title: LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion.
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.
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK.
authors: Nellie Y
authors: NY
authors: Loh
authors: 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.
authors: Matt J
authors: MJ
authors: Neville
authors: 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.
authors: Kyriakoula
authors: K
authors: Marinou
authors: Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol BS10 5NB, UK.
authors: Sarah A
authors: SA
authors: Hardcastle
authors: 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.
authors: Barbara A
authors: BA
authors: Fielding
authors: 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.
authors: Emma L
authors: EL
authors: Duncan
authors: 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.
authors: Mark I
authors: MI
authors: McCarthy
authors: Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol BS10 5NB, UK.
authors: Jonathan H
authors: JH
authors: Tobias
authors: Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol BS10 5NB, UK.
authors: Celia L
authors: CL
authors: Gregson
authors: 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: fredrik.karpe@ocdem.ox.ac.uk.
authors: Fredrik
authors: F
authors: Karpe
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK. Electronic address: costas.christodoulides@ocdem.ox.ac.uk.
authors: Constantinos
authors: C
authors: Christodoulides
mesh_terms: D050156:Adipogenesis; D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism*; D000328:Adult; D000483:Alleles; D050218:Body Fat Distribution; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D045162:Thiazolidinediones; D051176:beta Catenin; C000605941:iCTR14 compound
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