Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1α

Abstract

The Rb family, Rb, p107, and p130, play important roles in cell cycle control and cellular differentiation, and Rb has been suggested to regulate adipocyte differentiation. We report here that mice lacking p107 displayed a uniform replacement of white adipose tissue (WAT) with brown adipose tissue (BAT). Mutant WAT depots contained mutilocular adipocytes that expressed elevated levels of PGC-1alpha and UCP-1 typical of BAT. WAT from p107-/- mice contained markedly elevated numbers of adipogenic precursors that displayed downregulated expression of pRb. Consistent with the hypothesis that pRb is required for adult adipocyte differentiation, Cre-mediated deletion of Rb in adult primary preadipocytes blocked their differentiation into white adipocytes. Importantly, pRb was observed to bind the PGC-1alpha promoter and repress transcription. Therefore, p107 and pRb regulate PGC-1alpha expression to control the switch between white and brown adipocyte differentiation from a common pool of presumptive adult progenitors in fat tissue.

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

“…S2). Because mrSC is a cell population enriched under the tissue culture conditions used here, and because it was shown previously to be related to the adherent fraction of FACS-sorted S þ CL À cells, (21,24,26) we verified whether S þ CL À also could initiate an osteogenic program. Our results show that similar to mrSCs, cultured FACS-sorted S þ CL À cells display high AlkP activity staining following BMP-9 stimulation compared with unstimulated S þ CL À cells (Supplemental Fig.…”

“…(18,21,24) Briefly, gastrocnemius muscle was minced and digested with collagenase I (Sigma-Aldrich, Mississauga, Ontario, Canada) for 45 minutes at 378C. The tissue slurry was washed with DMEM containing 10% fetal bovine serum (FBS; Hyclone, Nepean, Ontario, Canada) and poured through a 100-mm and then a 50-mm cell strainer (BD Falcon, Mississauga, Ontario, Canada).…”

“…To quantify alkaline phosphatase activity, the pixel densities of the images were measured using a monochrome conversion of the images and a homemade script in ImageJ (Version 1.42q; National Institutes of Health, Bethesda, MD, USA). (32) Flow cytometric analysis and cell sorting mrSCs are adherent cells with a fibroblastic morphology that express the cell surface marker stem cell antigen (Sca1 þ ) but not endothelial and hematopoietic cell surface markers [CD31 and lineage (Lin)] (21,24,26) (Supplemental Fig. S1).…”

“…(21)(22)(23) In culture, mrSCs are multipotent and can differentiate into many mesodermal cell lineages. (21,(23)(24)(25)(26) One important characteristic of mrSCs is their high immunoreactivity with anti-Sca1 antibody. This peculiarity also has been used extensively, alone or in combination with other cell surface antigens, to identify and/or enrich mrSCs.…”

Le double jeu des régulateurs du cycle cellulaire

“…Lorsque le gène pRb est invalidé sélectivement dans le tissu adipeux, on note une augmentation de l'expression de nombreux gènes impliqués dans la fonction mitochondriale suggérant que pRb réprime l'activité mitochondriale [27]. Plus précisément, la protéine pRb se fixe directement sur le promoteur du gène peroxisome proliferator coactivator-1 alpha (PGC-1 alpha) et réprime sa transcription [28,34]. Enfin, l'inhibition du facteur de transcription E2F1 par ARN interférence dans les cellules Hela induit une augmentation de l'expression de gènes impliqués dans la biogenèse et la fonction mitochondriales [29].…”