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.
Highlights
Several metabolic traits, including insulin resistance and hyperinsulinemia, low HDL cholesterol, and hypoadiponectinemia, are strongly associated with each other, and with major diseases including diabetes mellitus and atherosclerosis
The same common genetic variants at the ARL15 locus are associated with indices of insulin resistance and coronary heart disease[1], with other studies confirming variation at the ARL15 locus to be associated with fasting insulin, HDL cholesterol and triglyceride concentrations[3,4,5]
Based on similarities between the pattern of metabolic traits associated with ARL15 locus variants, and the pattern of metabolic derangement seen in Mendelian lipodystrophies, it has been hypothesized that the genetic variation at the ARL15 locus may affect metabolic traits such as fasting insulin and HDL concentrations through a primary action on adipose tissue development or function[6,7]
Summary
Several metabolic traits, including insulin resistance and hyperinsulinemia, low HDL cholesterol, and hypoadiponectinemia, are strongly associated with each other, and with major diseases including diabetes mellitus and atherosclerosis. Genome-wide association studies (GWAS) agnostically seek statistical associations among common genetic variation and traits of interest. Genetic variation at a locus including only ARL15 was first associated with HDL cholesterol concentration and plasma concentration of adiponectin[1], a highly abundant and stable plasma protein almost exclusively secreted by adipocytes, and widely believed to act as an insulin-sensitising adipokine[2]. The same common genetic variants at the ARL15 locus are associated with indices of insulin resistance and coronary heart disease[1], with other studies confirming variation at the ARL15 locus to be associated with fasting insulin, HDL cholesterol and triglyceride concentrations[3,4,5]. We set out firstly to assess whether ARL15 plays a cell autonomous role in the biosynthesis or secretion of adiponectin and/or preadipocyte differentiation using conditional Arl[15] knockdown in the insulin-responsive, adiponectin-producing 3T3-L1 cell line, and secondly, to seek rare coding sequence variants in ARL15 in a cohort of volunteers with lipodystrophic or non lipodystrophic severe insulin resistance
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