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

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232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 different (not shown). As expected, inclusion of nifedipine in the sucrose enriched high-fish oil diet resulted in lower levels of plasma insulin in the fed state (Fig 6B). Importantly, the mice receiving the nifedipine-supplemented diet had lower adipose tissue mass and adipocytes had a normal appearance (Fig 6C). When nifedipine was added to a standard low fat diet, no effect on adipose tissue mass was observed (not shown), and expression of inflammatory markers in white adipose tissue was, with the exception of Serpine1 in iWAT, not reduced (Fig 6D). In line with unchanged energy efficiency, we did not detect any increased expression of Ucp1 in iWAT in nifedipine treated mice (Fig 6D). Moreover, nifedipine did not increase hepatic expression of Pck1 or genes involved in lipogenesis or amino acid degradation (Fig 7A). Thus, inhibition of insulin secretion was able to partly attenuate the obesogenic effect of sucrose in combination with fish oil, but did not reduce energy efficiency. Furthemore, nifedipine did not improve the reduced glucose tolerance observed after feeding fish oil in combination with sucrose, but a insulin tolerance test indicated that insulin sensitivity was improved (Fig 7B). Together, our data indicate that an inhibition of insulin secretion attenuates the adipogenic effect of sucrose in combination with fish oil. However, inhibition of insulin secretion is insufficient to reduce energy efficiency. 247 248 249 250 251 252 DISCUSSION Due to the well described beneficial effects of n-3 PUFAs on lipid metabolism and lipid-related disorders in humans, increasing the relative amount of n-3 PUFAs in diet or as supplement is presently recommended by Health Authorities. The potential use of n-3 PUFAs in weight control in humans is not fully explored, but the ability of these fatty acids to reduce the development of diet- 253 induced obesity rodents is well described (7, 10-15). In this study we demonstrate that the 254 255 composition of the diet determines the adipogenic potential of fish oil. In particular, we demonstrate that a high dose of fish oil promoted obesity when combined with sucrose, glucose or high GI 12
256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 starch. Thus, many if not all reported beneficial effects of fish oil intake might be diminishes or completely abrogated by a simultaneous intake of high GI carbohydrates. Insulin is the primary anabolic hormone promoting energy storage in the fed state and is an important driver for adipocyte differentiation (18). Of note, mice lacking insulin receptors in adipose tissue (FIRKO mice), are protected against obesity and remain glucose tolerant on a highfat diet (19). Further, white adipose tissue mass is dramatically reduced in Irs1 -/- Irs2 -/- doubleknockout mice (45). In contrast, mice lacking the insulin receptor in muscle (MIRKO mice) have increased glucose utilization in WAT (46), and exhibit a more than 50% increase in fat mass and adipocyte number (47). Similarly, mice overexpressing Slc2a4 (solute carrier family 2 (facilitated glucose transporter), member 4, GLUT4) (48) or Irs1 (20) in adipose tissue are obese. Finally, treating normal rats with insulin via osmotic minipumps increases Slc2a4 expression, glucose utilization and de novo fatty acid synthesis in adipose tissue, which are accompanied by weight gain and increased adipose tissue mass (49-51). The importance of insulin secretion and insulin levels in circulation is further supported by the finding that daily injections of insulin increases weight gain in transgenic mice expressing agouti in adipose tissue (52). Of note, unlike the traditional agouti mice, mice with transgenic expression of the agouti gene driven by the aP2 promoter do not get obese unless triggered by insulin (52). Transgenic mice treated with insulin gained significantly more weigh than their wild type littermates, and the authors suggested that the daily insulin treatment mimicked the hyperinsulinemia normally observed in mice expressing the agouti gene ubiquitously (52). Moreover, weight gain is a well recognized side effect of type 2 diabetic drugs that increase insulin sensitivity (53, 54). Together these observations suggest that hyperinsulinemia is a contributing factor to development of obesity and reducing hyperinsulinemia would thus possible counteract obesity development. In keeping with this view, inhibition of insulin secretion 13
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 and 10: was more than 3 times higher in the
Page 11 and 12: gluconeogenesis and ureagenesis (Fi
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: 208 209 210 211 212 213 214 215 216
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
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 92 and 93: In order to demonstrate that bile a
Page 94 and 95: Nutritional regulation of endogenou
Page 96 and 97:
in increased whole body energy expe
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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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