to determine whether the mimetics utilise differential signalling cascades to by-pass leptin resistance, and if so define the mediators involved and also to establish if the presence of the mimetic recovers leptin sensitivity in previously leptin resistant cells.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Training Grant - Industrial Case

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