Role of β3-adrenergic receptors in the action of a tumour lipid mobilizing factor

Russell, Stewart; Hirai, Kouzo; Tisdale, Michael J.

doi:10.1038/sj.bjc.6600086

Cited by 115 publications

(68 citation statements)

References 20 publications

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“…The lipolytic effect of ZAG was shown to be attenuated by the 3-adrenoreceptor (3-AR) antagonist, SR59230A (10), and shown to bind to the 3-AR through a high affinity binding site (Kd 78±4.5nM) (11). These results suggest that lipolysis mediated by ZAG is mediated through a 3-AR.…”

mentioning

confidence: 60%

“…Since ZAG is much larger than the normal catecholamine agonists it is possible that activation occurs through allosteric modulation. However, previous studies using LMF (11) have shown binding to be completely attenuated by propranolol, suggesting direct interaction with a 3-AR. It is likely that only part of the ZAG molecule is required for binding, since evidence from our own laboratory, and that of others (42) have suggested that tryptic fragments of a lipolytic factor (Mr about 5kDa) were still biologically active.…”

Section: Discussionmentioning

confidence: 81%

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Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Russell

Tisdale

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Objectives:The goal of the current study is to determine whether the -adrenoreceptor (-AR) plays a role in the anti-obesity and anti-diabetic effects of zinc-2-glycoprotein (ZAG). Material and Methods:This has been investigated in CHO-K1 cells transfected with the human 1-, 2-, 3-AR and in ob/ob mice. Cyclic AMP assays were carried out along with binding studies. Ob/ob mice were treated with ZAG and glucose transportation and insulin were examined in the presence or absence of propranonol.Results: ZAG bound to the 3-AR with higher affinity (Kd 46+1nM) than the 2-AR (Kd 71+3nM) while there was no binding to the 1-AR, and this correlated with the increases in cyclic AMP in CHO-K1 cells transfected with the various -AR and treated with ZAG. Treatment of ob/ob mice with ZAG increased protein expression of 3-AR in gastrocnemius muscle, and in white and brown adipose tissue, but had no effect on expression of 1-and 2-AR. A reduction of body weight was seen and urinary glucose excretion, increase in body temperature, reduction in maximal plasma glucose and insulin levels in the oral glucose tolerance test, and stimulation of glucose transport into skeletal muscle and adipose tissue, was completely attenuated by the non-specific -AR antagonist propranolol. Conclusion:The results suggest that the effects of ZAG on body weight and insulin sensitivity in ob/ob mice are manifested through a -3AR, or possibly a 2-AR.

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mentioning

confidence: 60%

Section: Discussionmentioning

confidence: 81%

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Russell

Tisdale

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…The lipolytic effect of ZAG has been postulated to be mediated by b3-adrenoceptors and the activation of the intracellular cAMP pathway. ZAG has been shown to be able to produce a comparable increase in cAMP levels to that obtained with isoprenaline and ZAG-induced lipolysis can be attenuated by the specific b3-adrenoceptor antagonist SR59230 in adipocytes (72,75,76) .…”

Section: Zag a Lipid-mobilising Factormentioning

confidence: 95%

New insights into adipose tissue atrophy in cancer cachexia

Chen

Trayhurn

2009

Proc. Nutr. Soc.

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Profound loss of adipose and other tissues is a hallmark of cancer cachexia, a debilitating condition associated with increased morbidity and mortality. Fat loss cannot be attributable to reduced appetite alone as it precedes the onset of anorexia and is much more severe in experimental models of cachexia than in food restriction. Morphological examination has shown marked remodelling of adipose tissue in cancer cachexia. It is characterised by the tissue containing shrunken adipocytes with a major reduction in cell size and increased fibrosis in the tissue matrix. The ultrastructure of ‘slimmed’ adipocytes has revealed severe delipidation and modifications in cell membrane conformation. Although the molecular mechanisms remain to be established, evidence suggests that altered adipocyte metabolism may lead to adipose atrophy in cancer cachexia. Increased lipolysis appears to be a key factor underlying fat loss, while inhibition of adipocyte development and lipid deposition may also contribute. Both tumour and host-derived factors are implicated in adipose atrophy. Zinc-α2-glycoprotein (ZAG), which is overexpressed by certain malignant tumours, has been identified as a novel adipokine. ZAG transcripts and protein expression in adipose tissue are up regulated in cancer cachexia but reduced with adipose tissue expansion in obesity. Studies in vitro demonstrate that recombinant ZAG stimulates lipolysis. ZAG may therefore act locally, as well as systemically, to promote lipid mobilisation in cancer cachexia. Further elucidation of ZAG function in adipose tissue may lead to novel targets for preventing adipose atrophy in malignancy.

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“…34 This is supported by the studies in which ZAG produced comparable increases in intracellular cyclic AMP levels to that obtained with isoprenaline, and ZAG-induced lipolysis can be attenuated by the specific b3-adenoceptor antagonist (SR59230) in adipocytes. [34][35][36] In addition to lipid mobilization, there is also evidence that ZAG promotes lipid utilization. In vivo studies have shown that ZAG stimulates overall fatty acid oxidation in NMRI mice and ob/ob mice.…”

Section: Zag: a Lipid-mobilizing Factormentioning

confidence: 99%

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

et al. 2010

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The importance of white adipose tissue in the control of energy balance is now firmly recognized. In addition to fuel storage, adipocytes secrete an array of proteins factors (adipokines), which regulate multiple physiological and metabolic processes as well as influence body fat accumulation. Zinc-a2-glycoprotein (ZAG), a lipid mobilizing factor initially characterized as a tumor product associated with cachexia, has recently been identified as a novel adipokine. Although the exact role of ZAG in adipose tissue remains to be clarified, there is evidence that ZAG expression appears to be inversely related to adiposity, being upregulated in cachexia whereas reduced in obesity. Investigations on the regulation of ZAG give insights into its potential function in adipose tissue with a link to lipid mobilization and an anti-inflammatory action. Recent work shows that ZAG stimulates adiponectin secretion by human adipocytes. Data from genetic studies suggest that ZAG may be a candidate gene for body weight regulation; this is supported by the demonstration that ZAG-knockout mice are susceptible to weight gain, whereas transgenic mice overexpressing ZAG exhibit weight loss. The present review summarizes these new perspectives of ZAG and the potential mechanisms by which it might modulate adipose tissue mass and function.

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Role of β3-adrenergic receptors in the action of a tumour lipid mobilizing factor

Cited by 115 publications

References 20 publications

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

Role of β-adrenergic receptors in the anti-obesity and anti-diabetic effects of zinc-α2-glycoprotien (ZAG)

New insights into adipose tissue atrophy in cancer cachexia

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

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