Cell‐Autonomous Brown‐Like Adipogenesis of Preadipocytes From Retinoblastoma Haploinsufficient Mice

Abstract

Mechanisms behind the emergence of brown adipocyte-like (brite or beige) adipocytes within white adipose tissue (WAT) are of interest. Retinoblastoma protein gene (Rb) haploinsufficiency associates in mice with improved metabolic regulation linked to a greater capacity for fatty acid oxidation and thermogenesis in WAT. We aimed to explain a feasible mechanism of WAT-to-BAT remodeling in this model. Differentiated primary adipocytes and Sca1-positive preadipocytes derived from adipose depots of Rb(+/-) mice and wild-type siblings were compared. Primary white Rb(+/-) adipocytes displayed under basal conditions increased glucose uptake and an enhanced expression of brown adipocyte-related genes (Pparg, Ppargc1a, Ppargc1b, Prdm16, Cpt1b) but not of purported beige/brite transcriptional markers (Cd137, Tmem26, Tbx1, Slc27a1, Hoxc9, Shox2). Lack of induction of beige markers phenocopied results in WAT of adult Rb(+/-) mice. Flow cytometry analysis evidenced an increased number of preadipocytes in WAT depots of Rb(+/-) mice. Sca1(+) preadipocytes from WAT of Rb(+/-) mice displayed increased gene expression of several transcription factors common to the brown and beige adipogenic programs (Prdm16, Pparg, Ppargc1a) and of receptors of bone morphogenetic proteins (BMPs); however, among the recently proposed beige markers, only Tbx1 was upregulated. Adult Rb(+/-) mice had increased circulating levels of BMP7. These results indicate that preadipose cells resident in WAT depots of Rb(+/-) mice retain an increased capacity for brown-like adipogenesis that appears to be different from beige adipogenesis, and suggest that the contribution of these precursors to the Rb(+/-) adipose phenotype is driven, at least in part, by interaction with BMP7 pathways. J. Cell. Physiol. 231: 1941-1952, 2016. © 2016 Wiley Periodicals, Inc.

The LXCXE Retinoblastoma Protein-Binding Motif of FOG-2 Regulates Adipogenesis

“…This cell-autonomous function of pRb, increasing the capacity for brown-like adipogenesis, was confirmed in recent studies (Hu et al, 2015;Petrov et al, 2016). Altogether, GATA, pRb, and E2F1 are intrinsically involved in adipogenesis.…”

“…Overall, the data presented here indicate that disruption of the LXCXE pRb-binding site of FOG-2 in adipocyte progenitors may induce WAT browning, providing support for a role of pRb in directing the differentiation of bipotent adipocyte precursors into white or brown adipocytes. This hypothesis is not new, and retinoblastoma protein haploinsufficiency (Mercader et al, 2009;Petrov et al, 2016), disruption (Calo et al, 2010;Dali-Youcef et al, 2007;Hansen et al, 2004), and indirect inhibition (Hu et al, 2015;Scimè et al, 2005;Wang et al, 2013) have identified pRb as a regulator of the commitment of preadipocytes to brown adipogenesis.…”

Beneficial Metabolic Effects of Chitosan and Chitosan Oligosaccharide on Epididymal WAT Browning and Thermogenesis in Obese Rats

“…Our results suggest that CTS, COST, and COSM may activate UCP1 in a PKA-MAPK-dependent manner and in a PKA-MAPK-independent manner (Supplementary Figure S2C) [33]. In addition, the lipid metabolism genes, Slc27a1 and TMEM26, which are specifically expressed in beige fat [34], are also increased with CTS, COST, and COSM treatment. The increased expression of these genes indicates an increase in WAT browning and thermogenesis, which become key strategies for addressing obesity.…”

White to beige conversion in PDE3B KO adipose tissue through activation of AMPK signaling and mitochondrial function

“…As shown in Fig. S2E, solute carrier family 27 member 1 (Slc27a1, also known as Fatp1) was increased 2.7-fold and transmembrane 26 (Tmem26) and short stature homeobox-2 (Shox2) were significantly decreased in eWAT of PDE3B KO mice21848586.…”