The obesogenic effects of polyunsaturated fatty acids are dependent ...

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In order to demonstrate that bile acids could induce fat oxidation in white adipocytes, we isolated preadipocytes from the eWAT depot, and treated differentiated adipocytes with increasing concentrations of taurocholic acid for 24hrs. Compared to untreated cells, a physiologic relevant dose of 25 µM taurocholic acid significantly raised fat oxidation capacity in the adipocytes (Fig 2L). Nutritional regulation of endogenous BA metabolism alters TAG concentrations in liver and plasma. Oral bile acid treatment lowers TAG concentrations in mouse liver (11) and blood (11,55). Moreover, BA treatment has been reported to down-regulate fatty acid de novo synthesis via repression of Sterol regulatory-element binding protein 1c (Srebp- 1c) and its downstream lipogenic target genes in mouse primary hepatocytes and liver (11,56). We found no significant differences in hepatic gene-expressions of Srebp-1c (24±4 vs 34±4, P=0.18), Acetyl-CoA carboxylase 1 (Acc1) (36±2 vs 43±2, P=0.10), fatty acid synthase (Fas) (3.8±0.8 vs 5.7±1.3, P=0.10) between the high-fat SPH and high-fat casein treated rats, respectively. Others have reported that in HepG2 cells, BA treatment represses transcription of microsomal triglyceride transfer protein (MTP) and APO B, both important for hepatic secretion of VLDL (57). However, the high-fat SPH-treated rats had higher liver expression of ApoB (6.3±0.6 vs 4.1±0.2, P=0.009) and Mtp (6.6±0.5 vs 5.0±0.2, P=0.14), compared to high-fat casein treated rats, respectively. Our results obtained using rat therefore deviate from the reported findings in mice and HepG2 cells. To gain further information on the mechanisms by which nutritional regulation of BA metabolism modulates hepatic TAG metabolism we used a microarray approach. To identify functional differences between treatment groups, we performed a Kegg pathway analysis. Six Kegg metabolic pathways were significantly altered, and four tended (P
Accordingly, when we measured mitochondrial CPT-1 capacity in the presence of 5 µM malonyl-CoA, we observed a stronger inhibition in SPH-treated rats than in casein treated rats, even though the difference not was significant (Fig. 4G). Furthermore, the fasting plasma levels of the ketone-body β- hydroxybutyrate, a marker of liver mitochondrial fatty acid oxidation was significantly elevated (Fig. 4H) and liver TAG deposition was lower in the SPH-treated rats (Fig. 4I, J), further supporting that the SPHtreated rats had higher liver fat catabolism. Exogenous bile acid supplementation (11), as well as the activation of the PPAR β/δ receptor (61) prevents increased plasma TAG through inhibition of hepatic VLDL secretion. Higher liver Vldlr expression might be one underlying mechanism to the lower plasma VLDL amounts, as both BA-treatment (10) and expression and activation of the PPARβ/δ receptor (62) might induce Vldlr transcription. As the rats given the high-fat SPH diet had both elevated plasma BA concentrations and induction of Pparβ/δ gene expression in liver, we hypothesized that plasma TAG would be decreased in these animals. As predicted, the plasma TAG concentrations were reduced in the non-fasted state (Fig. 4K), and this decrease was accompanied by a pronounced elevation in liver Vldlr expression (Fig. 4L). To verify that plasma VLDL concentration actually was reduced, we analyzed plasma samples by nuclear magnetic resonance (NMR), which confirmed that SPH-treated rats had decreased VLDL amounts (Fig. 4M). The NMR analysis also suggested that plasma LDL- or HDLcholesterol concentrations were elevated in the SPH-treated rats, but no significant differences were observed in plasma cholesterol levels by standard clinical chemistry methods (Fig. N, O). Our data supported the hypothesis that nutritional regulation of endogenous BA metabolism could modulate hepatic fatty acid oxidation capacity, liver TAG storage and plasma non-fasted TAG-rich VLDL concentrations. To investigate further the potential role of BAs in relation to the observed effects on TAG metabolism, we examined the rats treated with SPH+cholestyramine. Indeed, pharmacological removal of BAs by the cholestyramine treatment attenuated the