LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion.

Nellie Y Loh, Matt J Neville, Kyriakoula Marinou, Sarah A Hardcastle, Barbara A Fielding, Emma L Duncan, Mark I McCarthy, Jonathan H Tobias, Celia L Gregson, Fredrik Karpe, Constantinos Christodoulides

Journal: Cell metabolism 2016;21(2):262-273

PMID: 25651180

Free Full Text on Elsevier Science View on PubMed

Abstract

Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

Address: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Department of Experimental Physiology, Athens University School of Medicine, Athens 11527, Greece.; Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol BS10 5NB, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.; University of Queensland Diamantina Institute, School of Medicine and University of Queensland Centre for Clinical Research, Faculty of Medicine and Biomedical Sciences, University of Queensland, Woolloongabba, QLD 4102, Australia; Department of Endocrinology, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, QLD 4029, Australia.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK. Electronic address: [email protected].; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK. Electronic address: [email protected].

DOI: 10.1016/j.cmet.2015.01.009

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/stemcells.html

Other Literature Sources:

https://scite.ai/reports/25651180

MeSH Terms: Adipogenesis, Adipose Tissue, Adult, Alleles, Body Fat Distribution, Dose-Response Relationship, Drug, Female, Healthy Volunteers, Humans, Low Density Lipoprotein Receptor-Related Protein-5, Male, Middle Aged, Mutation, Stem Cells, Thiazolidinediones, Transcriptional Activation, beta Catenin