γ-synuclein is a novel player in the control of body lipid metabolism

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Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis

This work was supported by a Merit Scholarship from the Islamic Development Bank (to M.M.U.T.), The Agency for Science, Technology and Research, Singapore (A*STAR) (M.F.M.S), the Medical Research Council (MRC) [NIRG GO800203 and Research Grant MR/L002620/1 (to J.J.R.), Program GrantG09000554 (to S.O.R)], The Wellcome Trust [078986/Z/06/Z (to S.O.R.)], the MRC Centre for Obesity and Related Metabolic Disorders (MRC-CORD) [GO600717] and the NIHR Comprehensive Biomedical Research Centre [CG50826].Peer reviewedPublisher PD

Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms

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A Truncation Mutation in TBC1D4 in a Family with Acanthosis Nigricans and Postprandial Hyperinsulinemia

Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P = 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (P \u3c 0.05). When coexpressed with wild-type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild-type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action

Female adipose tissue-specific Bscl2 knockout mice develop only moderate metabolic dysfunction when housed at thermoneutrality and fed a high-fat diet

The authors would like to thank the staff at the University of Aberdeen’s Medical Research Facility. We are very grateful for the gift of the Adiponectin-Cre mice from Dr. Evan Rosen (Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, USA). Work was supported by the Medical Research Council (GDM/JJR; MR/L002620/1, MC/PC/15077), the Biotechnology and Biological Sciences Research Council (JJR; BB/K017772/1), the British Heart Foundation (MD; PG/14/43/30889) and The Agency for Science, Technology and Research, Singapore (A*STAR) (WH). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.Peer reviewedPublisher PD

Ablation of Bscl2/Seipin in hepatocytes does not cause metabolic dysfunction in congenital generalised lipodystrophy

Funding Work was supported by the Medical Research Council (GDM/JJR; MR/L002620/1, MC/PC/15077), the Biotechnology and Biological Sciences Research Council (JJR; BB/K017772/1), Diabetes UK (GDM/JJR; 18/0005884), the British Heart Foundation (MD;PG/14/43/30889) and the Wellcome Trust and the University of Aberdeen ISSF Fund (GDM; ISSF Fellowship Support Fund).Peer reviewedPublisher PD

The burden of metabolic syndrome on osteoarthritic joints

Versus Arthritis (grants 19667, 20050, 20775, 20865, 21156) and the Medical Research Council (grant MR/L020211/1).Peer reviewedPublisher PD

Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy

The authors are extremely grateful to Dr Donna MacCallum (University of Aberdeen) for assistance with AAV vector i.v. tail vein injections and Pat Bain (University of Aberdeen) for design and generation of the graphical abstract. The authors would also like to thank the staff at the University of Aberdeen’s Microscopy and Histology Core Facility and the Medical Research Facility for support with animal breeding and maintenance. This research was supported by funding from the EFSD/Lilly Young Investigator Research Award Programme, Wellcome Trust ISSF Fellowship Support Fund, and Diabetes UK RD Lawrence Fellowship (21/0006280) awarded to G.D.M. and Diabetes UK (18/0005884) awarded to J.J.R.Peer reviewedPublisher PD

Promethin is a Conserved Seipin Partner Protein

The M.B. lab is supported by the Deutsche Forschungsgemeinschaft (DFG), Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), University of Münster, Germany. The M.S. lab is funded by an SFB1190 by the DFG and a Volkswagen Stiftung “Life” Grant (93092). M.S. is an Incumbent of the Dr. Gilbert Omenn and Martha Darling Professorial Chair in Molecular Genetics. The J.J.R. lab is supported the Medical Research Council [Research Grant MR/L002620/1] and the Biotechnology and Biological Sciences Research Council [BB/K017772/1]. I.G.C. is supported by an EMBO Long-term Fellowship (ALTF-580-2017). M.E.B. is grateful to the Azrieli Foundation for the award of an Azrieli Fellowship.Peer reviewedPublisher PD

Bscl2 Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy

Funding: Work was supported by Diabetes UK (JJR;18/0005884, MD;17/0005621) the Medical Research Council (JJR; MR/L002620/1, MC/PC/15077), the British Heart Foundation (MD; PG/14/43/30889), The Agency for Science, Technology and Research, Singapore (A*STAR) (WH), The Wellcome Trust (ISSF Funding to GDM) and the European Union’s Horizon 2020 ERC consolidator award (MB:2016-726152-TYPHI).Peer reviewedPublisher PD