Elevated Fra-1 expression causes severe lipodystrophy

Abstract

Research Article 1465Introduction A reciprocal interaction between bone and energy metabolism has been described, whereby a hormone secreted by adipocytes influences bone formation and a factor produced by osteoblasts regulates fat metabolism (Lieben et al., 2009;Rosen, 2008). The crucial factor in this systemic loop is leptin, because its deficiency causes obesity and increases bone formation in the mouse (Ducy et al., 2000). Leptin is produced by white adipocytes and acts via the hypothalamus to regulate appetite and to favor energy expenditure. Bone formation is also negatively regulated by leptin through a second hypothalamic pathway, the -adrenergic sympathetic nervous system (Takeda et al., 2002). This pathway increases ATF-4-dependent expression of Esp (protein tyrosine phosphatase, receptor type, V; Ptprv) in osteoblasts, which leads to an inhibition of osteocalcin bioactivity. By contrast, insulin signaling in osteoblasts promotes the production of bioactive osteocalcin via acidification of the extracellular bone matrix as a consequence of increased bone resorption by osteoclasts (Ferron et al., 2010;Fulzele et al., 2010). In turn, osteocalcin, a hormone secreted by osteoblasts, modulates fat metabolism via the stimulation of pancreatic -cell proliferation and insulin secretion and thus, can indirectly, via adiponectin, lower insulin resistance (Hinoi et al., 2008;Yoshizawa et al., 2009). Thus, a common neuroendocrine systemic co-regulation of bone and adipose mass is established.In addition to this systemic regulation of bone and fat metabolism, a local control of cell fates balancing osteoblast and adipocyte differentiation, which is still poorly understood, must exist to integrate the systemic messages. Indeed, osteoblasts share with adipocytes a common mesenchymal progenitor, the mesenchymal stromal or stem cell (MSC) from which also arise other mesenchymal cell lineages such as chondrocytes, fibroblasts and myoblasts (Caplan, 2007). Mesenchymal cell fate decisions are driven by key transcription factors that confer identity to the cell. The major transcription factors regulating MSC differentiation to osteoblasts are -catenin and Runx2, both of which are required for the differentiation to pre-osteoblasts and osterix that drives osteoblast maturation (Karsenty, 2008;Komori, 2006). Similarly, adipocyte differentiation occurs first by activation of C/EBP and C/EBP, resulting in expression of PPAR2 and C/EBP, which then regulate late stages of adipogenesis (Lefterova and Lazar, 2009). Furthermore, a number of additional factors such as bone morphogenic proteins (BMPs) and signaling, for instance through the WNT pathway, have been described to regulate cell fate decisions between osteoblasts and adipocytes by promoting commitment or differentiation into one lineage at the expense of the other (Takada et al., 2007). All these observations strongly argue in favor of a cell-autonomous locally controlled relationship between osteoblastogenesis and adipogenesis. SummaryA shift from osteoblastogenesis...

BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo

“…FOSL1 inhibits B cell differentiation by binding to the BLIMP promoter and repressing its expression (41). In addition, FOSL1 blocks differentiation of an adipogenic cell line to adipocytes by binding to the C/EBPα promoter and repressing its expression (42). Our findings in the stellate cells are consistent with a previous report showing that FOSL1 represses collagen I expression in lung epithelial cells (43).…”

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia

“…19 In addition, AP-1 proteins, such as Fra-1 and DFosB, have also been shown to regulate adipogenesis through C/EBPa or C/EBPb expression respectively, thereby decreasing adipocyte differentiation. 10,11 Moreover, Fra-2 was shown to regulate leptin expression in adipocytes and osteocalcin in osteoblasts, both of which are involved in the control of body weight and fat distribution. 15,17 By using Fabp4-CreERT tamoxifen-inducible line, we were able to analyze the role of Fra-2 inactivation in adult mice.…”

CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients

“…With regard to the fi nding of increased CDKN2B mRNA in the adipose tissue samples of FCHL patients ( Table 2 ), fi rst it is important to appreciate that suppressing the commitment of precursor cells to the adipogenic lineage can raise fasting serum triglyceride ( 77 ). Second, the consequence of impaired adipogenesis and/or dysfunctional adipocyte death on serum triglyceride levels is likely to be exacerbated in FCHL patients because of the increased production of VLDL that occurs in this condition ( 11,12 ).…”