Our work investigates how obesity contributes to the development of type 2 diabetes and coronary heart disease. Specifically, we aim to uncover the molecular determinants that govern adipocyte number and distribution – critical factors influencing susceptibility to obesity-associated cardiometabolic disorders. Our ultimate goal is to translate these insights into novel therapeutic strategies. To achieve this, we integrate human genetic and physiological studies with functional assays in human adipose cells and Mendelian randomisation approaches.
Adipocytes Image
Supervisor Profile Page: Costas Christodoulides
About the Research
Adipose tissue plays a central role in systemic metabolic regulation. It safely stores excess energy in the form of triglycerides, protecting non-adipose tissues from ectopic lipid accumulation and lipotoxicity. In addition, it regulates whole-body energy balance and insulin sensitivity through the secretion of hormones such as leptin and adiponectin. Adipose expansion occurs either through an increase in adipocyte number (hyperplasia) or cell size (hypertrophy). Hyperplastic growth, particularly in the gluteofemoral depot, is associated with a metabolically healthy phenotype, whereas hypertrophy is linked to adipose tissue dysfunction and increased metabolic disease risk.
Our laboratory has a longstanding interest in how developmental signalling pathways regulate adipose tissue biology. In individuals with rare gain-of-function mutations in the WNT co-receptor LRP5, we demonstrated that these variants are associated with increased gluteofemoral fat mass and enhanced insulin sensitivity. We have also shown that LRP5 regulates cellular proteostasis and protects against age-related loss of lower-body fat and osteoporosis. Since LRP5 is a therapeutic target in osteoporosis, our findings highlight the translational relevance of this pathway.
Another major focus of our work involves deciphering the genetic signals that influence fat distribution and translating them into mechanisms that support healthy adipose expansion. Genetic variation at the RSPO3 locus is the strongest known determinant of human fat distribution. Using a combination of phenotypic characterisation in common and rare variant carriers, in vitro gain- and loss-of-function experiments in abdominal and gluteal adipose progenitors, and in vivo studies in zebrafish, we have demonstrated that RSPO3, a WNT-signalling potentiator, promotes upper-body fat accumulation and contributes to insulin resistance. Building on this framework, our ongoing work is exploring the role of TGF-beta signalling in the regulation of adipocyte function, fat distribution, and systemic metabolism.
Humans possess two main types of adipocytes: white adipocytes, which store energy, and brown adipocytes, which dissipate energy as heat via non-shivering thermogenesis. Increasing the number or activity of brown adipocytes presents a promising strategy for enhancing energy expenditure and treating obesity-related disorders. To better understand the role of brown fat in human metabolism, we have developed immortalised human brown preadipocyte lines derived from neck fat biopsies. Additionally, we are generating RNA-sequencing and ATAC-sequencing datasets from human brown fat to identify causal genetic variants and target genes that influence susceptibility to obesity and cardiometabolic disease.
This project is not suitable for part-time research.
Training Opportunities
Human adipose cell culture
Gene knockdown, knockout, overexpression, and CRISPR editing in immortalized fat progenitor cells
Functional assays in adipose progenitors (e.g., differentiation, proliferation, apoptosis)
Functional studies in mature adipocytes (e.g., glucose uptake, lipolysis)
Promoter-reporter assays
Adipose tissue histology
Design and execution of 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
1
Loh NY, Vasan SK, Roberts E, van Dam AD, Verma M, Phillips D, Wesolowska-Andersen A, Neville MJ, Noordam R, Gruneberg U, Tobias JH, Gregson CL, Karpe F, Christodoulides C. LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity. Commun Med (Lond). 5:51.
LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity – PubMed
2
Loh NY, Rosoff DB, Richmond R, Noordam R, Davey Smith G, Ray D, Karpe F, Lohoff FW, Christodoulides C. 2024. Bidirectional Mendelian randomization highlights causal relationships between circulating INHBC and multiple cardiometabolic diseases and traits. Diabetes. 73:2084-2094.
3
Verma M, Loh NY, Sabaratnam R, Vasan SK, van Dam AD, Todorčević M, Neville MJ, Toledo E, Karpe F, Christodoulides C. 2022. TCF7L2 plays a complex role in human adipose progenitor biology which may contribute to genetic susceptibility to type 2 diabetes. Metabolism. 133:155240.
4
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.
RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro – PubMed
5
Loh NY, Humphreys E, Karpe F, Tomlinson JW, Noordam R, Christodoulides C. 2022. Sex hormones, adiposity, and metabolic traits in men and women: a Mendelian randomisation study. Eur J Endocrinol. 186:407-416.
6
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.