Two key temporally distinguishable molecular and cellular components of white adipose tissue browning during cold acclimation

摘要

Conversion of white into brown adipose tissue may have important implicationsin obesity resistance and treatment. Several browning agents or conditions ignite thermo-genesis in white adipose tissue (WAT). To reveal the capacity of WAT to function in abrownish/burning mode over the long term, we investigated the progression of the ratretroperitoneal WAT (rpWAT) browning during 45 days of cold acclimation. During the earlystages of cold acclimation, the majority of rpWAT adipocytes underwent multilocularizationand thermogenic-profile induction, as demonstrated by the presence of a multitude ofuncoupling protein 1 (UCPl)-immunopositive paucilocular adipocytes containing peroxisomeproliferator-activated receptor (PPAR) coactivator-lAlpha (PGC-lAlpha） 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 UCPl/PGC-lAlpha immuno-positive. Molecular evidence showed that thermogenic recruitment of rpWAT occurred followingcold exposure, but returned to starting levels after cold acclimation. Compared with controls(22 ± 1°C), levels of UCP1 mRNA increased in parallel with PPARGamma (PPARa from days 1 to 7and PGC-lAlpha on day 1). Transcriptional recruitment of rpWAT was followed by an increase inUCP1 protein content (from days 1 to 21). Results clearly showed that most of the adipocyteswithin 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 attainmentof cold acclimation. Therefore, browning of WAT is dependent on both maintaining the thermo-genic response and retaining enough brown-like thermogenically competent adipocytes in thelong-term. Both aspects of browning could be important for long-term energy homeostasis andbody-weight regulation.