Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases

Petersen, Rasmus Koefoed; Jørgensen, Claus; Rustan, Arild C.; Frøyland, Livar; Müller‐Decker, Karin; Fürstenberger, Gerhard; Berge, Rolf K.; Kristiansen, Karsten; Madsen, Lise

doi:10.1194/jlr.m300192-jlr200

Cited by 67 publications

(66 citation statements)

References 60 publications

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“…Because Pref-1 has been characterized as an inhibitor of adipogenesis, the fact that EGF suppresses adipogenesis through PKA also suggests that EGF-like family proteins, such as Pref-1, may exert their effects on adipogenesis through the activation of PKA. Furthermore, it has been reported that H89 can block the anti-adipogenesis effect of arachidonic acid [47]. All these data indicate that PKA has a crucial role in suppressing adipocyte differentiation.…”

Section: Discussionmentioning

confidence: 65%

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Wang

Zhou

et al. 2008

Cell Res

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cAMP and protein kinase A (PKA) are widely known as signaling molecules that are important for the induction of adipogenesis. Here we show that a strong increase in the amount of cAMP inhibits the adipogenesis of 3T3-L1 fibroblast cells. Stimulation of PKA activity suppresses adipogenesis and, in contrast, inhibition of PKA activity markedly accelerates the adipogenic process. As adipogenesis progresses, there is a significant increase in the expression level of PKA regulatory subunits and a corresponding decrease in PKA activity. Moreover, treatment of 3T3-L1 cells with epidermal growth factor (EGF) stimulates PKA activity and blocks adipogenesis. Inhibition of PKA activity abolishes this suppressive effect of EGF on adipogenesis. Moreover, activation of PKA induces serine/threonine phosphorylation, reduces tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and the association between PKA and IRS-1. Taken together, our study demonstrates that PKA has a pivotal role in the suppression of adipogenesis. cAMP at high concentrations can suppress adipogenesis through PKA activation. These findings could be important and useful for understanding the mechanisms of adipogenesis and the relevant physiological events.

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Section: Discussionmentioning

confidence: 65%

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Wang

Zhou

et al. 2008

Cell Res

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“…Furthermore, ω-3 PUFA can modulate gene expression involved in lipid homeostasis in adipocytes (6, 7); however, the administration of either EPA or DHA in a static culture of 3T3-L1 cells only affects adipocyte differentiation slightly (8). In contrast, arachidonic acid (AA), an ω-6 PUFA and a precursor of prostaglandin (PG) synthesis, strongly inhibits adipocyte differentiation via a pathway dependent on the prostaglandin synthesis (8).…”

Section: Introductionmentioning

confidence: 99%

“…Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are fish-oilderived ω-3 polyunsaturated fatty acids (PUFA) and are interesting for their potential to lower the risk of cardiovascular events, especially with regard to their antithrombotic, anti-inflammatory, anti-atherogenic, and anti-arrhythmic actions (4,5). Furthermore, ω-3 PUFA can modulate gene expression involved in lipid homeostasis in adipocytes (6, 7); however, the administration of either EPA or DHA in a static culture of 3T3-L1 cells only affects adipocyte differentiation slightly (8). In contrast, arachidonic acid (AA), an ω-6 PUFA and a precursor of prostaglandin (PG) synthesis, strongly inhibits adipocyte differentiation via a pathway dependent on the prostaglandin synthesis (8).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Cyclooxygenase-2 in Synergistic Effect of Cyclic Stretching and Eicosapentaenoic Acid on Adipocyte Differentiation

et al. 2008

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Abstract. The present study examined the combined effects of fish-oil-derived ω-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and cyclic stretching on the adipocyte differentiation of 3T3-L1 cells. Treatment with EPA alone did not inhibit the differentiation, although it partially suppressed the expressions of peroxisome proliferator-activated receptor (PPAR)-γ 2 and CCAAT/ enhancer-binding protein (C / EBP)α transcripts, which are considered to be indispensable for the determination of adipocyte differentiation. However, the differentiation was significantly reduced when EPA but not DHA was concomitantly applied with cyclic stretching. In addition, EPA, but not DHA, could be a substrate of cyclooxygenase (COX)-2, and we found that the stretching significantly augmented the expression of COX-2 and that a selective COX-2 inhibitor (NS-398) inhibited the combined effect of the stretching and EPA. Taken together, it appears that the stretching and EPA exhibit a synergistic effect for the inhibition of adipocyte differentiation through stretch-induced COX-2.

