title: UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment.
abstract: Cidea is a gene highly expressed in thermogenesis-competent (UCP1-containing) adipose cells, both brown and brite/beige. Here, we initially demonstrate a remarkable adipose-depot specific regulation of Cidea expression. In classical brown fat, Cidea mRNA is expressed continuously and invariably, irrespective of tissue recruitment. However, Cidea protein levels are regulated posttranscriptionally, being conspicuously induced in the thermogenically recruited state. In contrast, in brite fat, Cidea protein levels are regulated at the transcriptional level, and Cidea mRNA and protein levels are proportional to tissue "briteness." Although routinely followed as a thermogenic molecular marker, Cidea function is not clarified. Here, we employed a gain-of-function approach to examine a possible role of Cidea in the regulation of thermogenesis. We utilized transgenic aP2-hCidea mice that overexpress human Cidea in all adipose tissues. We demonstrate that UCP1 activity is markedly suppressed in brown-fat mitochondria isolated from aP2-hCidea mice. However, mitochondrial UCP1 protein levels were identical in wild-type and transgenic mice. This implies a regulatory effect of Cidea on UCP1 activity, but as we demonstrate that Cidea itself is not localized to mitochondria, we propose an indirect inhibitory effect. The Cidea-induced inhibition of UCP1 activity (observed in isolated mitochondria) is physiologically relevant since the mice, through an appropriate homeostatic compensatory mechanism, increased the total amount of UCP1 in the tissue to exactly match the diminished thermogenic capacity of the UCP1 protein and retain unaltered nonshivering thermogenic capacity. Thus, we verified Cidea as being a marker of thermogenesis-competent adipose tissues, but we conclude that Cidea, unexpectedly, functions molecularly as an indirect inhibitor of thermogenesis.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.|Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Fischer
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Shabalina
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Mattsson
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Abreu-Vieira
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannon
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; natasa.petrovic@su.se.
authors.forename: Natasa
authors.initials: N
authors.lastname: Petrovic
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000473:pathology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002153:Calorimetry, Indirect; D003080:Cold Temperature; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022722:Thermogenesis / Q000235:genetics*; D000071256:Uncoupling Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C502539:CIDEA protein, human; D012333:RNA, Messenger; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1
keywords: beige adipose tissue; brite adipose tissue; brown adipose tissue; cell death-inducing DNA fragmentation factor α-like effector A; nonshivering thermogenesis; uncoupling protein 1