Absence of Intracellular Ion Channels TPC1 and TPC2 Leads to Mature-Onset Obesity in Male Mice, Due to Impaired Lipid Availability for Thermogenesis in Brown Adipose Tissue
Intracellular calcium-permeable channels have been implicated in thermogenic function of murine brown and brite/beige adipocytes, respectively transient receptor potential melastin-8 and transient receptor potential vanilloid-4. Because the endo-lysosomal two-pore channels (TPCs) have also been ascr...
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| Published in: | Endocrinology (Philadelphia) Vol. 156; no. 3; pp. 975 - 986 |
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| Main Authors: | , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Endocrine Society
01-03-2015
Oxford University Press |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Intracellular calcium-permeable channels have been implicated in thermogenic function of murine brown and brite/beige adipocytes, respectively transient receptor potential melastin-8 and transient receptor potential vanilloid-4. Because the endo-lysosomal two-pore channels (TPCs) have also been ascribed with metabolic functionality, we studied the effect of simultaneously knocking out TPC1 and TPC2 on body composition and energy balance in male mice fed a chow diet. Compared with wild-type mice, TPC1 and TPC2 double knockout (Tpcn1/2−/−) animals had a higher respiratory quotient and became obese between 6 and 9 months of age. Although food intake was unaltered, interscapular brown adipose tissue (BAT) maximal temperature and lean-mass adjusted oxygen consumption were lower in Tpcn1/2−/− than in wild type mice. Phosphorylated hormone-sensitive lipase expression, lipid density and expression of β-adrenergic receptors were also lower in Tpcn1/2−/− BAT, whereas mitochondrial respiratory chain function and uncoupling protein-1 expression remained intact. We conclude that Tpcn1/2−/− mice show mature-onset obesity due to reduced lipid availability and use, and a defect in β-adrenergic receptor signaling, leading to impaired thermogenic activity, in BAT. |
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| Bibliography: | This work was supported by Ministerio de Economia y Competitividad Grants BFU2011–29102 (to C.D.) and BFU2012–35255 (to R.N.), Xunta de Galicia Grants EM 2012/039 and 2012-CP069 (to R.N.), and Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III of Spain, which is supported by European Fund for Economic and Regional Development (FEDER) funds. The research leading to these results has also received funding from the European Community's Seventh Framework Programme under the following grants: FP7/2007–2013: 245009: NeuroFAST (to C.D.) and ERC StG-2011-OBESITY53–281408 (to R.N.). Generation of the Tpcn1/2−/− mice in Oxford was funded by a program grant from the Medical Research Council (UK) (G0901521). Part of this work was undertaken at University College London Hospitals/University College London (UCLH/UCL), London, UK, which received a proportion of funding from the United Kingdom Department of Health's National Institute for Health Research (UK) Biomedical Research Centres funding scheme. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 J.P. and C.D. contributed equally to this work. D.G.-T. and B.P.C. contributed equally to this work. |
| ISSN: | 0013-7227 1945-7170 |
| DOI: | 10.1210/en.2014-1766 |