The metabolic syndrome- associated small G protein ARL15 plays a role in adipocyte differentiation and adiponectin secretion

Nuno Rocha, Felicity Payne, Isabel Huang-Doran, Alison Sleigh, Katherine Fawcett, Claire Adams, Anna Stears, Vladimir Saudek, Stephen O'Rahilly, Inês Barroso, Robert K Semple

Research output: Contribution to journalArticlepeer-review

Abstract

Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of ARL15 in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy.

Original languageEnglish
Pages (from-to)17593
JournalScientific Reports
Volume7
Issue number1
Early online date14 Dec 2017
DOIs
Publication statusE-pub ahead of print - 14 Dec 2017

Keywords

  • Journal Article

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