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RESEARCH PRODUCT
Cardiolipin synthesis in brown and beige fat mitochondria is essential for systemic energy homeostasis
Torben HansenAllan LinnebergAllan LinnebergMorten LundhBente Klarlund PedersenNils J. FærgemanMarta Moreno-torresKatharina StohlmannXianlin HanJulia PeicsMartin JastrochSusanne MandrupElahu G. SustarsicBarbara KramarAndreas KjaerCamilla ScheeleMatthew P. GillumIuliia KaravaevaTrisha J. GrevengoedCramer ChristensenNiels GrarupYu-hua TsengMatthew D. LynesMark P. JedrychowskiKaja PlucinskaDitte NeessOluf PedersenCarsten H. NielsenMarit E. JørgensenMarit E. JørgensenIvan BrandslundMichael LarsenZachary Gerhart-hinesJakob Bondo HansenFarnaz ShamsiMichael A. KiebishBrice EmanuelliSusanne KeipertSøren NielsenSteven P. GygiTao MaJianing WangIsabel ForssJesper F. HavelundNaja Z. JespersenKlaus Qvortrupsubject
0301 basic medicineBiologiaBioenergeticsChop-10 ; Crls1 ; Beige Adipose ; Brown Adipose ; Cardiolipin ; Insulin Resistance ; Lipid Metabolism ; Mitochondria ; Phospholipids ; ThermogenesisPhysiologyGlucose uptakeAdipose tissueTransferases (Other Substituted Phosphate Groups)MitochondrionEnergy homeostasischemistry.chemical_compoundMice0302 clinical medicineAdipose Tissue Browninsulin resistancelipid metabolismCardiolipinAdipocytesCells CulturedThermogenesisthermogenesisCell biologyMitochondriamitochondriaCHOP-10lipids (amino acids peptides and proteins)BioquímicaCardiolipinsbeige adiposeArticle03 medical and health sciencesInsulin resistanceCRLS1medicineAnimalsHumansMolecular Biologyphospholipidsbrown adiposeMembrane ProteinsCell BiologyAdipose Tissue Beigemedicine.diseaseMice Inbred C57BL030104 developmental biologychemistrycardiolipinEnergy MetabolismThermogenesis030217 neurology & neurosurgerydescription
Summary 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-01-01 |