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Human fat distribution and metabolic disease: Identifying the mechanistic basis for site-specific fat storage to identify new ways of tackling the metabolic consequences of obesity.


Radcliffe Department of Medicine

About the Project

Identifying the mechanistic basis for site-specific fat storage to identify new ways of tackling the metabolic consequences of obesity.

Obesity is strongly related to a number of common chronic disease outcomes such as type 2 diabetes and cardiovascular disease. However, it appears that a major determinant of the metabolic consequences of being overweight depends on where and how fat is being stored in the body. For example, preponderance of lower body adiposity is related to much less adverse consequences that upper body adiposity, in particular if the fat being stored inside the abdomen. The factors determining where in body fat is being stored in a given individual is still poorly understood. This research programs aims at identifying the mechanistic basis for site-specific fat storage to identify new ways of tackling the metabolic consequences of obesity.

There is now good evidence that the fat storing cells (adipocytes) have different functions in different parts of the body and this gives a direct reflection on the tissue function with effects on the whole body metabolism. Lower body adipocytes tend to store fat very avidly and is resistant to releasing it, whereas upper body fat is also being stored well but is more easily being released. These intrinsic differences between the similarly-looking cells, rely on different transcriptional programs in the site specific pre- and mature adipocytes defining the equilibrium for fat storage and release but also the regeneration of the tissue, i.e. recruitment of new cell and the actual building of the tissue, which obviously requires certain scaffolding structures.

To answer questions on the regulation of site-specific tissue remodelling and fat storage we take a multilevel approach where we combine cell biology, genetics and whole body human physiology, including imaging, and access to human tissue material. Pathways to investigate the role human fat distribution to human disease sometimes arise from critical observations in human genetics, such from polygenic traits (typically exploration and functional annotation of GWAS loci for human fat distribution) or monogenic loci (typically rare lipodystrophic syndromes).

We are particularly interested in exploring the following areas:
◾Epigenetic control of regional adipocyte-specific phenotypes
◾How the composition of extracellular matrix affects regional adipocyte function
◾The role of long non-coding RNAs on transcriptomic patterns in regional adipocytes

◾Adipocyte biology, cell culture systems, genetic medication of cells to target certain pathway, i.e. knock-down, knock-in and CRISPR.
◾RNA work, RNASeq and monitoring transcriptional activation
◾Cross-reference transcriptomic, genetic and epigenetic platforms
◾Monitoring whole body human and cellular metabolic physiology using tracers
◾Designing and executing small-scale experimental studies in humans. Access to the Oxford Biobank (www.oxfordbiobank.org.uk) ensures high-quality selection of informative individuals.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as 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.

Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2020 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.

References

Karpe F, Pinnick KE. Biology of upper-body and lower-body adipose tissue-link to whole-body phenotypes. Nat Rev Endocrinol. 2015;11(2):90-100. PMID: 25365922

Denton N, Pinnick KE, Karpe F. Cartilage oligomeric matrix protein is differentially expressed in human subcutaneous adipose tissue and regulates adipogenesis. Mol Metab. 2018 Jul 27. pii: S2212-8778(18)30690-2. PMID: 30100245

Small KS, Todorčević M, Civelek M, El-Sayed Moustafa JS, Wang X, Simon MM, Fernandez-Tajes J, Mahajan A, Horikoshi M, Hugill A, Glastonbury CA, Quaye L, Neville MJ, Sethi S, Yon M, Pan C, Che N, Viñuela A, Tsai PC, Nag A, Buil A, Thorleifsson G, Raghavan A, Ding Q, Morris AP, Bell JT, Thorsteinsdottir U, Stefansson K, Laakso M, Dahlman I, Arner P, Gloyn AL, Musunuru K, Lusis AJ, Cox RD, Karpe F, McCarthy MI. Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition. Nat Genet. 2018;50(4):572-580. PMID: 29632379

Vasan SK, Osmond C, Canoy D, Christodoulides C, Neville MJ, Di Gravio C, Fall CHD, Karpe F. Comparison of regional fat measurements by dual-energy X-ray absorptiometry and conventional anthropometry and their association with markers of diabetes and cardiovascular disease risk. Int J Obes (Lond). 2018;42(4):850-857. 2017. PMID: 29151596

Pinnick KE, Nicholson G, Manolopoulos KN, McQuaid SE, Valet P, Frayn KN, Denton N, Min JL, Zondervan KT, Fleckner J; MolPAGE Consortium, McCarthy MI, Holmes CC, Karpe F. Distinct developmental profile of lower-body adipose tissue defines resistance against obesity-associated metabolic complications. Diabetes. 2014;63(11):3785-97. PMID: 24947352

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