Chronic energy surplus causes obesity and promotes insulin resistance and type 2 diabetes (T2D). A major contributor to insulin resistance is chronic, low-grade inflammation in metabolic tissues,... Show moreChronic energy surplus causes obesity and promotes insulin resistance and type 2 diabetes (T2D). A major contributor to insulin resistance is chronic, low-grade inflammation in metabolic tissues, also coined metaflammation. In this context, white adipose tissue and liver-resident innate and adaptive immune cells produce proinflammatory cytokines that exacerbate inflammation and inhibit canonical insulin signaling. Among them, macrophages and dendritic cells were shown to play central roles in metaflammation, although the environmental and cellular changes dictating proinflammatory activation in the context of obesity are not fully understood. This thesis describes novel mechanisms by which macrophages and dendritic cells control metabolic homeostasis in obese mice. In addition, we show that immunomodulatory molecules derived from parasitic worm eggs promote an immune response in metabolic tissues that maintains insulin sensitivity. Finally, we describe the pleiotropic beneficial effects of a novel plant-derived nutritional supplement on metaflammation and metabolic homeostasis in obese mice. Altogether, this work may provide new leads for interventions aimed at improving immunological control of metabolic dysfunctions. Show less
The main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of... Show moreThe main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of increasing urbanization in Indonesia. Our large-scale cluster-randomized controlled trial was performed in a rural area of Indonesia, which is endemic for soil-transmitted helminth (STH), and has been previously reported to have a low prevalence of IR and T2D. In STH-infected subjects, as assessed by microscopy, 12-month anthelmintic treatment increased IR, which was mediated by an increase in BMI and leptin to adiponectin ratio, as well as reduction in eosinophil count. Next, we also aimed to assess the different metabolic profile between populations living in rural and urban area, and to study the relative protective effect of rural environment to high-fat diet (HFD). In comparison to those living in rural area, individuals living in urban area had higher whole body IR, which was mainly mediated by the higher adiposity and leptin level, which were progressively increased with increased duration of time spent in urban area. Different environmental factors (including past or current exposure to STH) did not seem to affect the metabolic response to HFD intervention, independent from adiposity. Show less
Nearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T... Show moreNearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells. In addition to their involvement in anti-helminth immunity, recent studies have shown that components of the type 2 immune responses can have additional functions. For example, recent evidence indicates that multiple facets of the type 2 immune response can regulate tissue-specific metabolic processes and whole-body nutrient homeostasis, and protect against insulin resistance. In this work we use omega-1, a glycosylated RNase excreted from Schistsoma mansoni eggs with strong Th2-inducing capacities, to study the requirements that equip DCs for Th2 skewing. In addition, we analyse the effect of chronic S. mansoni infection and administration of S. mansoni-derived egg antigens on metabolic homeostasis in diet-induced obese mice. Elucidating how helminths generate Th2 responses and contribute to metabolic homeostasis will not only shed light on the mechanisms that promote control of parasite infection, but may provide valuable leads for the development of pharmaceutical agents for the treatment of metabolic disorders. Show less
