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Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

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Abstract

The P2X7 receptor is an ATP-gated cation channel expressed by a number of cell types. We have shown previously that disruption of P2X7 receptor function results in downregulation of osteogenic markers and upregulation of adipogenic markers in calvarial cell cultures. In the present study, we assessed whether loss of P2X7 receptor function results in changes to adipocyte distribution and lipid accumulation in vivo. Male P2X7 loss-of-function (KO) mice exhibited significantly greater body weight and epididymal fat pad mass than wild-type (WT) mice at 9 months of age. Fat pad adipocytes did not differ in size, consistent with adipocyte hyperplasia rather than hypertrophy. Histological examination revealed ectopic lipid accumulation in the form of adipocytes and/or lipid droplets in several non-adipose tissues of older male KO mice (9–12 months of age). Ectopic lipid was observed in kidney, extraorbital lacrimal gland and pancreas, but not in liver, heart or skeletal muscle. Specifically, lacrimal gland and pancreas from 12-month-old male KO mice had greater numbers of adipocytes in perivascular, periductal and acinar regions. As well, lipid droplets accumulated in the renal tubular epithelium and lacrimal acinar cells. Blood plasma analyses revealed diminished total cholesterol levels in 9- and 12-month-old male KO mice compared with WT controls. Interestingly, no differences were observed in female mice. Moreover, there were no significant differences in food consumption between male KO and WT mice. Taken together, these data establish novel in vivo roles for the P2X7 receptor in regulating adipogenesis and lipid metabolism in an age- and sex-dependent manner.

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Acknowledgements

This work was funded by the Canadian Institutes of Health Research (CIHR) [grant number 102542]. KLB and AX were supported in part by the Joint Motion Program—A CIHR Training Program in Musculoskeletal Health Research and Leadership. MWG was supported by a CIHR Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award. DWH holds the Dr. Sandy Kirkley Chair in Musculoskeletal Research at The University of Western Ontario. We thank Dr. Nattapon Panupinthu for performing preliminary studies, Linda Jackson and Tom Chrones for assistance with histology, Vasek Pitelka for aiding with animal anaesthesia, Dr. Joseph Umoh for micro-CT scanning, Drs. Tom Daley and Ian Welch for advice on histopathology, Cindy Sawyez and Brian Sutherland for assistance with biochemical analyses and Dr. Nica Borradaile for helpful comments.

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The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada, N6A 5C1

    Kim L. Beaucage, Andrew Xiao, Ryan J. Beach, Stephen M. Sims & S. Jeffrey Dixon

  2. Robarts Research Institute, The University of Western Ontario, London, ON, Canada, N6A 5C1

    Steven I. Pollmann & David W. Holdsworth

  3. Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON, Canada, N6A 5C1

    Matthew W. Grol

  4. Department of Pathology, The University of Western Ontario, London, ON, Canada, N6A 5C1

    Mark R. Darling

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  1. Kim L. Beaucage
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Beaucage, K.L., Xiao, A., Pollmann, S.I. et al. Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice. Purinergic Signalling 10, 291–304 (2014). https://doi.org/10.1007/s11302-013-9388-x

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