title: 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.
abstract: 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.
authors.affiliation: Department of Physiology (P.V.L., D.G.-T., B.P.C., R.N., C.D.), Centre for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela and Institute of Health Sciences, and Department of Morphological Sciences (P.V., T.G.-C.), School of Medicine and University Clinical Hospital, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; Department of Pharmacology (P.V.L., R.T., P.W.T., J.P.), Oxford University, Oxford OX1 3QT, United Kingdom; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (D.G.-T., B.P.C., R.N., C.D.), 15706, Santiago de Compostela, Spain; Department of Physiology, Anatomy, and Genetics (V.G., H.C.C.), Oxford University, Oxford OX1 3QX, United Kingdom; and Neurometabolic Unit (E.R., A.C., I.P.H.), National Hospital for Neurology and Neurosurgery, University College London Hospitals, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Pamela V
authors.initials: PV
authors.lastname: Lear
authors.forename: David
authors.initials: D
authors.lastname: González-Touceda
authors.forename: Begoña
authors.initials: B
authors.lastname: Porteiro Couto
authors.forename: Patricia
authors.initials: P
authors.lastname: Viaño
authors.forename: Vanessa
authors.initials: V
authors.lastname: Guymer
authors.forename: Elena
authors.initials: E
authors.lastname: Remzova
authors.forename: Ruth
authors.initials: R
authors.lastname: Tunn
authors.forename: Annapurna
authors.initials: A
authors.lastname: Chalasani
authors.forename: Tomás
authors.initials: T
authors.lastname: García-Caballero
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Tynan
authors.forename: Helen C
authors.initials: HC
authors.lastname: Christian
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.forename: John
authors.initials: J
authors.lastname: Parrington
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
mesh_terms: D002001:Adipose Tissue, Brown / Q000502:physiology*; D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D015800:Protozoan Proteins; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D015398:Signal Transduction; D000097903:Two-Pore Channels
chemical_list: D015220:Calcium Channels; D015800:Protozoan Proteins; D011943:Receptors, Adrenergic, beta; C546784:TPCN1 protein, mouse; D000097903:Two-Pore Channels; C546785:TPCN2 protein, mouse; C072098:aginactin protein, Dictyostelium