title: Two key temporally distinguishable molecular and cellular components of white adipose tissue browning during cold acclimation.
abstract: CONCLUSIONS
  White to brown adipose tissue conversion and thermogenesis can be ignited by different conditions or agents and its sustainability over the long term is still unclear. Browning of rat retroperitoneal white adipose tissue (rpWAT) during cold acclimation involves two temporally apparent components: (1) a predominant non-selective browning of most adipocytes and an initial sharp but transient induction of uncoupling protein 1, peroxisome proliferator-activated receptor (PPAR) coactivator-1α, PPARγ and PPARα expression, and (2) the subsistence of relatively few thermogenically competent adipocytes after 45 days of cold acclimation. The different behaviours of two rpWAT beige/brown adipocyte subsets control temporal aspects of the browning process, and thus regulation of both components may influence body weight and the potential successfulness of anti-obesity therapies.
  Conversion of white into brown adipose tissue may have important implications in obesity resistance and treatment. Several browning agents or conditions ignite thermogenesis in white adipose tissue (WAT). To reveal the capacity of WAT to function in a brownish/burning mode over the long term, we investigated the progression of the rat retroperitoneal WAT (rpWAT) browning during 45 days of cold acclimation. During the early stages of cold acclimation, the majority of rpWAT adipocytes underwent multilocularization and thermogenic-profile induction, as demonstrated by the presence of a multitude of uncoupling protein 1 (UCP1)-immunopositive paucilocular adipocytes containing peroxisome proliferator-activated receptor (PPAR) coactivator-1α (PGC-1α) and PR domain-containing 16 (PRDM16) in their nuclei. After 45 days, all adipocytes remained PRDM16 immunopositive, but only a few multilocular adipocytes rich in mitochondria remained UCP1/PGC-1α immunopositive. Molecular evidence showed that thermogenic recruitment of rpWAT occurred following cold exposure, but returned to starting levels after cold acclimation. Compared with controls (22 ± 1 °C), levels of UCP1 mRNA increased in parallel with PPARγ (PPARα from days 1 to 7 and PGC-1α on day 1). Transcriptional recruitment of rpWAT was followed by an increase in UCP1 protein content (from days 1 to 21). Results clearly showed that most of the adipocytes within rpWAT underwent transient brown-fat-like thermogenic recruitment upon stimulation, but only a minority of cells retained a brown adipose tissue-like phenotype after the attainment of cold acclimation. Therefore, browning of WAT is dependent on both maintaining the thermogenic response and retaining enough brown-like thermogenically competent adipocytes in the long-term. Both aspects of browning could be important for long-term energy homeostasis and body-weight regulation.
authors.affiliation: Department of Physiology, Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Jankovic
authors.affiliation: Faculty of Biology, Center for Electron Microscopy, University of Belgrade, Studentski trg 16, 11000, Belgrade, Serbia.
authors.forename: Igor
authors.initials: I
authors.lastname: Golic
authors.affiliation: Faculty of Biology, Center for Electron Microscopy, University of Belgrade, Studentski trg 16, 11000, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Markelic
authors.affiliation: Department of Physiology, Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Stancic
authors.affiliation: Department of Physiology, Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Otasevic
authors.affiliation: Department of Physiology, Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Biljana
authors.initials: B
authors.lastname: Buzadzic
authors.affiliation: Faculty of Biology, Center for Electron Microscopy, University of Belgrade, Studentski trg 16, 11000, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Korac
authors.affiliation: Department of Physiology, Institute for Biological Research 'Sinisa Stankovic', University of Belgrade, Bulevar despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Bato
authors.initials: B
authors.lastname: Korac
mesh_terms: D000064:Acclimatization; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000502:physiology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D003080:Cold Temperature; D058639:Cold-Shock Response; D004734:Energy Metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D011930:Reaction Time; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000605624:PRDM16 protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1