NLRP3 inflammasome inhibition with MCC950 improves insulin sensitivity and inflammation in a mouse model of frontotemporal dementia

Acknowledgments: This study was supported by ARUK project grant PG2017B-11 and ARUK summer scholarship funding from the Scottish ARUK network. The authors would like to thank Prof. Gernot Riedel for his support of the in vivo experimentation.Peer reviewedPostprin

Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism

Funding This study was funded by the Development Trust, University of Aberdeen.Peer reviewe

Induction of experimental diabetes and diabetic nephropathy using anomer-equilibrated streptozotocin in male C57Bl/6J mice

Open Access via the Elsevier Agreement This research has been funded by the Medical Research Scotland (PhD-1285-2018), PhD studentship to SEJKS, in partnership with AstraZeneca (Cambridge, United Kingdom).Peer reviewedPublisher PD

Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice

The authors would like to acknowledge University of Aberdeen PhD studentship to RD and Scottish Alzheimer’s Research UK Junior member research grant to RD to perform GLP-1 ELISA and Alzheimer’s Research UK grant to BP and MD (ARUK-PG2017B-11). We thank Dr Oliver Helk for advice concerning statistical analyses and Prof Gernot Riedel for kindly providing the PhenoTyper home cages and advice in behavioural studies.Peer reviewedPostprin

Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice

The authors would like to acknowledge University of Aberdeen PhD studentship to RD and Scottish Alzheimer’s Research UK Junior member research grant to RD to perform GLP-1 ELISA and Alzheimer’s Research UK grant to BP and MD (ARUK-PG2017B-11). We thank Dr Oliver Helk for advice concerning statistical analyses and Prof Gernot Riedel for kindly providing the PhenoTyper home cages and advice in behavioural studies.Peer reviewedPostprin

The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice

Acknowledgements The authors would like to acknowledge University of Aberdeen PhD studentship to RD and Alzheimer’s Research UK grant to BP and MD (ARUK-PG2017B-11). The authors also thank David Riddell and David McKinzie at Eli Lilly for involvement with sample handling for Aβ determination.Peer reviewedPostprin

Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR-/- mice

Acknowledgements This study was supported by funds from the British Heart Foundation (PG16/90/32518) project grant to N. Mody and a PhD studentship to S.M. by the James Mearns Trust and School of Medicine, Medical Sciences and Nutrition, University of Aberdeen (UoA). No potential conflicts of interest relevant to this article are reported. N. Mody and D.T. conceived the study, designed the experiments and wrote the manuscript. D.T., S.M, N. Morrice, R.D., S.K.S, P.H. performed experiments. P.W. and M.D. performed the ceramide analysis, M.D. contributed to the study conception, discussions and reviewed the manuscript. N.Mody is the guarantor of this work and, as such, had full access to all the data in this study and takes responsibility for the integrity and accuracy of the data analysis. The authors thank the UoA animal research facility, qPCR core facility (Institute of Medical Sciences, UoA) and Linda Davidson (NHS Grampian) for their technical contributions regarding animal studies, qPCR and histology respectively and Alison Rutter at UHI for lipidomics support. We thank UoA Masters students Emma Forbes and Nawaf Alsulami for assisting in experiments on ApoE-/- mice. The authors also wish to thank Patrick W F Hadoke (University of Edinburgh) and Heather M Wilson (UoA) for invaluable discussions about mechanisms of atherosclerosis and review of the manuscript, Matteo Zanda, Sergio Dall’Angelo, Chiara Zanato and Ilaria Patruno (all UoA) for medicinal chemistry support.Peer reviewedPublisher PD

Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR −/− mice

Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR−/− mice fed high-fat/high-cholesterol diet ± Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13, Cd68 and Col1a1. The mechanisms of Fenretinide’s beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR−/− mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a fourfold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome