Adult-onset degeneration of adipose tissue in mice deficient for the Sox8 transcription factor

Guth, Sabine; Schmidt, Katy; Heß, Andreas; Wegner, Michael

doi:10.1194/jlr.m800531-jlr200

Cited by 10 publications

(9 citation statements)

References 52 publications

(73 reference statements)

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“…Interestingly, the very similar phenotype, including the cell-autonomous increased bone mass associated with the decreased fat mass, was also observed in two other mouse models, the ENO2-DfosB transgenic mice (Sabatakos et al, 2000) and the Sox8-deficient mice (Guth et al, 2009;Schmidt et al, 2005). In both cases, the fat phenotypes were shown to be associated with a cell-autonomous defect in adipocyte differentiation.…”

Section: Discussionsupporting

confidence: 56%

Elevated Fra-1 expression causes severe lipodystrophy

Luther

Drießler

Megges

et al. 2011

Journal of Cell Science

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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...

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Section: Discussionsupporting

confidence: 56%

Elevated Fra-1 expression causes severe lipodystrophy

Luther

Drießler

Megges

et al. 2011

Journal of Cell Science

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“…Lines between genes indicate a direct gene–gene interaction from the HINT database ( Das and Yu 2012 ). Gene names that are underlined, in boldface type, and italicized represent genes that have been previously associated with the ulcerative colitis ( Duerr et al 2006 ; Raelson et al 2007 ; WTCCC 2007 ; Barrett et al 2008 ; Silverberg et al 2009 ; Franke et al 2010 ; McGovern et al 2010 ; Anderson et al 2011 ; Festen et al 2011 ; Ellinghaus et al 2012 ; Jostins et al 2012 ; Scharl et al 2012 ; Parkes et al 2013 ), attention-deficit/hyperactivity disorder ( Wan et al 1998 ; Maden 2007 ; Davis et al 2008 ; Naka et al 2008 ; McGrath et al 2009 ; Need et al 2009 ; Chen et al 2010 ; Cirulli et al 2010 , 2012 ; Fuentealba et al 2010 ; Neale et al 2010 ; Hu et al 2011 ; Luciano et al 2011 ; Tang et al 2011 ; De Jager et al 2012 ; Rivière et al 2012 ; Schuurs-Hoeijmakers et al 2012 ; Peixoto and Abel 2013 ; Rietveld et al 2013 ), and waist–hip ratio ( Cantile et al 2003 ; Eguchi et al 2008 , 2011 ; Guth et al 2009 ; Hagberg et al 2010 ; Heid et al 2010 ; Siervo et al 2012 ;…”

Section: Resultsmentioning

confidence: 99%

“…HOXA9 and EMX2 , another homeobox gene, were induced after extreme weight loss following bariatric surgery ( Tchkonia et al 2013 ). The subnetwork shows SOX8 , which encodes a transcription factor thought to play a role in development; mice deficient in SOX8 develop surprisingly normally, but undergo a severe degeneration of adipose tissue as adult mice ( Guth et al 2009 ). Guth et al (2009) posit that SOX8 plays a role in adipocyte development, especially during replenishment of the adipocyte pool in adult mice.…”

Section: Resultsmentioning

confidence: 99%

“…The subnetwork shows SOX8 , which encodes a transcription factor thought to play a role in development; mice deficient in SOX8 develop surprisingly normally, but undergo a severe degeneration of adipose tissue as adult mice ( Guth et al 2009 ). Guth et al (2009) posit that SOX8 plays a role in adipocyte development, especially during replenishment of the adipocyte pool in adult mice. IRF4 is also contained in this subnetwork and encodes interferon regulatory factor 4 (IRF4), which is part of a family of transcription factors that are involved in various immune functions including regulation of innate immunity via the Toll-like receptor (TLR) signaling pathway ( Eguchi et al 2011 ).…”

Section: Resultsmentioning

confidence: 99%

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Gene and Network Analysis of Common Variants Reveals Novel Associations in Multiple Complex Diseases

2016

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Genome-wide association (GWA) studies typically lack power to detect genotypes significantly associated with complex diseases, where different causal mutations of small effect may be present across cases. A common, tractable approach for identifying genomic elements associated with complex traits is to evaluate combinations of variants in known pathways or gene sets with shared biological function. Such gene-set analyses require the computation of gene-level P-values or gene scores; these gene scores are also useful when generating hypotheses for experimental validation. However, commonly used methods for generating GWA gene scores are computationally inefficient, biased by gene length, imprecise, or have low true positive rate (TPR) at low false positive rates (FPR), leading to erroneous hypotheses for functional validation. Here we introduce a new method, PEGASUS, for analytically calculating gene scores. PEGASUS produces gene scores with as much as 10 orders of magnitude higher numerical precision than competing methods. In simulation, PEGASUS outperforms existing methods, achieving up to 30% higher TPR when the FPR is fixed at 1%. We use gene scores from PEGASUS as input to HotNet2 to identify networks of interacting genes associated with multiple complex diseases and traits; this is the first application of HotNet2 to common variation. In ulcerative colitis and waist–hip ratio, we discover networks that include genes previously associated with these phenotypes, as well as novel candidate genes. In contrast, existing methods fail to identify these networks. We also identify networks for attention-deficit/hyperactivity disorder, in which GWA studies have yet to identify any significant SNPs.

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“…At the same time, body composition analysis on older male mice suggests a shift from away from body fat towards increased lean body mass, which is similar to Sox8 −/− mutant mice, which also show reduced growth (42). Sox8 −/− mice display progressive adult-onset adipose tissue degeneration (43) and low bone mass (44), which are additional potential causes of growth deficiency in Sox21 −/− mice, but not included within the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

Sox21 deletion in mice causes postnatal growth deficiency without physiological disruption of hypothalamic-pituitary endocrine axes

Cheung

Camper

2017

Molecular and Cellular Endocrinology

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The hypothalamic-pituitary axes are the coordinating centers for multiple endocrine gland functions and physiological processes. Defects in the hypothalamus or pituitary gland can cause reduced growth and severe short stature, affecting approximately 1 in 4000 children, and a large percentage of cases of pituitary hormone deficiencies do not have an identified genetic cause. SOX21 is a protein that regulates hair, neural, and trophoblast stem cell differentiation. Mice lacking Sox21 have reduced growth, but the etiology of this growth defect has not been described. We studied the expression of Sox21 in hypothalamic-pituitary development and examined multiple endocrine axes in these mice. We find no evidence of reduced intrauterine growth, food intake, or physical activity, but there is evidence for increased energy expenditure in mutants. In addition, despite changes in pituitary hormone expression, hypothalamic-pituitary axes appear to be functional. Therefore, SOX21 variants may be a cause of non-endocrine short stature in humans.

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Adult-onset degeneration of adipose tissue in mice deficient for the Sox8 transcription factor

Cited by 10 publications

References 52 publications

Elevated Fra-1 expression causes severe lipodystrophy

Elevated Fra-1 expression causes severe lipodystrophy

Gene and Network Analysis of Common Variants Reveals Novel Associations in Multiple Complex Diseases

Sox21 deletion in mice causes postnatal growth deficiency without physiological disruption of hypothalamic-pituitary endocrine axes

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