Introduction: N3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects for the hypothalamus, but their extra-hypothalamic outcome lack documentation. We evaluated the central consequences of the substitution of saturated fatty acids with n-3 or n-6 PUFA in obesogenic diets.Methods: Twenty-one miniature pigs were fed ad libitum obesogenic diets enriched in fat provided either as lard, fish oil (source for n-3 PUFAs), or sunflower oil (source for n-6 PUFAs) for ten weeks. The blood-brain barrier (BBB) permeability was quantified by CT perfusion. Central autonomic network was evaluated using heart rate variability, and PET 18FDG was performed to assess brain metabolism.Results: BBB permeability was higher in lard group, but heart rate variability changed only in fish oil group. Brain connectivity analysis and voxel-based comparisons show regional differences between groups except for the cingulate cortex in fish oil vs. sunflower oil groups.Discussion: : The minute changes in brain metabolism in obese pigs feed with fish oil compared with saturated fatty acids were sufficient to induce detrimental changes in heart rate variability. On the contrary, the BBB's decreased permeability in n-3 and n-6 PUFAs groups was protective against an obesity-driven damaged BBB.