Body weight is regulated in the brain through appetite and energy expenditure, driving food intake and altering basal metabolism and physical activity. Obesity is a major contributor to preventable death worldwide and is linked to the development of several diseases including type-2 diabetes, cardiovascular disease, cancer, and poorer outcomes from COVID-19. Additionally, obesity and overweight have a global economic burden similar only to that of armed violence, war and terrorism combined. Therefore, it is crucial that we understand processes driving body weight regulation to develop new and effective interventions.
Our recent work has identified the transcription factor zinc finger homeobox-3 (ZFHX3) as a novel regulator of body weight, growth, appetite and energy expenditure; likely acting in the hypothalamus of the brain to alter expression of key neuropeptides to change behaviour and whole-body physiology. At the same time, a similar mutation found in humans is associated with low body mass index (BMI), indicating a conserved effect of ZFHX3 to influence body weight in mammalian species including humans. This project will investigate how ZFHX3 alters downstream pathways, and which of these pathways drive the observed physiological changes, using genetic, cell and whole animal techniques.
The overall aim of this project is to investigate the molecular action of ZFHX3 on candidate neuropeptide targets to drive altered appetite and metabolism. The project will take advantage of neuronal cell lines expressing these neuropeptides and mouse primary brain cells, and will involve state of the art neurosurgery, genetic manipulation, behavioural and metabolic techniques in mice in the following three aims:
- Anatomical mapping and co-localisation of ZFHX3 with candidate neuropeptides in mouse brain tissues, using fluorescence microscopy and spatial transcriptomics.
- Molecular action of ZFHX3 in brain cell lines, to alter gene expression and cell metabolism following genetic manipulation, and reporter assays to detect protein-DNA interactions.
- Neurosurgical manipulation of Zfhx3 and/or candidate neuropeptide expression in key brain regions of mice, followed by behavioural and metabolic phenotyping to determine physiological effects.
Training will be provided for all techniques required for this project, including metabolic phenotyping of mice (including blood sampling, glucose tolerance tests, metabolic cage measurements and neurosurgery). This project capitalises on the cutting-edge technology and expertise in neuroscience and metabolism available in the School of Science and Technology at NTU. Together this project will provide valuable insight to the brain regulation of energy balance, to target development of future therapeutics for obesity and metabolic disease.