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Characterisation of the neuronal network that senses insulin in the Dorsal Vagal Complex of the brain


Project Description

Background to the post
Diabetes and obesity are epidemic diseases that are rising among the world population. At list 70% of the world population will be overweight or obese by 2020. Associated with obesity there is a very high chance to develop Diabetes.
The Central Nervous system (CNS) regulates energy homeostasis by integrating hormonal signals from peripheral tissues. Changes in the sensitivity to these hormones in the CNS are associated with the development of obesity and diabetes. Understanding how to restore the sensitivity to hormones is one of the major challenges for scientists today.
We have shown that in rodents, the Dorsal Vagal Complex (DVC) of the brain lowers glycemia by inhibiting Hepatic Glucose Production (HGP) and decreases food intake and body weight. Three days of High Fat Diet (HFD) feeding are sufficient to cause insulin resistance in the brain, completely abolishing the ability the DVC to sense insulin and modulate glucose metabolism and feeding behaviour. The DVC is an important integration centre since it receives signals from the peripheral organs and relays them to the brain, while also relaying brain signals to the peripheral organs. The identities of neuronal populations in the DVC sensing insulin and those neurones relaying this information to regulate feeding behaviour and glucose metabolism are completely unknown. We aim to dissect the neuronal network that in response to changes in insulin levels triggers a signal to peripheral organs to regulate glucose metabolism and feeding behaviour. As the brain is emerging as one of the major coordinator of metabolic functions, understanding the neuronal network that senses insulin in the DVC will add new knowledge and potentially open up new approaches to target the brain ability to regulate metabolic functions in metabolic diseases like obesity and diabetes. Interestingly, intranasal delivery of insulin to target the CNS lowers hepatic glucose production (HGP) and food intake in humans.

Summary of the research programme
This project will apply
1) In vitro techniques such as biochemical assays, western blotting (WB), molecular cloning and adenovirus preparation.
2) In vivo techniques will be performed rodents. They will receive
-DVC stereotactic surgery to implant cannulae for brain infusion to facilitate the localised administration of pharmacological compounds or adenoviruses.
-Vascular surgeries will be performed for systemic infusions and blood analysis.
-You will perform pancreatic (basal insulin)-euglycemic clamp studies (measuring the amount of glucose the liver releases in the blood) and glucose tolerance tests (measuring how blood glucose levels return back to normal after glucose injection). Using these procedures, you will investigate the effects that DVC insulin sensing and resistance have on HGP and on whole-body glucose regulation, respectively.
-In addition, you will monitor the effects on body weight and food intake.
3)To study the neuronal networks involved in insulin sensing in the DVC, you will apply immunohistochemistry and electrophysiology techniques ex vivo and you will use genetically encoded calcium sensors and optogenetics techniques in vivo.

Research environment
You will be based in purpose-built laboratory space within the School of Biomedical Sciences at the University of Leeds. We have a strong neuroscience cohort, both within the School and with other faculties at the University ([email protected]) which incorporates scientists and clinicians undertaking all aspects of research. This enables productive and positive collaborative ventures which move us closer to a clinical endpoint. It also provides a lively environment for discussion and dissemination of neuroscience.

Funding Notes

The successful candidate will receive a School of Biomedical Sciences studentship covering UK/EU fees plus a stipend (£15,009) for 4 years.
Candidates should have, or be expecting, a 2.1 hons at Undergraduate level or above, in a relevant subject. If English is not your first language, you will need a recognised English Language qualification to be admitted onto any of the University's degree programmes
Please apply online View Website
Please include supervisor name and project title. A research proposal is not required. Please upload a CV and transcripts.

References

1. Filippi, B. M. et al. Dynamin-Related Protein 1-Dependent Mitochondrial Fission Changes in the Dorsal Vagal Complex Regulate Insulin Action. CellReports 18, 2301–2309 (2017).
2. Filippi, B. M. et al. Insulin signals through the dorsal vagal complex to regulate energy balance. Diabetes 63, 892–899 (2014).
4. Filippi, B. M., Abraham, M. A., Yue, J. T. Y. & Lam, T. K. T. Insulin and glucagon signaling in the central nervous system. Rev Endocr Metab Disord 14, 365–375 (2013).
3. Filippi, B. M., Yang, C. S., Tang, C. & Lam, T. K. T. Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab 16, 500–510 (2012).


How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

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