Christodoulides, C

Dumbill, R

Karpe, F

Langenberg, C

Loh, NY

Neville, MJ

Pinnick, KE

Todorcevic, M

Toledo, EM

van Dam, AD

Wittemans, LBL

van Dam, Andrea

Daniel Toledo Maldonado, Enrique

Loh, Ny

Neville, Matthew

Pinnick, Ke

Todorcevic, Marijana

Wittemans, Lbl

Karpe, Fredrik

Oxford University Research Archive

All authors are aware of and approve the submission of this paper. Each author has participated sufficiently in the work represented by the abstract submission to take public responsibility for the content.  Grant acknowledgement: Novo Nordisk Postdoctoral Research Fellowship  The study has been reviewed by the Local Ethics Committee and it has therefore been performed in accordance with the ethical standards laid down in the Helsinki Declaration (see World Medical Association: www.wma.net).   A recruit-by genotype approach to investigate the biological function of GWAS hits in human adipose cell populations  Andrea D. van Dam1, Enrique M. Toledo2, Nellie Y. Loh1, Matt J. Neville1, Katherine E. Pinnick1, Maja Todorčević1, Tim Walker2, Diana Mantripp1, Jane Cheeseman1, Kerry A. McLaughlin1, Amy Barrett1, Richard Dumbill3, Fredrik Karpe1, Costas Christodoulides1  1Oxford Centre for Diabetes Endocrinology and Metabolism, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, UK 2Novo Nordisk Research Centre Oxford, UK 3General Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford  Background and aims Developmental pathways regulating regional adiposity to understand human fat distribution is are still poorly characterized. This project explores the role of hedgehog signaling using a single-cell RNAseq approach in combination with large-scale genetics and adipocyte biology making use of the hedgehog interacting protein (HHIP) locus (rs1812175, rs13146972) which is strongly associated with hip circumference adjusted for BMI (HIPadjBMI).   Materials and methods Single-cell RNASeq was performed in stromovascular fractions from paired  abdominal and gluteal adipose tissue (volunteers from the Oxford Biobank). The GWAS association (rs1812175, near HHIP, for HIPadjBMI) was confirmed in a large cohort with DXA quantified regional fat masses (n=17,212, Oxford Biobank, Fenland and EPIC-Norfork). Functional studies of HHIP knockdown was performed in immortalised human regional pre-adipocytes.  Results Single-cell RNASeq showed robust HHIP expression exclusively in the pre-adipocyte cluster and a limited expression in endothelial cells and we therefore pursued functional studies using adipocyte models. The HIPadjBMI increasing allele of rs1812175 was associated with increased gluteal fat mass (β=0.08, p=1.37E-06, n=17,212), corresponding to a per allele of ~xx g. Carriers of the HIPadjBMI increasing allele had larger adipocytes in both the abdominal and gluteal depots compared to BMI- and age-matched controls.  Comparison of single-cell RNASeq data from carriers of the HIPadjBMI increasing allele and controls recruited from the Oxford Biobank will provide further insight into whether there is an HHIP-dependent transcriptome and the role of HHIP eQTLs. HIPadjBMI increasing allele (rs1812175) is in high linkage disequilibrium with two variants in the HHIP promoter (rs1355603 and rs13106087). In HHIP promoter reporter assays the HIPadjBMI increasing allele at rs1355603 displayed lower activity than the major allele. We therefore pursued knockdown of HHIP in primary gluteal Aps which promoted adipogenesis.  Conclusion This study provides evidence for a functional role of HHIP in regional adipogenesis that is consistent with large scale genetic association studies. Reduction in in HHIP signaling has the potential of affecting human fat distribution in a metabolically favorable pattern. 

English

Hedgehog signalling as a determinant of human fat expansion and distribution

Hedgehog signalling as a determinant of human fat expansion and distribution

Abstract

Similar works

Full text

Available Versions

Oxford University Research Archive