Visualizing alteration in mitochondrial structures in Brain astrocytes and neurones due to obesity and diabetes

This project investigates a novel mechanism by which brain insulin resistance contributes to metabolic and cognitive dysfunction, focusing on the Nucleus of the Tractus Solitarius (NTS) within the dorsal vagal complex (DVC). While peripheral insulin resistance is well-characterized, the brain’s role in systemic metabolic regulation remains underexplored. Our research addresses this gap by examining how high-fat diet (HFD)-induced mitochondrial fragmentation in astrocytes and neurons disrupts insulin signaling in the DVC, leading to impaired glycemic control and increased food intake.

<p>Preliminary findings reveal that in rodents, high-fat diet feeding and obesity lead to an increase in mitochondrial fragmentation in the nucleus of the solitary tract in the brainstem. This, triggers insulin resistance, hyperphagia, and elevated blood glucose levels. Additionally, we have demonstrated that increasing mitochondrial fragmentation in astrocytes alone is enough to induce insulin resistance, affecting both glycemia and feeding. Building on this, our specific objectives are:</p> <ol> <li>Characterize mitochondrial structural changes in astrocytes and neurons within the NTS under conditions of obesity and diabetes, using correlative tomography and plasma FIB technology to achieve high-resolution visualization.</li> <li>Determine whether fragmented mitochondria undergo mitophagy, using confocal imaging to assess degradation pathways and their role in cellular stress responses.</li> <li>Investigate alterations in the extracellular matrix (ECM) triggered by mitochondrial fragmentation in astrocytes. We will use light sheet microscopy to visualize ECM remodeling, focusing on markers such as Aggrecan and Brevican, which are upregulated in response to mitochondrial stress.</li> </ol> <p>Recent data from primary astrocyte cultures suggest that mitochondrial fragmentation increases the expression of ECM-associated proteins, potentially altering the extracellular environment and affecting neuronal communication. By integrating these findings, the project will provide insight into how mitochondrial dysfunction in glial cells contributes to broader neural and metabolic dysregulation.</p> <p>The project’s novelty lies in its multi-modal approach, combining advanced imaging and molecular techniques to uncover the cellular and extracellular consequences of mitochondrial fragmentation.</p> <h5>References</h5> <ol> <li>New, L.E., Wang, N., Smith, H.E., Birks, R., Afridi, S.K., Griffiths, J.C., Hains, R., Johnston, J., and Filippi, B.M. (2025). Insulin evokes release of endozepines from astrocytes of the NTS to modulate glucose metabolism in male rats. Mol. Metab. 101, 102255. <a href="https://www.findaphd.com/common/clickCount.aspx?theid=144804&type=184&DID=735&url=https%3a%2f%2fdoi.org%2f10.1016%2fj.molmet.2025.102255" rel="nofollow" target="_blank">https://doi.org/10.1016/j.molmet.2025.102255</a>.</li> <li>Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake. Life Sci. 2023 Sep 1;328:121922. doi:10.1016/j.lfs.2023.121922.2.</li> <li>Inhibition of mitochondrial fission and iNOS in the dorsal vagal complex protects from overeating and weight gain. Mol Metab. 2021 Jan;43:101123.) doi:10.1016/j.molmet.2020.101123.3. (First author PhD student)</li> <li>Dynamin-Related Protein 1-Dependent Mitochondrial Fission Changes in the DorsalVagal Complex Regulate Insulin Action. Cell Rep. 2017 Mar 7;18(10):2301-2309. doi:10.1016/j.celrep.2017.02.03</li> </ol>

<p>To apply for this project opportunity applicants should complete an <a href="https://biologicalsciences.leeds.ac.uk/research-degrees/doc/how-to-apply">online application form</a> and attach the following documentation to support their application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks</li> <li>Evidence that you meet the University's minimum English language requirements (if applicable)</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Biological Sciences as your programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<p>This project is open to applicants who have the funding to support their own studies or who have a sponsor who will cover these costs. </p>

<p>For information about the application process please contact the Faculty Admissions Team:</p> <p>e: <a href="mailto:fbsgrad@leeds.ac.uk">fbsgrad@leeds.ac.uk</a></p>