Hypoxia Inhibition of Adipocytogenesis in Human Bone Marrow Stromal Cells Requires Transforming Growth Factor-β/Smad3 Signaling

Zhou, Shuanhu; Lechpammer, Stanislav; Greenberger, Joel S.; Glowacki, Julie

doi:10.1074/jbc.m412953200

Cited by 87 publications

(88 citation statements)

References 71 publications

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“…These findings support a recent findings demonstrating that Twist-1 interferes with BMP-2 induced expression of collagen type II and aggrecan [50]. Interestingly, the present study found that adipose accumulation and adipogenic related gene expression were enhanced in human MSC cultures following enforced expression of either Twist-1 or Dermo-1, consistent with studies showing that suppression of osteo/chondrogenesis via BMP/ TGFb signaling is associated with increased adipogenesis [50,[63][64][65][66][67]. Therefore, it is likely that a reciprocal regulation of the Twist transcription factors occurs with different BMP/TGFb and Wnt signaling components that collectively act to regulate the lineage commitment of MSC toward adipogenic or ostechondrogenic development [49,50,62,65,68].…”

Section: Discussionsupporting

confidence: 81%

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

et al. 2009

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The TWIST family of basic helix-loop-helix transcription factors, Twist-1 and Dermo-1 are known mediators of mesodermal tissue development and contribute to correct patterning of the skeleton. In this study, we demonstrate that freshly purified human bone marrow-derived mesenchymal stromal/stem cells (MSC) express high levels of Twist-1 and Dermo-1 which are downregulated following ex vivo expansion. Enforced expression of Twist-1 or Dermo-1 in human MSC cultures increased expression of the MSC marker, STRO-1, and the early osteogenic transcription factors, Runx2 and Msx2. Conversely, overexpression of Twist-1 and Dermo-1 was associated with a decrease in the gene expression of osteoblast-associated markers, bone morphogenic protein-2, bone sialoprotein, osteopontin, alkaline phosphatase and osteocalcin. High expressing Twist-1 or Dermo-1 MSC lines exhibited an enhanced proliferative potential of approximately 2.5-fold compared with control MSC populations that were associated with elevated levels of Id-1 and Id-2 gene expression. Functional studies demonstrated that high expressing Twist-1 and Dermo-1 MSC displayed a decreased capacity for osteo/chondrogenic differentiation and an enhanced capacity to undergo adipogenesis. These findings implicate the TWIST gene family members as potential mediators of MSC self-renewal and lineage commitment in postnatal skeletal tissues by exerting their effects on genes involved in the early stages of bone development.

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Section: Discussionsupporting

confidence: 81%

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

et al. 2009

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“…The inhibition by low O 2 tension in the present study was greater in the adipocytes than preadipocytes. Adipocyte differentiation has been shown to be inhibited by incubation under hypoxic conditions and the reduction in PPARg gene expression appears to be a key part of the mechanistic explanation for this (Yun et al 2002, Carriere et al 2004, Kim et al 2005, Zhou et al 2005.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes

Wang¹,

Wood²,

Trayhurn³

2008

Journal of Endocrinology

131

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The effect of hypoxia on the expression and secretion of major adipokines by human preadipocytes has been examined. Hypoxia (1% O 2 ) led to an increase in the HIF-1a transcription factor subunit in cultured preadipocytes, as did incubation with the hypoxia mimetic CoCl 2 . Leptin mRNA was essentially undetectable in preadipocytes incubated under normoxia (21% O 2 ), but exposure to 1% O 2 , or CoCl 2 , for 4 or 24 h resulted in an induction of leptin gene expression (measured by real-time PCR). Immunoreactive leptin was not detected in the medium from normoxic preadipocytes, but was present in the medium from the hypoxic cells. Hypoxia stimulated expression of the GLUT-1 facilitative glucose transporter gene and the vascular endothelial growth factor (VEGF) gene in preadipocytes, as in adipocytes. PPARg and aP2 mRNA levels, markers of adipocyte differentiation, were reduced by hypoxia in both cell types. In marked contrast to adipocytes, interleukin-6 (IL-6), angiopoietin-like protein 4, and plasminogen activator inhibitor-1 expression by preadipocytes was not stimulated by low O 2 tension. Consistent with the gene expression results, VEGF release into the medium from preadipocytes was increased by hypoxia, but there was no change in IL-6 secretion. It is concluded that hypoxia induces human preadipocytes to synthesize and secrete leptin. Preadipocytes and adipocytes differ in their responsiveness to low O 2 tension, maturation of the response to hypoxia developing on differentiation.

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“…They have also been found to secrete increased levels of IL-1b and TNFa in response to leptin (62) . Hypoxia has been shown to inhibit differentiation of mouse preadipocytes, probably as a result of a decrease in PPARg levels (63)(64)(65)(66) . Consistent with this outcome are findings in human preadipocytes in which exposure to hypoxic conditions results in a fall in PPARg gene expression, together with increased HIF-1a protein and GLUT-1 expression (67) .…”

Section: Hypoxia and Insulin Resistancementioning

confidence: 99%

Cellular hypoxia and adipose tissue dysfunction in obesity

et al. 2009

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Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFa, IL-1b, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O 2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammationrelated adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O 2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity.

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Hypoxia Inhibition of Adipocytogenesis in Human Bone Marrow Stromal Cells Requires Transforming Growth Factor-β/Smad3 Signaling

Cited by 87 publications

References 71 publications

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

TWIST Family of Basic Helix-Loop-Helix Transcription Factors Mediate Human Mesenchymal Stem Cell Growth and Commitment

Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes

Cellular hypoxia and adipose tissue dysfunction in obesity

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