Cyclooxygenases and UCP1 PLoS ONE | www.plosone.org 8 June 2010 | Volume 5 | Issue 6 | e11391
Cyclooxygenases and UCP1 Figure 6. UCP1 expression is attenuated by an EP 4 receptor antagonist in Rb 2/2 adipocytes and induced by the EP4 receptor agonist 16,16dmPGE 2 in vivo. A.Expressions <strong>of</strong> EP 1 ,EP 2 ,EP 3 ,EP 4 and FP receptors were measured by RT-qPCR in iBAT and iWAT isolated from warm- and cold-acclimated mice, and in Rb 2/2 adipocytes treated with vehicle or isoproterenol (100 nM) and 9-cis-retinoic acid (1 mM). B. Rb 2/2 adipocytes were treated with vehicle or isoproterenol (100 nM) and 9-cis-retinoic acid (1 mM) by RT-qPCR in absence and presence <strong>of</strong> AL8810, AH6809, or AH23848, which <strong>are</strong> FP, EP 1 /EP 2 and EP 4 receptor antagonists, respectively. Expressions <strong>of</strong> genes were measured by RT-qPCR. <strong>The</strong> bars represent mean 6 standard error. Different letters indicate statistically significant differences (p,0.05). C. C57BL/6J mice were subcutaneously injected with vehicle or 16,16dmPGE 2 (50 mM/kg) every 12 h for 48 h. Expressions <strong>of</strong> genes were measured by RT-qPCR. <strong>The</strong> bars represent mean 6 standard error (n = 5). * indicates statistical significant difference between vehicle and 16,16 dmPGE 2 treated mice (p,0.05). doi:10.1371/journal.pone.0011391.g006 mice. Also, injection <strong>of</strong> a stable analog <strong>of</strong> the COX2 downstream product PGE 2 , 16,16-dimethyl-PGE 2 , induced UCP1 expression in iWAT. Forced expression <strong>of</strong> COX2, alone or in combination with COX1, induced UCP1 expression in a cell model resembling inguinal adipocytes. Finally, the inhibition <strong>of</strong> COX activity not only attenuated diet-induced UCP1 expression in iWAT, but also increased weight gain in Sv129 mice kept at thermoneutrality. <strong>The</strong> association between diet-induced thermogenesis and the recruitment <strong>of</strong> brown adipose tissue was first noted more than 30 years ago and believed to involve the classical brown adipose tissue located in the interscapular region [59]. <strong>The</strong> anti-obesity role <strong>of</strong> UCP1 was challenged by the finding that UCP1 KO mice were not obese [60]. However, the recent demonstration that UCP1 ablation per se induced obesity when the mice were kept at thermoneutrality [61] clearly indicates that UCP1 is important in diet-induced energy dissipation at thermoneutrality. Our data indicate that inhibition <strong>of</strong> COX activity increased weight gain and concomitantly attenuated diet-induced UCP1 expression in iWAT, but not iBAT in Sv129 mice kept at thermoneutrality, pointing to a novel role <strong>of</strong> COX activity in the control <strong>of</strong> energy balance and the development <strong>of</strong> obesity. <strong>The</strong>se results <strong>are</strong> in line with our earlier observation that enhanced cAMP signaling in response to an increased glucagon/insulin ratio led to an increased COX-mediated PGE 2 production. This was accompanied by increased expression <strong>of</strong> UCP1 in iWAT, but not in iBAT, and decreased feed efficiency [62]. Although neither COX1 KO nor COX2 KO mice <strong>are</strong> obese, COX2 +/2 KO mice have more adipose tissue than wild-type littermates when fed an <strong>obesogenic</strong> diet [48]. <strong>The</strong> reason why COX2 +/2 , but not COX2 KO mice were reported to be prone to obesity is not clear. However, these studies were not performed at thermoneutrality [48]. A similar phenomenon is actually seen in GLUT4 KO mice, where the majority <strong>of</strong> GLUT4 2/+ , but not GLUT4 2/2 mice develops diabetes [63]. Moreover, release <strong>of</strong> PGE 2 from adipose tissue in COX2 +/2 mice was reported to be reduced comp<strong>are</strong>d to adipose tissue from wild-type mice [48] and adipose tissue cultures obtained from obese rats have lower PGE 2 release rates than cultures from lean rats [38]. In addition, microsomal prostaglandin α Figure 7. Indomethacin prevents high-fat diet-induced UCP1 expression in iWAT but not iBAT in the obesity-resistant Sv129 mouse strain. Mice were fed a very high-fat diet (VHF) with or without indomethacin supplementation (16 ppm) for 4 weeks at a temperature <strong>of</strong> 28–30uC. One group <strong>of</strong> mice was killed before the experiment started. A. Body weight gain and energy intake relative to body weight gain. B. Different adipose tissue depots were dissected and weighed. C and D. Representative paraffin-embedded representative sections from iWAT and iBAT were stained with hematoxylin and eosin. <strong>The</strong> scale bars represent 50 mM. E. Expressions <strong>of</strong> genes in iWAT and iBAT were measured by RT-qPCR. <strong>The</strong> bars represent mean 6 standard error (n = 6). * indicates statistical significant difference (p,0.05) between different groups. doi:10.1371/journal.pone.0011391.g007 PLoS ONE | www.plosone.org 9 June 2010 | Volume 5 | Issue 6 | e11391
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The obesogenic effects of polyunsat
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Table of Contents Acknowledgement .
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Abstract in Danish Polyumættede n-
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Polyunsaturated fatty acids in the
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was more than 3 times higher in the
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gluconeogenesis and ureagenesis (Fi
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high dietary PUFAs, the modulation
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In a pair of population studies, an
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18. Massiera, F. et al. Arachidonic
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54. Xu, J. et al. Polyunsaturated f
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Annexes 1. Ma T, Liaset B, Hao Q, P
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Fish Oil, Sucrose and Obesity Obesi
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Fish Oil, Sucrose and Obesity Figur
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Fish Oil, Sucrose and Obesity Table
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