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

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was considerably less in the fish oil-fed mice than in the corn oil-fed mice (Fig.3A), but it was not directly related to the lipogenic gene expression in their livers (Fig.3B). Since the mice on high fat diets consumed equivalent amounts of food, the lean ones had markedly reduced energy efficiency (Fig.3D, 4B). The following points could partly explain the differences, 1). protein-fed animals could have more brownish phenotype in inguinal WAT (iWAT) judged by the up-regulation of Ucp1 expression, which dispenses energy as heat (Fig.3E, 4E); 2). elevated gluconeogenesis in mice fed protein-enriched diets even in the fed state, indicated by the enhanced glucose production during pyruvate tolerance test and hepatic gene expressions (Fig.6A and B); 3). nitrogen metabolism was another potential contributor to the energy-wasting effect as protein cannot be stored but must be processed immediately (Fig.6B). In order to evaluate the role of insulin in modulating the obesogenic effects of fish oil, isocaloric high fish oil diets with different sucrose to protein weight ratios were fed to the mice (Annex 2). Supporting our previous findings, the fat mass development (Fig.1D), energy efficiency (Fig.1B), inflammation levels in adipose tissues (Fig.1E) were all does-dependently correlated to sucrose content of the diets. mRNA levels of the indicators pointing to the three energy consumption processes, Ucp1 in the iWAT--- thermogenesis (Fig.1E); Pck1 in the live--- gluconeogenesis and Agxt in the liver--- ureagenesis (Fig.1F), were inversely associated as earlier suggested. By exchanging sucrose with glucose or fructose in a fish oil-supplemented diet, we further pinpointed that the insulin stimulating agent glucose moiety in sucrose facilitated the obesitypromoting effect of fish oil, as mice fed a fructose diet gained less WAT weights (Fig.2D) and had lower plasma triglycerides levels (Fig.2E). However, in the same set of mice, hepatic genes related to β-oxidation were down-regulated and the expression of lipogenic genes were increased (Fig.2F). Our theory was further supported by including starches promote different insulin responses (different glycemic index-GI). Although these animals did not differ in weight gain, the WAT masses were significantly higher in high GI diet-fed mice (Fig.4A and C), and this was accompanied by the increased expression of lipogenic genes Fasn and Scd1 (Fig.4G). Furthermore, pharmaceutical regulators of insulin secretion were introduced to the feeding regime. Inclusion of insulin secretagogue glybenclamide in the protein-enriched high fish oil diet did not result in a separation of the body weight gains (Fig.5A). A tendency of fat mass differences was observed (Fig.5B), and could be linked to observed changes in gene expression related to 10
gluconeogenesis and ureagenesis (Fig.5E). On the other hand, inhibition of insulin secretion by nifedipine did achieve the expected fat mass-reducing effect (Fig.6C) . Discussion, perspectives Low carbohydrate, high protein diet It has been suggested that a modest increase in protein ingestion combined with a low glycemic index diet could be protective against obesity in children 39 . Further, as reported in a recent large European cohort study, after an initial weight loss, a diet with lower glycemic index and higher protein content is most ideal for maintaining body weight and preventing weight regain 40 . When consuming a diet very low in carbohydrates, such as in the case of our protein-enriched mouse feed with only 8% of calories from carbohydrates, the animals need to mobilize liver glycogen storage and increase gluconeogenesis in order to sustain blood glucose levels. After feeding for a long period of time, glycogen will be exhausted, and the body will have to turn to other energy sources. Even in the fed state, these protein-fed mice still kept high rates of β-oxidation, indicated by the high circulating levels of 2-hydroxybutyrate (Annex 1Fig.5B (1.5B)), suggesting the need to mobilize fat and/or protein for basal metabolism. This situation, to a certain degree, mimics what has been observed in long term fasting. During starvation, following the decrease of circulating glucose, insulin levels drop dramatically and glucagon secretion is elevated. Although gluconeogenesis contributes partially to the blood glucose supply, it will be prioritized for central nervous system and red blood cells functions. Despite the protein-fed mice kept lean as their low fat diet-fed littermates, they showed the same degree of glucose intolerance as the obese ones on sucrose-enriched diet. If our analogy to fasting is accurate, the glucose intolerance we have observed in lean protein-fed mice can be delineated. As fasting reduced insulin secretion in rats, this repression can only be rescued by refeeding with diets high in carbohydrates 41 . Although no difference was observed in the insulin tolerance test (Fig 1.s1B), there are reports both in rats and humans showing that consuming low carbohydrate, high protein diet can attenuate the suppression of hepatic glucose output by insulin 42,43 . In order to 11
Page 1 and 2: The obesogenic effects of polyunsat
Page 3 and 4: Table of Contents Acknowledgement .
Page 5 and 6: Abstract in Danish Polyumættede n-
Page 7 and 8: Polyunsaturated fatty acids in the
Page 9: was more than 3 times higher in the
Page 13 and 14: high dietary PUFAs, the modulation
Page 15 and 16: In a pair of population studies, an
Page 17 and 18: 18. Massiera, F. et al. Arachidonic
Page 19 and 20: 54. Xu, J. et al. Polyunsaturated f
Page 21 and 22: Annexes 1. Ma T, Liaset B, Hao Q, P
Page 23 and 24: Fish Oil, Sucrose and Obesity Obesi
Page 25 and 26: Fish Oil, Sucrose and Obesity Figur
Page 27 and 28: Fish Oil, Sucrose and Obesity Table
Page 33 and 34: Fish Oil, Sucrose and Obesity 6. Ma
Page 35 and 36: Carbohydrate source and insulin sec
Page 37 and 38: 20 21 22 23 24 25 26 27 28 29 30 31
Page 39 and 40: 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
Page 45 and 46: 208 209 210 211 212 213 214 215 216
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.
Page 61 and 62:
561 562 563 564 565 566 567 568 569
Page 63 and 64:
635 636 637 638 639 640 641 642 643
Page 65:
711 712 713 714 715 716 717 718 719
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Cyclooxygenases and UCP1 Although i
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Cyclooxygenases and UCP1 Figure 2.
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Cyclooxygenases and UCP1 Figure 4.
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Cyclooxygenases and UCP1 PLoS ONE |
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Cyclooxygenases and UCP1 E synthase
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Cyclooxygenases and UCP1 29. Granne
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JBC Papers in Press. Published on J
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hydrolysate (SPH), would be protect
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was used as the liver cytosolic fra
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In order to demonstrate that bile a
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Nutritional regulation of endogenou
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in increased whole body energy expe
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38. Kanehisa M, and Goto S. (2000)
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FOOTNOTES This work was carried out
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fed the same diets, plus the SPH-di
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Figure 2 A nmol/ min/ mg prot 2,4 1
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Figure 4 A 6 Liver Pparα B 21 Live
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Figure 7 A Plasma ALAT B Liver Ucp2
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Ruzzin et al. investigated the meta
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Ruzzin et al. CD14, and rho kinases
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Ruzzin et al. salmon oil induced a
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