Dietary fat and the prevention of type 2 diabetes; impact on inflammation and underlying mechanisms.

The incidence of metabolic syndrome, which is a risk factor for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) is increasing rapidly. Changes in dietary fat composition from saturated fat (SFA) to monounsaturated fat (MUFA) from olive oil, which is highly consumed in a Mediterranean diet, might improve risk factors for CVD and T2DM. However, the underlying molecular mechanisms for these beneficial health effects are not completely known. Moreover, more knowledge is needed about health status and biomarkers that allow early detection of onset of diseases such as metabolic syndrome, CVD and T2DM. The aim of this thesis was twofold; first, to investigate the acute and longer-term effects of intake of different types of dietary fat. Second, to examine whether a more comprehensive phenotyping of health status can be achieved by application of nutrigenomics tools and challenges tests. A controlled dietary intervention study was performed in healthy abdominally overweight subjects to investigate the effects of 8-weeks consumption of diets high in SFA or MUFA on insulin sensitivity, serum lipids and adipose tissue whole genome gene expression. Moreover, the effects of replacement of SFA by MUFA, as part of a western-type diet and as part of a Mediterranean diet, on peripheral blood mononuclear cell (PBMC) whole genome gene expression and plasma protein levels were investigated. Plasma protein profiles of the subjects before the intervention were used to define proteins and protein clusters that were associated with BMI and insulin concentrations. Similar analyses were performed in a second overweight population to verify the findings. In two other studies, the response capacity of subjects with different metabolic risk phenotypes to a high-fat challenge varying in fat type and to an extreme caloric restriction challenge were determined. Results from our first study showed that consumption of a SFA-rich diet increased expression of inflammation-related genes in adipose tissue whereas consumption of a MUFA-rich diet led to a more anti-inflammatory gene expression profile, without changes in insulin sensitivity or increases in body weight. Moreover, high MUFA intake from olive oil, both in a western-type diet and in a Mediterranean-type diet, lowered expression of genes involved in oxidative phosphorylation in PBMCs and lowered serum LDL and plasma ApoB, Connective Tissue Growth Factor and myoglobin concentrations. In plasma of the healthy participants clusters of proteinsassociated with BMI or insulin could be identified. These clusters included previously reported biomarkers for disease and potential new biomarkers. The high-fat challenge study showed that the plasma metabolic response and the PBMC gene expression response to high-fat challenges were affected by the presence of obesity and/or diabetes. Comparison of responses to high SFA, MUFA and n-3 PUFA loads showed that a highMUFA load induced the most pronounced response. The caloric restriction study revealed that PBMC gene expression profiles were different between metabolic syndrome subjects and healthy subjects, mainly for genes involved in pathways related to mitochondrial energy metabolism. Moreover, we observed that the caloric restriction challenge magnified differences in PBMC gene expression profiles between the subject groups. In conclusion, this thesis showed that 8-weeks consumption of a SFA-rich diet resulted in a pro-inflammatory gene expression profile in adipose tissue whereas consumption of a MUFA-rich diet caused a more anti-inflammatory profile, in addition to reductions in LDL cholesterol, some plasma proteins and expression of oxidative phosphorylation genes in PBMCs. Since the effects of the diets on inflammation were still local and not accompanied by systemic changes in inflammatory status or insulin sensitivity we hypothesize that adipose tissue could be an early response organ for dietary fat-induced changes. The changes in pro-inflammatory gene expression might be one of the first hallmarks in the development of adipose tissue inflammation and insulin resistance which on the longer term may lead to inflammation-related diseases such as metabolic syndrome. Our studies showed the potential of whole genome expression profiling, plasma profiling and the use of challenges tests to detect subtle diet effects and small differences in health status. Using these tools in future studies will result in more knowledge about health status and about mechanisms behind dietary effects. Eventually this might lead to earlier detection of small deviations from a healthy phenotype and to evidence-based dietary advice to improve health and to prevent disease.