Stress, obesity and (stress-related) mood disorders such as depression and anxiety disorders are highly prevalent in modern society. These diseases often coincide. This may be because they trigger... Show moreStress, obesity and (stress-related) mood disorders such as depression and anxiety disorders are highly prevalent in modern society. These diseases often coincide. This may be because they trigger and reinforce each other, creating a vicious cycle. Social and psychological factors play a role in this cycle, but in this thesis we focused on the underlying biological mechanisms. We identified new obesity-related factors that likely affect fear and discovered new sites of action in the brain for factors that are already known to regulate fear. We also applied three novel drug treatment strategies. Each of these target (different) components of the stress system and were shown to alleviate stress- or diet-induced metabolic disease in mice. Certain strategies reduced obesity, while others seemed to prevent or even cure fatty liver disease in mice. This thesis thus represents a step towards breaking the vicious cycle between stress, obesity and (stress-related) mood disorders. Show less
Our increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher... Show moreOur increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher availability and intake of food, which often appears unhealthy, and lower energy expenditure related to a sedentary lifestyle. Although the most efficient ways to slow this high prevalence of obesity are just eating less and more healthy, and moving more, to reduce energy intake and increase energy expenditure, respectively, current strategies to achieve this in the long-term are still both insufficient and ineffective, and novel strategies are still eagerly warranted.This thesis emphasizes dietary butyrate as a promising and feasible therapeutic strategy to combat obesity and related cardiometabolic diseases with respect to not only reducing appetite but also activating brown adipose tissue. In a series of subsequent mechanistic studies, we elucidated the mechanisms underlying these metabolic properties systematically from gut to the brain, showing the involvement of gut microbiota, intestinal GLP-1 secretion, vagal nerve activation, and finally central GLP-1 receptor signaling to inhibit NPY neuronal activation. The findings of this thesis provide valuable information on the development of novel therapeutic strategies for combating obesity and associated cardiometabolic diseases. Show less
The objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long... Show moreThe objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long-term prognostic implications of subclinical myocardial dysfunction on all-cause mortality. Show less
The research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in... Show moreThe research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in depth characterization of lysosome function in health and disease. An integrative approach was used to study the physiological role of the lysosome, characterizing the function of lysosomal hydrolases and signalling on a cellular level as well as within the context of tissue. Show less
Type 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op... Show moreType 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op deze ziekten. Dit komt gedeeltelijk door hun ongunstige lichaamssamenstelling met veel buikvet en vetopslag in organen zoals spieren en lever, wat hun werking verstoort. Het verminderen van overgewicht verlaagt het risico op type 2 diabetes en hart- en vaatziekten. Verminderen van voedselinname en verhogen van het energieverbruik kan hieraan bijdragen. Een veelbelovende aanpak om het energieverbruik te verhogen, is het stimuleren van vet- en suikerverbranding door lichaamseigen bruin vetweefsel. In dit proefschrift onderzochten wij eerst mechanismen die bijdragen aan cardiometabole ziekten in Zuid-Aziaten. Wij observeerden verminderde Wnt signaaltransductie in wit vet van Zuid-Aziaten, wat samenhing met minder insulinegevoeligheid in dit weefsel. Ook vonden wij een andere samenstelling van LDL-deeltjes in Zuid-Aziaten, wat samenhing met een verhoogde neiging van deze deeltjes om samen te klonteren. Daarna onderzochten wij de effectiviteit van geneesmiddelen om bruin vet activiteit te verhogen en de cardiometabole gezondheid te verbeteren. Wij lieten zien dat stimuleren van de beta-adrenerge receptor de stofwisseling verhoogt en vetverbranding door bruin vet stimuleert, echter niet méer dan koudeblootstelling. Ook vonden wij dat GLP-1 receptoragonisme de suikeropname door bruin vet stimuleert, wat mogelijk bijdraagt aan een gunstig effect op het lichaamsgewicht en suiker- en vetstofwisseling. Deze studies hebben bijgedragen aan kennis over risicofactoren voor cardiometabole ziekten en de ontwikkeling van nieuwe therapeutische strategieën om deze ziekten tegen te gaan, vooral in Zuid-Aziaten. Show less
