Inhibition of brown adipocyte differentiation is also observed in transgenic mice where Wnt10b is overexpressed from the FABP4 promoter. The work of Tseng and coworkers supports this idea as they observed an inverse relationship between expression of Wnt10a and the ability of various insulin receptor substrate-deficient cells to differentiate into brown adipocytes (54). Both of these factors are expressed in preadipocytes and BAT but not within differentiated brown adipocytes (Fig. Endogenous signaling in brown adipocytes is likely mediated by Wnt10a and/or Wnt10b. To overcome the suppression of UCP1 by Wnt signaling requires expression of PPAR ␥ and the important metabolic coactivator PGC-1 ␣ (Fig. Enforced expression of PPAR ␥ or C/EBP ␣ in Wnt10b- expressing Rb Ϫ / Ϫ MEFs rescues the adipogenic program but not the thermogenic program (i.e., expression of UCP1). Activation of canonical Wnt signaling in Rb MEFs and HIB-1B cells inhibits accumulation of lipid and blocks expression of adipocyte genes, including the brown adipocyte marker, UCP1 (Fig. In the present study, we use cell culture and transgenic models to investigate mechanisms whereby Wnt signaling regulates differentiation and metabolism of brown adipocytes. We also demonstrated that expression of Wnt10b from the FABP4 promoter results in a lack of functional BAT (33). We have shown previously that activation of Wnt signaling inhibits differentiation of preadipocytes in vitro and development of white adipocytes in vivo (3, 26, 33, 48). The inverse relationship between Wnt10b and expression of PGC-1 ␣ and UCP1 in interscapular tissue of ob/ob mice provides further correlative evidence that Wnt signaling inhibits metabolism of brown adipocytes. 7B), and although not statis- tically significant, the twofold increase in Wnt10a expression suggests that additional Wnt signaling components may also be regulated (Fig. We report here that expression of Wnt10b in interscapular tissue of ob/ob mice is increased by about 2.5-fold (Fig. Consistent with previous reports (10, 25), the interscapular tissue of ob/ob mice has characteristics of WAT, with a high proportion of unilocular fat cells and reduced expression of UCP1 and PGC-1 ␣ (Fig. To establish whether reciprocal regulation of UCP1 and Wnt10b also occurs in physiological states where thermogenesis is suppressed, we explored leptin-deficient mice ( ob/ob ) as a model. These data are consistent with alterations in Wnt10b and with Wnt signaling components’ playing a regulatory role in expression of PGC-1 ␣ and UCP1 and, thus, adaptive thermogenesis. Although differences could not be detected with Wnt10a, the cold challenge stimulated a 40% decline in Wnt10b expression.
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