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  • Constantinos Christodoulides, Fredrik Karpe

ABOUT THE RESEARCH

Our work focuses on understanding how obesity drives the development of type 2 diabetes and cardiovascular 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. To achieve this, we employ human genetic and physiological approaches, coupled with functional studies in human adipose cells and model organisms.

Adipose tissue plays a central role in the control of glucose and lipid metabolism. Firstly, it provides a safe depot for excess calorie storage as triglycerides, thereby protecting extra-adipose tissues from lipotoxicity consequent to ectopic fat deposition. Secondly, it directly regulates systemic energy balance and insulin sensitivity via the secretion of hormones e.g. 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 from fat progenitors, namely stem cells and preadipocytes, and is associated with metabolic health especially when involving the gluteofemoral depot. In contrast, adipocyte hypertrophy results in adipose tissue dysfunction and metabolic disease. 

We have a longstanding interest on the role of WNTs, a family of growth factors, 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 are 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. Related to this, we are also focused in translating genetic association signals for fat distribution and type 2 diabetes into mechanisms for adipose tissue expansion. Using this approach, we recently showed that RSPO3, a stem cell growth factor potentiating WNT signalling, promotes upper-body fat distribution. Ongoing work along the same lines is investigating the role of Hedgehog and TGF-beta signalling in the regulation of adipocyte number, function, and distribution. 

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 immortalised human brown preadipocytes. Additionally, we are generating single cell RNA- and ATAC-sequencing data from human brown fat. Using these tools/resources we aim to unravel causal variants and genes acting in brown adipocytes to alter genetic susceptibility to obesity and related diseases.

The successful candidate will pursue a project linked to the above lines of investigation.

 

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.

 

PUBLICATIONS

Loh NY, Minchin JE, Pinnick KE, Verma M, Todorcevic M, Denton N, El-Sayed Moustafa J, Kemp JP, Gregson CL, Evans DM, Neville MJ, Small KS, McCarthy MI, Mahajan A, Rawls JF, Karpe F, and Christodoulides C. 2020. RSPO3 regulating body fat distribution and adipocyte biology. Nat. Commun. 11:2797

Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, McCarthy MI, Tobias JH, Gregson CL, Karpe F, and Christodoulides C. 2015. LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion. Cell Metab. 21:262-72.

Vasan SK, Noordam R, Gowri MS, Neville MJ, Karpe F, Christoulides C. 2019. The Proposed Systemic Thermogenic Metabolites Succinate and 12,13-diHOME Are Inversely Associated With Adiposity and Related Metabolic Traits: Evidence From a Large Human Cross-Sectional Study. Diabetologia. 62:2079-2087.

Verma M, Loh NY, Vasan SK, van Dam AD, Todorčević M, Neville JM, Karpe F, Christodoulides C. TCF7L2 plays a complex role in human adipose progenitor biology which may contribute to genetic susceptibility to type 2 diabetes. bioRxiv 854661.

Loh NY, Vasan SK, Verma M, Wesolowska-Andersen A, Neville JM, Osmond C, Gregson CL, Karpe F, Christodoulides C. LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity. bioRxiv 976647.

Liu J, Kuipers EN, Sips HCM, Dorleijn JC, van Dam AD, Christodoulides C et al. 2019. Conditionally immortalised brown preadipocytes can switch between proliferative and differentiated states. Biochim Biophys Acta Mol Cell Biol Lipids. 1864 (12), 158511