Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis

Elahu G. Sustarsic, Tao Ma, Matthew D. Lynes, Michael Larsen, Iuliia Karavaeva, Jesper F. Havelund, Carsten H. Nielsen, Mark P. Jedrychowski, Marta Moreno-Torres, Morten Lundh, Kaja Plucinska, Naja Z. Jespersen, Trisha J. Grevengoed, Barbara Kramar, Julia Peics, Jakob B. Hansen, Farnaz Shamsi, Isabel Forss, Ditte Neess, Susanne Keipert & 24 andre Jianing Wang, Katharina Stohlmann, Ivan Brandslund, Cramer Christensen, Marit E. Jørgensen, Allan Linneberg, Oluf Pedersen, Michael A. Kiebish, Klaus Qvortrup, Xianlin Han, Bente Klarlund Pedersen, Martin Jastroch, Susanne Mandrup, Andreas Kjær, Steven P. Gygi, Torben Hansen, Matthew P. Gillum, Niels Grarup, Brice Emanuelli, Søren Nielsen, Camilla Scheele, Yu Hua Tseng, Nils J. Færgeman, Zachary Gerhart-Hines*

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Resumé

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. Sustarsic et al. reveal that synthesis of the mitochondrial phospholipid cardiolipin is a hallmark of brown and beige fat activation by cold temperature. This single lipid species in thermogenic fat not only shapes adipose mitochondrial bioenergetics but also exerts profound control over whole-body insulin sensitivity and metabolic flexibility.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind28
Udgave nummer1
Sider (fra-til)159-174.e11
ISSN1550-4131
DOI
StatusUdgivet - 3. jul. 2018

Fingeraftryk

Homeostasis
Fats
Energy Metabolism
Insulin Resistance
Adipocytes
Phospholipids
Endoplasmic Reticulum Stress
Communication
Beige Adipose Tissue
Insulin
Lipids
Health

Citer dette

Sustarsic, E. G., Ma, T., Lynes, M. D., Larsen, M., Karavaeva, I., Havelund, J. F., ... Gerhart-Hines, Z. (2018). Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis. Cell Metabolism, 28(1), 159-174.e11. https://doi.org/10.1016/j.cmet.2018.05.003
Sustarsic, Elahu G. ; Ma, Tao ; Lynes, Matthew D. ; Larsen, Michael ; Karavaeva, Iuliia ; Havelund, Jesper F. ; Nielsen, Carsten H. ; Jedrychowski, Mark P. ; Moreno-Torres, Marta ; Lundh, Morten ; Plucinska, Kaja ; Jespersen, Naja Z. ; Grevengoed, Trisha J. ; Kramar, Barbara ; Peics, Julia ; Hansen, Jakob B. ; Shamsi, Farnaz ; Forss, Isabel ; Neess, Ditte ; Keipert, Susanne ; Wang, Jianing ; Stohlmann, Katharina ; Brandslund, Ivan ; Christensen, Cramer ; Jørgensen, Marit E. ; Linneberg, Allan ; Pedersen, Oluf ; Kiebish, Michael A. ; Qvortrup, Klaus ; Han, Xianlin ; Pedersen, Bente Klarlund ; Jastroch, Martin ; Mandrup, Susanne ; Kjær, Andreas ; Gygi, Steven P. ; Hansen, Torben ; Gillum, Matthew P. ; Grarup, Niels ; Emanuelli, Brice ; Nielsen, Søren ; Scheele, Camilla ; Tseng, Yu Hua ; Færgeman, Nils J. ; Gerhart-Hines, Zachary. / Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis. I: Cell Metabolism. 2018 ; Bind 28, Nr. 1. s. 159-174.e11.
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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. Sustarsic et al. reveal that synthesis of the mitochondrial phospholipid cardiolipin is a hallmark of brown and beige fat activation by cold temperature. This single lipid species in thermogenic fat not only shapes adipose mitochondrial bioenergetics but also exerts profound control over whole-body insulin sensitivity and metabolic flexibility.",
keywords = "beige adipose, brown adipose, cardiolipin, CHOP-10, CRLS1, insulin resistance, lipid metabolism, mitochondria, phospholipids, thermogenesis",
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 = "Copyright {\circledC} 2018 The Author(s). Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "7",
day = "3",
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language = "English",
volume = "28",
pages = "159--174.e11",
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Sustarsic, EG, Ma, T, Lynes, MD, Larsen, M, Karavaeva, I, Havelund, JF, Nielsen, CH, Jedrychowski, MP, Moreno-Torres, M, Lundh, M, Plucinska, K, Jespersen, NZ, Grevengoed, TJ, Kramar, B, Peics, J, Hansen, JB, Shamsi, F, Forss, I, Neess, D, Keipert, S, Wang, J, Stohlmann, K, Brandslund, I, Christensen, C, Jørgensen, ME, Linneberg, A, Pedersen, O, Kiebish, MA, Qvortrup, K, Han, X, Pedersen, BK, Jastroch, M, Mandrup, S, Kjær, A, Gygi, SP, Hansen, T, Gillum, MP, Grarup, N, Emanuelli, B, Nielsen, S, Scheele, C, Tseng, YH, Færgeman, NJ & Gerhart-Hines, Z 2018, 'Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis', Cell Metabolism, bind 28, nr. 1, s. 159-174.e11. https://doi.org/10.1016/j.cmet.2018.05.003

Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis. / Sustarsic, Elahu G.; Ma, Tao; Lynes, Matthew D.; Larsen, Michael; Karavaeva, Iuliia; Havelund, Jesper F.; Nielsen, Carsten H.; Jedrychowski, Mark P.; Moreno-Torres, Marta; Lundh, Morten; Plucinska, Kaja; Jespersen, Naja Z.; Grevengoed, Trisha J.; Kramar, Barbara; Peics, Julia; Hansen, Jakob B.; Shamsi, Farnaz; Forss, Isabel; Neess, Ditte; Keipert, Susanne; Wang, Jianing; Stohlmann, Katharina; Brandslund, Ivan; Christensen, Cramer; Jørgensen, Marit E.; Linneberg, Allan; Pedersen, Oluf; Kiebish, Michael A.; Qvortrup, Klaus; Han, Xianlin; Pedersen, Bente Klarlund; Jastroch, Martin; Mandrup, Susanne; Kjær, Andreas; Gygi, Steven P.; Hansen, Torben; Gillum, Matthew P.; Grarup, Niels; Emanuelli, Brice; Nielsen, Søren; Scheele, Camilla; Tseng, Yu Hua; Færgeman, Nils J.; Gerhart-Hines, Zachary.

I: Cell Metabolism, Bind 28, Nr. 1, 03.07.2018, s. 159-174.e11.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis

AU - Sustarsic, Elahu G.

AU - Ma, Tao

AU - Lynes, Matthew D.

AU - Larsen, Michael

AU - Karavaeva, Iuliia

AU - Havelund, Jesper F.

AU - Nielsen, Carsten H.

AU - Jedrychowski, Mark P.

AU - Moreno-Torres, Marta

AU - Lundh, Morten

AU - Plucinska, Kaja

AU - Jespersen, Naja Z.

AU - Grevengoed, Trisha J.

AU - Kramar, Barbara

AU - Peics, Julia

AU - Hansen, Jakob B.

AU - Shamsi, Farnaz

AU - Forss, Isabel

AU - Neess, Ditte

AU - Keipert, Susanne

AU - Wang, Jianing

AU - Stohlmann, Katharina

AU - Brandslund, Ivan

AU - Christensen, Cramer

AU - Jørgensen, Marit E.

AU - Linneberg, Allan

AU - Pedersen, Oluf

AU - Kiebish, Michael A.

AU - Qvortrup, Klaus

AU - Han, Xianlin

AU - Pedersen, Bente Klarlund

AU - Jastroch, Martin

AU - Mandrup, Susanne

AU - Kjær, Andreas

AU - Gygi, Steven P.

AU - Hansen, Torben

AU - Gillum, Matthew P.

AU - Grarup, Niels

AU - Emanuelli, Brice

AU - Nielsen, Søren

AU - Scheele, Camilla

AU - Tseng, Yu Hua

AU - Færgeman, Nils J.

AU - Gerhart-Hines, Zachary

N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018/7/3

Y1 - 2018/7/3

N2 - 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. Sustarsic et al. reveal that synthesis of the mitochondrial phospholipid cardiolipin is a hallmark of brown and beige fat activation by cold temperature. This single lipid species in thermogenic fat not only shapes adipose mitochondrial bioenergetics but also exerts profound control over whole-body insulin sensitivity and metabolic flexibility.

AB - 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. Sustarsic et al. reveal that synthesis of the mitochondrial phospholipid cardiolipin is a hallmark of brown and beige fat activation by cold temperature. This single lipid species in thermogenic fat not only shapes adipose mitochondrial bioenergetics but also exerts profound control over whole-body insulin sensitivity and metabolic flexibility.

KW - beige adipose

KW - brown adipose

KW - cardiolipin

KW - CHOP-10

KW - CRLS1

KW - insulin resistance

KW - lipid metabolism

KW - mitochondria

KW - phospholipids

KW - thermogenesis

U2 - 10.1016/j.cmet.2018.05.003

DO - 10.1016/j.cmet.2018.05.003

M3 - Journal article

VL - 28

SP - 159-174.e11

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 1

ER -