Characterization of leptin actions on hypothalamic neurons in models of leptin resistance

Supervisor: Professor Michael Ashford and Dr Maria Strömstedt

Biomedical Research Institute, University of Dundee.

Project background

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. 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 hypothalamic neurons and normally alters the levels of various neuropeptides and their release 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.  Methods of enhancing leptin action have been developed that reduce food intake and body weight in leptin resistant obese rodents, although the mechanism(s) of action underlying this outcome is unknown. It is intended to examine how this intervention alters hypothalamic neuron function, in comparison to the native hormone, using previously well-defined neuronal cell models and diet-induced obese rodents, in order to determine the molecular basis for this effect.

The project will provide training in cell culture, cell signalling, imaging and electrophysiology measurements. As part of the Biomedical Research Institute at the University of Dundee the student will benefit from and be expected to take part in the regular seminars and lectures as well as in the journal club for PhDs in all disciplines in the BRI.

How to apply 

Applications are invited for a BBSRC CASE studentship from suitably qualified students, who have, or who expect to attain at least a 2i degree classification in physiology, pharmacology, biochemistry, neuroscience or related disciplines. This studentship is available for a period of four years from 1st October 2011. 

The student is expected to spend at least 6 months in Mölndal working on this project as part of a larger multi-disciplinary drug discovery team.

Applicants should send their applications, including CV, the names, addresses and telephone numbers of 2 referees and a covering letter, to Mrs Lisa
Thompson, Institute Secretary, by email to Lisa Thompson or by 
mail to: Biomedical Research Institute, 
Level 5
 Ninewells Hospital and Medical School,
 Dundee
 DD1 9SY,
UK. Informal enquiries to Professor Mike Ashford, Tel: +44 (0) 1382 632497

Biomedical Research Institute (Dundee)

The Biomedical Research Institute is an autonomous research centre within the College of Medicine, Dentistry and Nursing at the University of Dundee. It creates an environment that brings together molecular and cell biologists with clinical scientists to lead research programmes that have a direct application to the study of common complex human diseases.

 AstraZeneca (Mölndal)

The AstraZeneca R&D Mölndal (Sweden) site is one of the 2 largest sites within AstraZeneca and has around 2500 people in research and development. AstraZeneca is committed to contributing an environment where there is successful integration of basic research to understand the fundamentals that under-pin their drug discovery projects. 

Astrocyte regulation of neuronal function: analyzing their contribution to oxidative and metabolic stress in neurodegeneration