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“…Usually, the differentiation of confluent cultured 3T3-L1 preadipocytes is initiated by exposure to a mixture of hormonal inducers including insulin, dexamethasone, and IBMX to induce a sequential activation of transcription factors, which is followed by the continued cell culture in the maturation medium with insulin for the promotion of adipogenesis (Ham et al 2001;Petersen et al 2003). More recently, we have reported that the cultured adipocytes during the maturation phase can biosynthesize PGI 2 as determined by the amount of stable 6-keto-PGF 1a reflecting the generation of endogenous PGI 2 , an unstable COX metabolite, at much higher levels than the preadipocytes at growth and differentiation phases, which is associated with up-regulation of the gene expression of PGIS and the IP receptor (Rahman et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…For the initiation of the differentiation program of this cell line, the growth-arrested cells were generally stimulated with a hormone mixture of insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IBMX) in the differentiation medium, which leads to the programmed expression of C/EBPs and PPARc. Following the induction of differentiation program, mature adipocytes with accumulated fats are generated by the promotion of adipogenesis during the maturation phase (Ham et al 2001;Petersen et al 2003). We have been making use of cultured 3T3-L1 cells for studying the regulation of the arachidonate cyclooxygenase (COX) pathway at different life stages of adipocytes (Xu et al 2006;Mazid et al 2006;Rahman et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of fat storage by prostacyclin and selective agonists of prostanoid IP receptor during the maturation phase of cultured adipocytes

Khan¹,

Syeda²,

Nartey³

et al. 2016

Cytotechnology

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We have previously shown that cultured adipocytes have the ability to biosynthesize prostaglandin (PG) I 2 called alternatively as prostacyclin during the maturation phase by the positive regulation of gene expression of PGI synthase and the prostanoid IP receptor. To clarify how prostacyclin regulates adipogenesis, we investigated the effects of prostacyclin and the specific agonists or antagonists for the IP receptor on the storage of fats during the maturation phase of cultured adipocytes. Exogenous PGI 2 and the related selective agonists for the IP receptor including MRE-269 and treprostinil rescued the storage of fats attenuated by aspirin, a cyclooxygenase inhibitor. On the other hand, selective antagonists for IP such as CAY10441 and CAY10449 were effective to suppress the accumulation of fats as GW9662, a specific antagonist for peroxisome proliferator-activated receptor (PPAR)c. Thus, pro-adipogenic action of prostacyclin can be explained by the action mediated through the IP receptor expressed at the maturation stage of adipocytes. Cultured adipocytes incubated with each of PGI 2 and MRE-269 together with troglitazone, an activator for PPARc, exhibited additively higher stimulation of fats storage than with either compound alone. The combined effect of MRE-269 and troglitazone was almost abolished by coincubation with GW9662, but not with CAY10441. Increasing concentrations of troglitazone were found to reverse the inhibitory effect of CAY10441 in a dose-dependent manner while those of MRE-269 failed to rescue adipogenesis suppressed by GW9662, indicating the critical role of the PPARc activation as a downstream factor for the stimulated adipogenesis through the IP receptor. Treatment of cultured adipocytes with cell permeable stable cAMP analogues or forskolin as a cAMP elevating agent partly restored the inhibitory effect of aspirin. However, excess levels of cAMP stimulated by forskolin attenuated adipogenesis. Supplementation with H-89, a cell permeable inhibitor for protein kinase A (PKA), had no effect on the promoting action of PGI 2 or MRE-269 along with aspirin on the storage of fats, suggesting that the promotion of adipogenesis mediated by the IP receptor does not require the PKA activity.

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Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases

Cited by 67 publications

References 60 publications

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Involvement of Cyclooxygenase-2 in Synergistic Effect of Cyclic Stretching and Eicosapentaenoic Acid on Adipocyte Differentiation

Stimulation of fat storage by prostacyclin and selective agonists of prostanoid IP receptor during the maturation phase of cultured adipocytes

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