Christodoulides Group: Deciphering the role of white and brown adipocytes in cardiometabolic diseases

Our work focuses on understanding how obesity drives the development of type 2 diabetes and coronary heart disease. Specifically, it aims to decipher molecular determinants of adipocyte number and distribution within the body - key factors of susceptibility to obesity-associated cardiometabolic diseases - with the goal of translating insights into novel treatments. To achieve this, we employ human genetic and physiological approaches, coupled with functional studies in human adipose cells and Mendelian randomisation studies.

Adipose Tissue

About the Research 

Adipose tissue plays a central role in the control of systemic metabolism. It provides a safe depot for excess calorie storage as triglycerides, protecting extra-adipose tissues from ectopic fat deposition and lipotoxicity. Additionally, it directly regulates systemic energy balance and insulin sensitivity via the secretion of hormones such as leptin and adiponectin. Adipose tissue expands through an increase in adipocyte number (hyperplasia) or size (hypertrophy). Hyperplastic adipose tissue growth is mediated via new adipocyte generation and is associated with a healthy metabolic profile, especially when involving the gluteofemoral fat depot. In contrast, adipocyte hypertrophy results in adipose tissue dysfunction and metabolic disease.

We have a longstanding interest in the role of developmental signaling pathways in the regulation of adipose tissue biology. By studying subjects with rare gain-of-function mutations in the WNT co-receptor LRP5, we showed that these variants were associated with increased gluteofemoral fat mass and enhanced whole-body insulin sensitivity. Notably, LRP5 is a drug target for osteoporosis treatment, illustrating the translational value of this research.

Another lab focus is translating genetic association signals for fat distribution into mechanisms for healthy adipose tissue expansion. Genetic variation at the RSPO3 locus is the the strongest genetic determinant of human fat distribution. Using a combination of phenotypic studies in common and low-frequency RSPO3 variant carriers, in vitro gain- and loss-of-function experiments in abdominal and gluteal adipose cells, and in vivo studies in zebrafish, we demonstrated that RSPO3, a stem cell growth factor potentiating WNT signaling, promotes upper-body fat distribution and insulin resistance. Ongoing work along the same lines is investigating the role of TGF-beta signaling in the regulation of adipocyte number, distribution, and function.

Mammals possess two adipocyte types: white adipocytes, which store energy, and brown adipocytes, which dissipate energy as heat. A promising approach to treating obesity and related diseases is to stimulate energy expenditure by increasing the number and/or activity of brown adipocytes. To decipher the role of human brown fat in systemic metabolism, we have generated immortalized human brown preadipocytes derived from neck fat biopsies. Additionally, we are generating RNA and ATAC-sequencing data from human brown fat. Using these tools and resources, we aim to unravel causal variants and genes acting in brown adipocytes to alter genetic susceptibility to obesity and related diseases.

Training Opportunities 

• Human adipose cell culture.
• Gene knock-down, knock-out, over-expression, editing (CRISPR) in immortalised human fat progenitors.
• Functional studies in adipose progenitors e.g. differentiation, proliferation, apoptosis.
• Functional studies in adipocytes e.g. glucose uptake, lipolysis.
• Promoter-reporter assays.
• Adipose tissue histology.
• Designing and executing small-scale experimental human studies

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

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.

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.

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 build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Additional Supervisors 

Publications