The prevalence of obesity across the world has increased dramatically in recent years, thus increasing the prevalence of obesity-associated diseases, such as type 2 diabetes and cardiovascular disease. Obesity is considered a complex and multifactorial condition, affected by interactions between environmental and genetic factors. A better understanding of the role of these factors might enable the development of more comprehensive and effective strategies for prevention and treatment. The overall objective of this PhD thesis was to investigate how genetic variants, circulating microRNAs, and dietary fibres affects obesity and weight loss. Specifically, we aimed at studying the function of angiopoietin-like protein 3 (ANGPTL3) in relation to body weight, lipid metabolism, and risk markers related to liver health status before and during a low-calorie diet induced weight loss. We further aimed at identifying genetic variants affecting the level of circulating ANGPTL3 (Paper I). Moreover, we investigated whether supplementation with specific prebiotic dietary fibres would induce greater body weight loss compared to placebo during 12 weeks of dietary energy restriction and whether the dietary fibres would have an effect on body composition, gut microbiota, and metabolic markers (Paper II). Finally, specific circulating miRNAs were analysed in relation toobesity and the presence of the metabolic syndrome, as well as the response to weight loss (Paper The objectives were investigated through two randomised controlled studies, the DiOGenes study and the My New Gut II (MNGII) study. We used data from the initial eight weeks of the DiOGenes study. In this period, participants were encouraged to lose weight through a low caloric diet (800kcal/day with the additional use of 200 g of vegetables). The MNGII study was a double-blinded, parallel intervention trial. The participants were randomised to either dietary fibre supplement or matched placebo before initiation of a 12 weeks energy-restricted (-500 kcal/day) weight loss period. Results from the DiOGenes study demonstrated that circulating ANGPTL3 and cytokeratin 18 (CK18) are positively correlated and that changes in ANGPTL3 and CK-18 are affected by genetic regulation during energy restriction. This suggests an extended function of ANGPTL3 in the inflammatory state of liver steatosis and towards liver metabolic processes (Paper I). Our results from the MNGII study demonstrated that 12-week supplementation with inulin and resistant maltodextrin does not provide an additional weight loss during an energy-restricted diet but led to reduced blood pressure. Additionally, fibre supplementation stimulated the growth of potentially beneficial bacteria genera (Paper II). Finally, we observed changes in circulating miRNAs in response to an energy-restricted weight loss intervention, and our results suggested that an assessment of miR-122 -5p could indicate the status of metabolic health (Paper III). In conclusion, the results from this PhD thesis support the understanding of a complicated interplayof several biological mechanisms in obesity and weight loss including genetic variants, circulatingmiRNAs, and dietary fibres.