Targets for TNF-α-induced lipolysis in human adipocytes

Rydén, Mikael; Arvidsson, Elisabet; Blomqvist, Lennart; Perbeck, L.; Dicker, Andrea; Arner, Peter

doi:10.1016/j.bbrc.2004.04.010

Cited by 179 publications

(158 citation statements)

References 34 publications

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“…The evidence that TNF-␣ is able to suppress the activating effect of the PPAR␥ agonist rosiglitazone on G0S2 expression supports such possibility. Moreover, previous experiments using selective kinase inhibitors demonstrate that TNF-␣ regulates lipolysis in adipocytes through rapid and transient activation of downstream kinases such as ERK1/2, JNK, and IB kinase (41,42,(45)(46)(47). Whether signaling pathways dependent on these kinases are involved in the switch-off of G0S2 transcription is an important topic for future investigation.…”

Section: Discussionmentioning

confidence: 96%

“…Statistical analysis was determined by Student's t test or one-way analysis of variance. (39,41,45,46). To examine the modulation of individual players in the lipolytic proteome, we treated fully differentiated 3T3-L1 adipocytes with TNF-␣ for various periods of time.…”

Section: Methodsmentioning

confidence: 99%

“…Mechanistically, activation of TNF receptor-1-dependent pathways is both necessary and sufficient for such lipolytic induction (44). The downstream signals involve the activation of several kinases such as ERK1/2, JNK, and IB kinase (41,42,(45)(46)(47) with resultant effects, including down-regulation of several genes involved in preventing basal lipolysis. Decreased expression of perilipin (48) and another LD protein FSP27 (49) is proposed to promote lipolysis through augmentation of action of the lipases.…”

mentioning

confidence: 99%

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Relative Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Tumor Necrosis Factor-α (TNF-α)-induced Lipolysis in Adipocytes

Yang

Zhang

Heckmann

et al. 2011

Journal of Biological Chemistry

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TNF-␣ potently stimulates basal lipolysis in adipocytes, which may contribute to hyperlipidemia and peripheral insulin resistance in obesity. Recent studies show that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) act sequentially in catalyzing the first two steps of adipose lipolysis in response to ␤-adrenergic stimulation. Here, we sought to determine their functional roles in TNF-␣-induced lipolysis. Silencing of ATGL expression in adipocytes almost completely abolished basal and TNF-␣-induced glycerol release. In comparison, the glycerol release under the same conditions was only partially decreased upon reduction in expression of either HSL or the ATGL coactivator CGI-58. Interestingly, overexpression of ATGL restored the lipolytic rates in cells with silenced HSL or CGI-58, indicating a predominant role for ATGL. While expression of ATGL, HSL and CGI-58 remains mostly unaffected, TNF-␣ treatment caused a rapid abrogation of the ATGL inhibitory protein G0S2. TNF-␣ drastically decreased the level of G0S2 mRNA, and the level of G0S2 protein could be maintained by inhibiting proteasomal protein degradation using MG-132. Furthermore, coexpression of G0S2 was able to significantly decrease TNF-␣-stimulated lipolysis mediated by overexpressed ATGL or CGI-58. We propose that the early reduction in G0S2 content is permissive for TNF-␣-induced lipolysis.During extended starvation and exercise, catecholamines stimulate the hydrolysis of triacylglycerol (TAG) 2 stores within the lipid droplets (LDs) in adipocytes. The so-called lipolysis makes available surplus fuel in the form of free fatty acids (FFAs) and glycerol for use by other organs and tissues. During the instances of nutritional overload such as obesity, elevated basal adipose lipolysis contributes to the increase of systemic FFA levels, thereby exacerbating peripheral lipotoxicity and insulin resistance (1-4). Considering the importance of TAG turnover at both physiological and pathological levels, it is not surprising that enzymes governing lipolysis have attracted immense research interest over the years. Among many intracellular lipases identified thus far that possess in vitro capacity to hydrolyze TAG, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) are the most characterized functionally (5, 6). A body of evidence has emerged recently, suggesting that ATGL and HSL act sequentially in mediating adipocyte lipolysis in response to ␤-adrenergic stimulation (7-12). In this newly established model, ATGL initiates lipolysis by specifically removing the first FA from TAGs to produce DAG substrates, which are then hydrolyzed by HSL to generate an additional FA and MAG substrates. MAGs are converted into FA and glycerol by MAG lipase in the final step of lipolysis.HSL was discovered nearly half a century ago due to its induction during fasting and by catabolic hormones (13,14). It has broad substrate specificity toward acylglycerols, including TAG, DAG, and MAG, as well as cholesteryl, retinyl, and lipoidal esters....

