Background Obesity is increasing worldwide and is a major contributor to morbidity and mortality. Notably, abdominal (central) obesity carries a high risk of obesity-related diseases, while peripheral fat accumulation can act in a protective manner. A redistribution of fat from peripheral to central depots is seen after the menopause and is associated with an increasing prevalence of diabetes and cardiovascular disease. A key mediator may be ectopic fat accumulation in the liver. Our hypothesis was that a Palaeolithic-type diet (PD) consumed ad libitum improves body composition and metabolic risk markers, including liver fat and insulin sensitivity, in obese postmenopausal women. Methods In study I the study subjects (n=10) used a PD during 5 weeks. In study II and III (n=70) the effect of a Palaeolithic-type diet (PD) was compared to a diet according to the Nordic Nutrition Recommendations diet (NNR) during a 2-year randomized clinical trial (RCT). Food records and nitrogen excretion in urine validated food intake. Anthropometric measurements were performed in a standardized manner. Body composition was calculated using Dual Energy X-ray Absorptiometry (DXA). Total energy expenditure was calculated by accelerometry (Actiheart®) in combination with indirect calorimetry. Liver and muscle fat content was estimated by magnet resonance spectroscopy (1H-MRS). Insulin sensitivity was measured either with hyperinsulinemic euglycemic clamps (paper I) or oral glucose tolerance tests (OGTTs) (paper III). Results In study I a significant weight loss, linked to improved lipid and blood pressure levels, was associated with a 49% decrease in liver fat. Concomitantly, hepatic insulin sensitivity improved, while peripheral insulin sensitivity (and muscle fat) was unaltered. In study II/III both groups had a significant and sustained weight loss after 2 years. The PD was more effective than the NNR diet regarding loss of weight and fat mass after 6 months, but not after 24 months. Serum triglyceride levels were significantly lower at 24 months in the PD group. Liver fat decreased throughout the study in both groups. Hepatic insulin sensitivity improved during the first 6 months of the study, while peripheral insulin sensitivity did not change. Hepatic insulin sensitivity was associated with liver fat at baseline, but not during the diet intervention. Energy expenditure did not change in any of the study groups. Conclusion Ad libitum diets can have sustained beneficial effects on weight and body composition in obese postmenopausal women, a PD being more effective on short-term than a diet according to the NNR. This is associated with a reduction in liver fat that may reduce the risk of future diabetes and cardiovascular disease. Further studies are needed in order to explore the association between liver fat and metabolic dysfunction, including insulin sensitivity.

The aim of this thesis was to investigate the effects of dietary fatty acids on body composition and ectopic fat in humans, with emphasis on the role of the omega-6 polyunsaturated fatty acid (PUFA) linoleic acid (18:2n-6) and the saturated fatty acid (SFA) palmitic acid (16:0). The overall hypothesis was that linoleic acid would be beneficial compared with palmitic acid during overfeeding, as previously indicated in animals. Papers I, II and IV were double-blinded, randomized interventions in which different dietary fats were provided to participants and Paper III was a cross-sectional study in a community-based cohort (PIVUS) in which serum fatty acid composition was assessed as a biomarker of dietary fat intake. In Paper I, overfeeding with sunflower oil (n-6 PUFA) for 7 weeks caused less accumulation of liver fat, visceral fat and total body fat (as assessed by MRI) compared with palm oil (SFA) in young and lean subjects despite similar weight gain among groups. Instead, sunflower oil caused a larger accumulation of lean tissue. In Paper II, plasma from Paper I was analyzed with NMR-based metabolomics, aiming to identify metabolites differentially affected by the two dietary treatments. Acetate decreased by PUFA and increased by SFA whereas lactate increased by PUFA and decreased by SFA. In Paper III, the proportion of linoleic acid in serum was inversely associated with contents of visceral-, subcutaneous- and total body adipose tissue whereas the proportion of palmitic acid was directly associated with visceral- and total body adipose tissue in 70-year old men and women. In Paper IV, overfeeding with sunflower oil for 8 weeks caused less accumulation of liver fat compared with palm oil also in overweight and obese subjects. SFA increased visceral fat in men only. Accumulation of lean tissue was similar between groups. In conclusion, SFA (palmitic acid) from palm oil promotes marked liver fat accumulation in both normal-weight and overweight/obese subjects during overeating, whereas n-6 PUFA (linoleic acid) from sunflower oil prevents such liver fat accumulation. Diverging effects of SFA and PUFA on visceral adipose tissue and lean tissue may only be applicable in some groups and/or circumstances. These results imply that negative effects associated with weight gain (e.g. fatty liver) may be partly counteracted by the type fat in the diet, overall supporting a beneficial role of diets higher in unsaturated fat compared with saturated fat for preventing liver fat accumulation.

Le projet de cette thèse porte sur le développement de dépôts lipidiques ectopique et leur modulation suite à des intervenions thérapeutiques par imagerie résonance magnétique.Dans notre première étude, nous avons établi l’ordre chronologique d’apparition de graisses ectopiques et d’anomalies cardiaques dans un modèle de souris soumises à un régime riche en graisse et en sucre. Un traitement de courte durée à l’exendine-4 permet une amélioration de tous les paramètres altérés. Dans la deuxième étude, nous avons évalué l’impact d’un traitement de l’obésité sur les dépôts ectopique de graisse cardiaque (TAE et stéatose), hépatique et pancréatique à deux temps (6 mois et 32 mois) après chirurgie bariatrique. Nous avons montré que ce traitement chirurgical permet une réduction de tous ces dépôts, avec une cinétique différente. Enfin, dans la troisième étude, nous nous sommes intéressés à l’effet du poids de naissance sur le développement de tissu adipeux épicardique. Cette étude nous a permis de mettre en évidence qu’il existe une accumulation plus importante de TAE à l’âge adulte lorsque le poids de naissance est augmenté ; et que les paramètres poids de naissance et croissance entre 2 et 12 ans, jouent un rôle important dans la mise en place de ce dépôts de graisse ectopique. En somme, ces résultats permettent une avancée dans la compréhension du développement des dépôts de graisses et de leur modulation. / The project of this thesis mainly focuses on ectopic lipid deposition development and their flexibility following therapeutic intervention. In our first study, we set out chronological order of ectopic fat onset and cardiac abnormalities in a high fat high sucrose mice model. Short duration exendin-4 treatment reverses every altered parameter. In the second study, we assessed treatment of obesity effect on cardiac ectopic fat deposition (EAT and steatosis), as well as hepatic and pancreatic fat at two different time points (6 months and 32 months) after bariatric surgery. We show significant reduction of every ectopic fat deposition, however in different kinetic. Finally, in a third study, we investigate birth weight effect on epicardial adipose tissue development. This study demonstrate important EAT accumulation in adulthood when birth weight is increased. Furthermore, birth weight and catch up growth in childhood between 2 and 12 years parameters impact significantly the development of epicardial fat.In summary, these results provide better understanding of ectopic fat deposition development and modulation.