reduction in liver and non-fasted plasma TAG concentrations (Fig. 4P, Q), and attenuated the elevation in liver mitochondrial fat oxidation capacity and nonfasted plasma β-hydroxybutyrate (Fig. 4R, S). We conclude that nutritional regulation of endogenous BA metabolism contributes significantly to the observed modulation of lipid metabolism introduced by SPH treatment. Nutritional regulation of endogenous BA metabolism modulates skeletal muscle Ucp3 expression. PPARβ/δ is abundantly expressed in skeletal muscle, a peripheral tissue that accounts for approximately 40% of total body mass. Activation of PPARβ/δ leads to increased expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle (63-65). One of the genes robustly induced by PPARβ/δ activation is Ucp3, and mice over-expressing the human UCP3 in skeletal muscle are protected from diet-induced adiposity (66). In keeping with the strong hepatic Pparβ/δ induction combined with the lean phenotype of the SPH treated rats, we hypothesized that PPARβ/δ signaling was altered also in skeletal muscle of the SPH treated rats. As in liver, skeletal muscle expressions of Pparα and its target genes Acox1 were down-regulated in the SPH treated rats (Fig. 5A). In contrast, expression of Pparβ/δ , and its downstream target genes Adrp and angiopoietin-like 4 (Angptl4, also called fasting-induced adipose factor, Fiaf) were significantly induced (Fig. 5B). Concomitantly, Cpt-1b, Ucp2 and in particular Ucp3 expressions were elevated (Fig. 5C). To further corroborate a regulatory role for BAs on skeletal muscle Ucp3 expression, we measured the Ucp3 expression in the SPH+c’am treated rats. Of note, skeletal muscle Ucp3 induction by SPH treatment was completely abolished by reducing plasma BA concentrations with cholestyramine (Fig. 5D). Our data indicate that besides the known regulatory effects of BAs on liver and adipose tissue metabolism, skeletal muscle fatty acid oxidation and uncoupling may also be regulated through altered bile acid metabolism. Downloaded from www.jbc.org by guest, on July 7, 2011 8
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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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Fish Oil, Sucrose and Obesity 6. Ma
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Carbohydrate source and insulin sec
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20 21 22 23 24 25 26 27 28 29 30 31
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68 69 70 71 72 73 74 75 76 77 78 79
Page 41 and 42: 114 115 116 117 118 119 120 121 122
Page 43 and 44: 160 161 162 163 164 165 166 167 168
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Page 47 and 48: 256 257 258 259 260 261 262 263 264
Page 49 and 50: 302 303 304 305 306 307 308 309 310
Page 51 and 52: 350 351 FIGURE LEGENDS 352 353 354
Page 53 and 54: 398 399 400 401 402 403 404 subunit
Page 55 and 56: 446 447 448 449 450 451 gamma, coac
Page 57 and 58: 484 485 486 TABLE 1. Macronutrient
Page 59 and 60: Energy (kJ/g) 17.16 25.12 25.12 25.
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Page 63 and 64: 635 636 637 638 639 640 641 642 643
Page 65: 711 712 713 714 715 716 717 718 719
Page 74 and 75: Cyclooxygenases and UCP1 Although i
Page 76 and 77: Cyclooxygenases and UCP1 Figure 2.
Page 78 and 79: Cyclooxygenases and UCP1 Figure 4.
Page 80 and 81: Cyclooxygenases and UCP1 PLoS ONE |
Page 82 and 83: Cyclooxygenases and UCP1 E synthase
Page 84 and 85: Cyclooxygenases and UCP1 29. Granne
Page 86 and 87: JBC Papers in Press. Published on J
Page 88 and 89: hydrolysate (SPH), would be protect
Page 90 and 91: was used as the liver cytosolic fra
Page 94 and 95: Nutritional regulation of endogenou
Page 96 and 97: in increased whole body energy expe
Page 98 and 99: 38. Kanehisa M, and Goto S. (2000)
Page 100 and 101: FOOTNOTES This work was carried out
Page 102 and 103: fed the same diets, plus the SPH-di
Page 104 and 105: Figure 2 A nmol/ min/ mg prot 2,4 1
Page 106 and 107: Figure 4 A 6 Liver Pparα B 21 Live
Page 108 and 109: Figure 7 A Plasma ALAT B Liver Ucp2
Page 110 and 111: Ruzzin et al. investigated the meta
Page 112 and 113: Ruzzin et al. CD14, and rho kinases
Page 114 and 115: Ruzzin et al. salmon oil induced a
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