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Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Relative Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Tumor Necrosis Factor-α (TNF-α)-induced Lipolysis in Adipocytes

Yang

Zhang

Heckmann

et al. 2011

Journal of Biological Chemistry

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“…TNF-a activation has been shown to lead to downregulation of perilipin (Ryden et al 2002, Zhang et al 2002. This effect is dependent upon the stimulation of the mitogen-activated protein kinases, p44/ 42, and the NH 2 -terminal jun kinase (Zhang et al 2002, Ryden et al 2004). The present study demonstrated that injection with the Ad-DCD virus induced an increase in the concentration of the circulating TNF-a.…”

Section: Discussionmentioning

confidence: 99%

Effect of dermcidin, an antimicrobial peptide, on body fat mobilization in normal mice

Kim¹,

Ka²,

Moon³

et al. 2008

Journal of Endocrinology

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Dermcidin (DCD), an antimicrobial peptide that is secreted by sweat glands, is reportedly a human homolog of mouse proteolysis-inducing factor. This study was conducted to investigate the effect of DCD on body fat mobilization. The expression level of DCD in the livers of Ad-DCD-injected mice was higher than in those of Ad-b-galactosidase (Ad-bgal)-injected mice 7 days after injection. In addition, injection with the Ad-DCD virus led to decreased body weight and epididymal fat mass when compared with controls. The plasma triglyceride level was decreased, whereas the free fatty acid and glycerol levels were increased in the Ad-DCDinjected group. Epididymal adipose tissues obtained from Ad-DCD-injected mice consisted of smaller adipocytes than tissues obtained from Ad-b-gal-injected mice. The gene expression profiles revealed an upregulation of hormonesensitive lipase and adipose fatty acid-binding protein, both of which are involved in adipocyte lipolysis, in Ad-DCDinjected mice, and this lipolytic effect of DCD paralleled the increase of circulating tumor necrosis factor-a (TNF-a) level that was observed. The perilipin levels in adipose tissue were decreased in Ad-DCD-injected mice when compared with those of the control mice. Taken together, these results suggest that DCD-mediated body fat reduction might occur as a result of TNF-a-induced downregulation of perilipin in adipose tissue.

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“…This list also includes catecholamines, insulin, atrial natriuretic peptide and tumour necrosis factor alpha. [20][21][22][23][24][25][26][27][28] Is the presently examined neuropeptide family of physiological importance for lipolysis regulation in man? No definitive answer can be given for the moment but there is evidence to suggest a functional role.…”

Section: Discussionmentioning

confidence: 99%

Effects of pain controlling neuropeptides on human fat cell lipolysis

et al. 2010

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Objective: Neuropeptides NPFF and NPSF are involved in pain control, acting through the G-protein coupled receptors (GPR)74 (high affinity for NPFF) and GPR147 (equal affinity for NPFF and NPSF). GPR74 also inhibits catecholamine-induced adipocyte lipolysis and regulates fat mass in humans. The aim of this study was to compare the effects of NPFF and NPSF on noradrenalineinduced lipolysis and to determine the expression of their receptors in human fat cells. Design: Adipose tissue was obtained during surgery. Adipocytes were prepared and kept in primary culture. Lipolysis, protein expression and gene expression were determined. Results: NPFF counteracted noradrenaline-induced lipolysis, which was more marked after 48 h than after 4 h exposure and was solely attributed to inhibition of b-adrenoceptor signalling. NPSF counteracted noradrenaline-induced lipolysis maximally after 4 h of exposure, which was attributed to a combination of inhibition of b-adrenoceptor signalling and decreased activation of the protein kinase-A hormone sensitive lipase complex by cyclic AMP. Both neuropeptides were effective in nanomolar concentrations. NPFF and NPSF had no effects on the expression of genes involved in catecholamine signal transduction. Both GPR74 and GPR147 were expressed at the protein level in fat cells from various adipose regions. GPR74 mRNA levels were higher in adipose tissue from obese as compared with non-obese subjects. High gene expression of either receptor correlated with low noradrenaline-induced lipolysis (Po0.05). Conclusions: Pain controlling neuropeptides NPFF and NPSF may be important for the regulation of lipolysis in man probably acting through GPR74 and GPR147. At low concentrations they inhibit catecholamine-induced lipolysis through rapid and longterm post-transcriptional effects at several steps in adrenoceptor signalling in fat cells.

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Targets for TNF-α-induced lipolysis in human adipocytes

Cited by 179 publications

References 34 publications

Relative Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Tumor Necrosis Factor-α (TNF-α)-induced Lipolysis in Adipocytes

Relative Contribution of Adipose Triglyceride Lipase and Hormone-sensitive Lipase to Tumor Necrosis Factor-α (TNF-α)-induced Lipolysis in Adipocytes

Effect of dermcidin, an antimicrobial peptide, on body fat mobilization in normal mice

Effects of pain controlling neuropeptides on human fat cell lipolysis

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