@article{a0202bcb7fdf4edc855a37d94803c2eb,
title = "Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis",
abstract = "Activation of energy expenditure in thermogenic fat is a promising strategy to improve metabolic health, yet the dynamic processes that evoke this response are poorly understood. Here we show that synthesis of the mitochondrial phospholipid cardiolipin is indispensable for stimulating and sustaining thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response through overexpression of cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency in thermogenic adipocytes diminishes inducible mitochondrial uncoupling and elicits a nuclear transcriptional response through endoplasmic reticulum stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake, which renders animals insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin has a powerful impact on organismal energy homeostasis through thermogenic fat bioenergetics.",
keywords = "CHOP-10, CRLS1, beige adipose, brown adipose, cardiolipin, insulin resistance, lipid metabolism, mitochondria, phospholipids, thermogenesis, Mitochondria/metabolism, Humans, Mice, Inbred C57BL, Adipocytes/metabolism, Cells, Cultured, Membrane Proteins/genetics, Cardiolipins/biosynthesis, Animals, Thermogenesis, Energy Metabolism, Transferases (Other Substituted Phosphate Groups)/genetics, Adipose Tissue, Brown/metabolism, Mice, Adipose Tissue, Beige/metabolism",
author = "Sustarsic, {Elahu G.} and Tao Ma and Lynes, {Matthew D.} and Michael Larsen and Iuliia Karavaeva and Havelund, {Jesper F.} and Nielsen, {Carsten H.} and Jedrychowski, {Mark P.} and Marta Moreno-Torres and Morten Lundh and Kaja Plucinska and Jespersen, {Naja Z.} and Grevengoed, {Trisha J.} and Barbara Kramar and Julia Peics and Hansen, {Jakob B.} and Farnaz Shamsi and Isabel Forss and Ditte Neess and Susanne Keipert and Jianing Wang and Katharina Stohlmann and Ivan Brandslund and Cramer Christensen and J{\o}rgensen, {Marit E.} and Allan Linneberg and Oluf Pedersen and Kiebish, {Michael A.} and Klaus Qvortrup and Xianlin Han and Pedersen, {Bente Klarlund} and Martin Jastroch and Susanne Mandrup and Andreas Kj{\ae}r and Gygi, {Steven P.} and Torben Hansen and Gillum, {Matthew P.} and Niels Grarup and Brice Emanuelli and S{\o}ren Nielsen and Camilla Scheele and Tseng, {Yu Hua} and F{\ae}rgeman, {Nils J.} and Zachary Gerhart-Hines",
note = "Funding Information: We thank members of the Gerhart-Hines and Tseng labs for discussions. We are grateful to Genoway for assistance in the design and generation of Crls1 floxed mice. We thank Dr. Miao Wang for technical assistance with targeted brown fat lipidomics. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH , and by NCI , NHGRI , NHLBI , NIDA , NIMH , and NINDS . The Core Facility for Integrated Microscopy (CFIM) is acknowledged for access to electron microscopes. This work was supported by funding from NIDDK grants R01DK077097 and R01DK102898 (Y.H.-T.), F32DK102320 (M.D.L.), 30DK036836 (Joslin Diabetes Center's Diabetes Research Center), the Danish Diabetes Academy (M.M.-T. and N.Z.J.), the Novo Nordisk Foundation (T.H., M.P.G., B.E., N.G., C.S., and Z.G.-H.), and the Danish Council for Independent Research-Medical Sciences (M. Lundh, N.J.F.), including Sapere Aude Starting grant 4002-00024 (Z.G.-H). In addition, this project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 ). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( http://cbmr.ku.dk/ ). Funding Information: We thank members of the Gerhart-Hines and Tseng labs for discussions. We are grateful to Genoway for assistance in the design and generation of Crls1 floxed mice. We thank Dr. Miao Wang for technical assistance with targeted brown fat lipidomics. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The Core Facility for Integrated Microscopy (CFIM) is acknowledged for access to electron microscopes. This work was supported by funding from NIDDK grants R01DK077097 and R01DK102898 (Y.H.-T.), F32DK102320 (M.D.L.), 30DK036836 (Joslin Diabetes Center's Diabetes Research Center), the Danish Diabetes Academy (M.M.-T. and N.Z.J.), the Novo Nordisk Foundation (T.H., M.P.G., B.E., N.G., C.S., and Z.G.-H.), and the Danish Council for Independent Research-Medical Sciences (M. Lundh, N.J.F.), including Sapere Aude Starting grant 4002-00024 (Z.G.-H). In addition, this project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://cbmr.ku.dk/).",
year = "2018",
month = jul,
day = "3",
doi = "10.1016/j.cmet.2018.05.003",
language = "English (US)",
volume = "28",
pages = "159--174.e11",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}