Increased Energy Expenditure and Insulin Sensitivity in the High Bone Mass ΔFosB Transgenic Mice

Department of Orthopaedics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Endocrinology (Impact Factor: 4.5). 10/2008; 150(1):135-43. DOI: 10.1210/en.2008-0678
Source: PubMed


Obesity and osteoporosis are major health issues affecting millions of individuals. Transgenic mice overexpressing DeltaFosB, an activator protein-1 transcription factor, under the control of the enolase 2 (ENO2) promoter exhibit both an increase in bone density and a decrease in adipose mass. Here we demonstrate that DeltaFosB overexpression increases fatty-acid oxidation and energy expenditure, leading to a decrease in adipocyte size and adipose mass. In addition, the ENO2-DeltaFosB mice exhibit increased insulin sensitivity and glucose tolerance. Targeted overexpression of DeltaFosB in adipocytes using the adipocyte protein 2 promoter failed to induce changes in fat or in bone, showing that the effect on metabolic activity is not due to cell-autonomous effects of DeltaFosB within adipocytes. Detailed analysis of the ENO2-DeltaFosB mice demonstrated that energy expenditure was increased in muscle, independent of locomotor activity. These findings provide evidence that signaling downstream of DeltaFosB is a potential target for not only osteoporosis but also obesity and diabetes.

Download full-text


Available from: Glenn C Rowe, Jan 28, 2014
26 Reads
  • Source
    • "Osteocalcin was recently characterized as a hormone that regulates insulin production by increasing -cell proliferation (Lee et al., 2007). Surprisingly, but similarly to the DfosBtg mice (Rowe et al., 2009), the increased circulating osteocalcin in Fra1tg mice did not result in an increased level of circulating insulin or in an increased number or volume of "
    [Show abstract] [Hide abstract]
    ABSTRACT: A shift from osteoblastogenesis to adipogenesis is one of the underlying mechanisms of decreased bone mass and increased fat during aging. We now uncover a new role for the transcription factor Fra-1 in suppressing adipogenesis. Indeed, Fra1 (Fosl1) transgenic (Fra1tg) mice, which developed progressive osteosclerosis as a result of accelerated osteoblast differentiation, also developed a severe general lipodystrophy. The residual fat of these mice appeared immature and expressed lower levels of adipogenic markers, including the fatty acid transporter Cd36 and the CCAAT/enhancer binding protein Cebpa. Consequently accumulation of triglycerides and free fatty acids were detected in the serum of fasting Fra1tg mice. Fra-1 acts cell autonomously because the adipogenic differentiation of Fra1 transgenic primary osteoblasts was drastically reduced, and overexpression of Fra-1 in an adipogenic cell line blocked their differentiation into adipocytes. Strikingly, Cebpa was downregulated in the Fra-1-overexpressing cells and Fra-1 could bind to the Cebpa promoter and directly suppress its activity. Thus, our data add to the known common systemic control of fat and bone mass, a new cell-autonomous level of control of cell fate decision by which the osteogenic transcription factor Fra-1 opposes adipocyte differentiation by inhibiting C/EBPα.
    Journal of Cell Science 05/2011; 124(Pt 9):1465-76. DOI:10.1242/jcs.079855 · 5.43 Impact Factor
  • Source
    • "We sought to further investigate the Zfp521-mediated antagonism of Runx2 activity by generating bitransgenic mice in which overexpression of Zfp521 was regulated by the enolase 2 (ENO2) promoter (ENO2-tTA;TetOp-Zfp521 mice, hereafter referred to as Zfp521 Tg mice). We successfully used this bitransgenic system in earlier osteoblast-related work (Sabatakos et al., 2000, 2008; Rowe et al., 2009) and selected it for this study because the ENO2 promoter is active in both early osteoblasts (Fig. S1 A) and in more mature osteoblasts in the long bones of adult mice (Fig. S4 A). In addition, the ENO2 promoter is not regulated by Runx2 (unpublished data), unlike many of the classical promoters used to control overexpression in subsets of osteoblasts such as Osx, Collagen I, or Osteocalcin. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Runx2 is indispensable for osteoblast lineage commitment and early differentiation but also blocks osteoblast maturation, thereby causing bone loss in Runx2 transgenic mice. Zinc finger protein 521 (Zfp521) antagonizes Runx2 in vivo. Eliminating one Zfp521 allele mitigates the cleidocranial dysplasia-like phenotype of newborn Runx2(+/-) mice, whereas overexpressing Zfp521 exacerbates it. Overexpressing Zfp521 also reverses the severe osteopenia of adult Runx2 transgenic mice. Zfp521 binds to both Runx2 and histone deacetylase 3 (HDAC3), promotes their association, and antagonizes Runx2 transcriptional activity in an HDAC3-dependent manner. Mutating the Zfp521 zinc finger domains 6 and 26 reduces the binding of Zfp521 to Runx2 and inhibition of Runx2 activity. These data provide evidence that Zfp521 antagonizes Runx2 in vivo and thereby regulates two stages of osteoblast development, early during mesenchymal cell lineage commitment and later during osteoblast maturation. Thus, the balance and molecular interplay between Zfp521 and Runx2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis.
    The Journal of Cell Biology 12/2010; 191(7):1271-83. DOI:10.1083/jcb.201009107 · 9.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging leads to the disruption of the homeostatic balance of multiple biological systems. In bone marrow multipotent mesenchymal cells undergo differentiation into various anchorage-dependent cell types, including osteoblasts and adipocytes. With age as well as with treatment of antidiabetic drugs such as thiazolidinediones, mesenchymal cells favor differentiation into adipocytes, resulting in an increased number of adipocytes and a decreased number of osteoblasts, causing osteoporosis. The mechanism behind this differentiation switch is unknown. Here we show an age-related decrease in the expression of Maf in mouse mesenchymal cells, which regulated mesenchymal cell bifurcation into osteoblasts and adipocytes by cooperating with the osteogenic transcription factor Runx2 and inhibiting the expression of the adipogenic transcription factor Pparg. The crucial role of Maf in both osteogenesis and adipogenesis was underscored by in vivo observations of delayed bone formation in perinatal Maf(-/-) mice and an accelerated formation of fatty marrow associated with bone loss in aged Maf(+/-) mice. This study identifies a transcriptional mechanism for an age-related switch in cell fate determination and may provide a molecular basis for novel therapeutic strategies against age-related bone diseases.
    The Journal of clinical investigation 09/2010; 120(10):3455-65. DOI:10.1172/JCI42528 · 13.22 Impact Factor
Show more