Brown adipose tissue WNT signalling as a therapeutic target for obesity and type 2 diabetes
Obesity is associated with the development of insulin resistance linked to the pathogenesis of type 2 diabetes and cardiovascular disease (CVD). The rising prevalence of obesity has focused attention on the discovery of safe and effective therapeutics promoting insulin sensitivity and/or weight-loss.
A promising approach is to stimulate energy expenditure through thermogenesis by increasing the number and/or activity of brown adipocytes. The presence of brown adipose tissue (BAT) in adult humans is now established. BAT activity correlates inversely with total and visceral adiposity and fasting plasma glucose. In interventional studies, chronic cold exposure led to increased BAT activity, reduced body fat mass and improved insulin sensitivity.
WNTs are a family of secreted glycoproteins which play a key role in adipose tissue biology. Activation of WNT signalling in brown adipocytes in transgenic mice stimulated their conversion into white adipocytes. Notably, variants within/near several Wnt pathway genes were shown to be associated with BMI at or near genome-wide significance. Accordingly, multiple WNT signalling genes are differentially expressed in brown vs. white human adipocytes.
The current project will examine the role of the WNT pathway in human BAT biology and susceptibility to obesity and CVD. Targets have been selected based on proprietary and public (e.g. biochemical, genetic, gene expression) datasets. The successful student will use a combination of in vitro functional and human physiological studies. The former will utilise established lentiviral vector systems to inducibly over-express and knock-down specific WNT pathway genes in immortalised human BAT progenitors uniquely available in our lab. These studies will be complemented by genome editing experiments using CRISPR Cas9. The effects of these genetic manipulations on proliferation, differentiation will subsequently be assessed. Induction of mitochondrial number, basal and cAMP-stimulated UCP1 promoter activity, adipocyte O2 consumption, and lipolysis will also be determined. These experiments will benefit from collaborative links with P. Rensen’s group in Leiden (The Netherlands). Human studies will examine the adipose and metabolic phenotype of low frequency and/or common Wnt pathway variant carriers. These will be facilitated by access to the Oxford Biobank comprising biochemical, DXA, and exome array data from >8500 volunteers who can be recalled for clinical studies. Experiments will include assessment of fat mass and fat distribution (DXA), glucose tolerance (OGTTs) and (in low frequency variant carriers) resting metabolic rate and in vivo BAT activity using thermal imaging.
• Human physiology • Human adipocyte culture and differentiation • Lentiviral mediated gene knock-down, over-expression • Genome editing • Adipose tissue histology • Luciferase reporter assays • Respirometry
The DPhil would be based at the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEDM). As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.
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