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

Wang, Bohan; Wood, I. Stuart; Trayhurn, Paul

doi:10.1677/joe-08-0156

Cited by 126 publications

(94 citation statements)

References 49 publications

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“…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) . The overall response of preadipocytes to hypoxia appears to be blunted compared with that of adipocytes, there being some marked differences such as a lack of response in angiopoietin-like protein 4 and IL-6 expression to low O 2 tension.…”

Section: Hypoxia and Insulin Resistancesupporting

confidence: 69%

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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Section: Hypoxia and Insulin Resistancesupporting

confidence: 69%

Cellular hypoxia and adipose tissue dysfunction in obesity

et al. 2009

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“…One of the mechanisms by which Smad and p38/MAPKs are responsible for BMP2-induced adipocytic differentiation is through the induction and up-regulation of the proadipogenic transcription factor PPARγ (Hata et al, 2003). Decreased expression of PPARγ has previously been reported in hypoxic adipocytes (Yin et al, 2009) and preadipocytes (Wang et al, 2008b). However, in the present study a significant decrease in PPARγ mRNA level was not observed, but down-regulation of its activator was found, providing another plausible mechanism for hypoxia-induced inhibition of adipogenesis (Quinkler et al, 2006).…”

Section: Discussionmentioning

confidence: 97%

A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes

Mazzatti

Lim

O’Hara

et al. 2012

Archives of Physiology and Biochemistry

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“…In adipose tissue, hypoxia dysregulates the expression of some adipokines and proinflammatory cytokines (2)(3)(4)24,29,30), such as leptin, adiponectin, IL-1␤, and IL-6, although tumor necrosis factor-␣ expression seems to be insensitive to hypoxia in human adipocytes (29). These cytokines are known to be involved in the downregulation of the insulin signaling pathway and to induce local and systemic insulin resistance (2,15).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Decreases Insulin Signaling Pathways in Adipocytes

et al. 2009

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OBJECTIVE-Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated whether this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on the insulin signaling pathway in adipocytes. RESEARCH DESIGN AND METHODS-The hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic conditions (1% O 2 ) or modulation of hypoxia-inducible factor (HIF) expression. Insulin signaling was monitored through the phosphorylation state of several key partners of the pathway and glucose transport.RESULTS-In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by a decrease in the phosphorylation of insulin receptor. In 3T3-L1 adipocytes, this inhibition of insulin receptor phosphorylation is followed by a decrease in the phosphorylation state of protein kinase B and AS160, as well as an inhibition of glucose transport in response to insulin. These processes were reversible under normoxic conditions. The mechanism of inhibition seems independent of protein tyrosine phosphatase activities. Overexpression of HIF-1␣ or -2␣ or activation of HIF transcription factor with CoCl 2 mimicked the effect of hypoxia on insulin signaling, whereas downregulation of HIF-1␣ and -2␣ by small interfering RNA inhibited it.CONCLUSIONS-We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression. Hypoxia could be envisioned as a new mechanism that participates in insulin resistance in adipose tissue of obese patients. Diabetes 58:95-103, 2009 O besity results from an imbalance between energy intake and energy expenditure. Abdominal obesity and adipose tissue dysfunction are major risk factors for chronic diseases, such as insulin resistance, type 2 diabetes, and cardiovascular diseases. Insulin resistance is associated with alterations in glucose and lipid homeostasis. At the molecular level, insulin resistance is triggered by a dysregulation of the insulin signaling cascade. Insulin stimulates the tyrosine kinase activity of its receptor, leading to tyrosine phosphorylation of its substrates, such as insulin receptor substrate (IRS)-1 and -2 or Shc. They are upstream of two major signaling pathways: the phosphatidylinositol 3-kinase/protein kinase B (PKB) pathway, responsible for most of the metabolic actions of insulin, and the Rasextracellular signal-related kinase pathway, which regulates gene expression (1).During the genesis of obesity, adipose tissue is one of the first tissues affected by insulin resistance. This phenomenon is closely associated with the development of a proinflammatory state within the adipose tissue. In addition to this proinflammatory state, obesity is associated with the formation of hypoxic areas within the tissue. This has been demonstrated in obese mice (ob/ob and dietary induced obesity) using various methods, such as immunohistochemistry ...

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

Cited by 126 publications

References 49 publications

Cellular hypoxia and adipose tissue dysfunction in obesity

Cellular hypoxia and adipose tissue dysfunction in obesity

A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes

Hypoxia Decreases Insulin Signaling Pathways in Adipocytes

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