Ma 2018 MiPschool Tromso C1

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Cardiolipin synthesis in brown and beige fat mitochondria is essential for systemic energy homeostasis.

Link: MitoEAGLE

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, Joergensen ME, Linneberg A, Pedersen O, Kiebish MA, Qvortrup K, Han X, Pedersen BK, Jastroch M, Mandrup S, Kjaer A, Gygi SP, Hansen T, Gillum MP, Grarup N, Emanuelli B, Nielsen S, Scheele C, Tseng YH, Faergeman NJ, Gerhart-Hines Z (2018)

Event: MiPschool Tromso-Bergen 2018


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: Cardiolipin, CRLS1, Phospholipidslipid, Metabolism, Mitochondria, Brown adipose, Beige adipose, Thermogenesis, Insulin resistance, CHOP-10 Bioblast editor: Plangger M


Organism: Human, Mouse  Tissue;cell: Fat 

Event: C1, Oral 


Sustarsic EG(1,2), Ma T(1,2), Lynes MD(3), Larsen M(2), Karavaeva I(1,2), Havelund JF(4), Nielsen CH(2,5), Jedrychowski MP(6), Moreno-Torres M(4), Lundh M(1), Plucinska K(1), Jespersen NZ(1,7), Grevengoed TJ(1), Kramar B(1), Peics J(1,2), Hansen JB(1,2), Shamsi F(3), Forss I(4), Neess D(4), Keipert S(8), Wang J(9), Stohlmann K(1), Brandslund I(10,11), Christensen C(10), Jørgensen ME(12,13), Linneberg A(14,15,16), Pedersen O(1), Kiebish MA(17), Qvortrup K(2), Han X(9), Pedersen BK(7), Jastroch M(8), Mandrup S(4), Kjær A(2,5), Gygi SP(6), Hansen T(1), Gillum MP(1), Grarup N(1), Emanuelli B(1), Nielsen S(7), Scheele C(1,7), Tseng YH(3), Færgeman NJ(4), Gerhart-Hines Z(1,2).

  1. Novo Nordisk Foundation Center Basic Metabolic Research
  2. Dept Biomedical Sciences; Univ Copenhagen, Denmark
  3. Section Integrative Physiology Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
  4. Dept Biochemistry Molecular Biol, Univ Southern Denmark, Odense, Denmark
  5. Dept Clinical Physiology, Nuclear Medicine PET Cluster Molecular Imaging, Rigshospitalet, Copenhagen, Denmark
  6. Dept Cell Biol, Harvard Medical School, Boston, MA, USA
  7. Centre Inflammation Metabolism and Centre Physical Activity Research, Rigshospitalet, Univ Hospital Copenhagen, Denmark
  8. Helmholtz Diabetes Center and German Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany
  9. Barshop Inst Longevity Aging Studies, Univ Texas Health Science Center San Antonio, TX, USA
  10. Lillebaelt Hospital, Vejle, Denmark
  11. Inst Regional Health Research, Univ Southern Denmark, Odense, Denmark
  12. Steno Diabetes Center, Gentofte, Denmark
  13. National Inst Public Health, Southern Denmark Univ, Copenhagen, Denmark
  14. Research Center Prevention Health, Glostrup, Denmark
  15. Center Clinical Research Prevention, Bispebjerg Frederiksberg Hospital, Copenhagen, Denmark
  16. Dept Clinical Medicine, Univ Copenhagen, Denmark
  17. BERG Health, Framingham, MA, USA