Abstract
ABSTRACTThe small GTPase ARF family member ARL15 gene locus is associated in population studies with increased risk of type 2 diabetes, lower adiponectin and higher fasting insulin levels. Previously, loss of ARL15 was shown to reduce insulin secretion in a human β-cell line and loss-of-function mutations are found in some lipodystrophy patients. We set out to understand the role of ARL15 in adipogenesis and showed that endogenous ARL15 palmitoylated and localised in the Golgi of mouse liver. Adipocyte overexpression of palmitoylation-deficient ARL15 resulted in redistribution to the cytoplasm and a mild reduction in expression of some adipogenesis-related genes. Further investigation of the localisation of ARL15 during differentiation of a human white adipocyte cell line showed that ARL15 was predominantly co-localised with a marker of the cis face of Golgi at the preadipocyte stage and then translocated to other Golgi compartments after differentiation was induced. Finally, co-immunoprecipitation and mass spectrometry identified potential interacting partners of ARL15, including the ER-localised protein ARL6IP5. Together, these results suggest a palmitoylation dependent trafficking-related role of ARL15 as a regulator of adipocyte differentiation via ARL6IP5 interaction.This article has an associated First Person interview with the first author of the paper.
Highlights
The World Health Organisation (WHO) estimates there were 422 million people with diabetes in 2014
Endogenous ARL15 is predominantly localised in the Golgi network Using a protein over-expression method, the localisation of GFP-tagged ARL15 in 3T3-L1 preadipocytes has been shown in the Golgi network (Rocha et al, 2017); whereas in C2C12 myotubes, ARL15 was found to be in the cytoplasm and moved to the perinuclear Golgi region upon insulin stimulation (Zhao et al, 2017)
We conducted immunostaining in human white adipocyte tissue derived cell line preadipocytes to confirm the localisation of endogenous ARL15
Summary
The World Health Organisation (WHO) estimates there were 422 million people with diabetes in 2014. Genome wide association population studies have identified over 243 genetic loci with 403 distinct association signals for T2D (Mahajan et al, 2018). Many of these loci indicate a role for islet beta-cell function in T2D risk, 26 signals were attenuated by BMI adjustment suggesting T2D risk was driven by adiposity. A further 15 loci were more strongly associated with BMI-adjusted signals with effects on insulin secretion and/or ectopic fat storage (Mahajan et al, 2018). There is genetic evidence of insulin resistance in T2D that is linked to ectopic fat distribution and reduced subcutaneous adiposity (Scott et al, 2014; Yaghootkar et al, 2014). In addition there are rare monogenic conditions such as lipodystrophy that result in partial or complete loss of adipose tissue and cause severe insulin resistance and diabetes (Semple et al, 2011)
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