Serum levels of RBP4 and adipose tissue levels of PTP1B are increased in obese men resident in northeast Scotland without associated changes in ER stress response genes

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The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes

Copyright © 2014. Published by Elsevier Inc. Acknowledgments This work was supported by the British Heart Foundation Intermediate Basic Research Fellowship FS/09/026/27398 to N.M. and Biotechnology and Biological Sciences Research Council doctoral training grant awarded to G.D.M.Peer reviewedPostprin

Fenretinide Treatment Prevents Diet-Induced Obesity in Association With Major Alterations in Retinoid Homeostatic Gene Expression in Adipose, Liver and Hypothalamus

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Hepatic protein tyrosine phosphatase 1B (PTP1B) deficiency protects against obesity-induced endothelial dysfunction

Acknowledgments This work was supported by a Diabetes UK project grant to Dr M. Delibegović (BDARD08/0003597), Tenovus Scotland grant to Dr. M. Delibegovic and Dr. A. Agouni and travel grants from the Physiological Society and Company of Biologists to Dr. A. Agouni. Dr Delibegovic is also funded by an RCUK Fellowship, British Heart Foundation, EFSD/Lilly diabetes programme grant and the Royal Society. Dr Agouni is funded by the Royal Society and the Physiological Society. This work is supported by the INSERM and CHU of Angers. The authors are thankful to the functional imaging center of Angers (CIFAB) for the use of echocardiography.Peer reviewedPostprin

Neuronal human BACE1 knock-in induces systemic diabetes in mice

Acknowledgements The authors thank S. Tammireddy (Diabetes and Cardiovascular Science, University of the Highlands and Islands, Inverness, UK) for technical support with the lipidomics component. Funding We would like to thank R. Simcox, Romex Oilfield Chemicals, for financial support for KP, and acknowledge additional contributions from the Scottish Alzheimer’s Research UK network for the lipidomics work. The College of Life Science and Medicine, University of Aberdeen, sponsored the imaging study. MD was funded by British Heart Foundation and Diabetes UK; NM was funded by a British Heart Foundation Intermediate Fellowship; KS was funded by a European Foundation for the Study of Diabetes/Lilly programme grant; and RD was funded by an Institute of Medical Sciences PhD studentship.Peer reviewedPublisher PDFPublisher PD

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKa pathway

Objective: Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE−/− mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk

Design, synthesis, radiosynthesis and biological evaluation of Fenretinide analogues as anticancer and metabolic syndromepreventive agents

We thank the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement N° 675417 (PET3D project) for financial support of the project and the studentship of I.P. We also thank the British Heart Foundation for the project grant PG/16/90/32518.Peer reviewedPostprin

Response to comment by Moxon et al

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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

Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21.

Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice. Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4, with a concomitant decrease in IRE1α phosphorylation. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight. Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans