Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic... Show moreGlucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic control. In this thesis, the effects of treatment on the different adipose tissue depots and on cardiac function are described. In a randomised controlled trial, we treated patients with type 2 diabetes from South Asian descent, a population with increased risk to develop type 2 diabetes and cardiovascular disease compared to Western Europeans, with liraglutide, a GLP-1 receptor agonist, or placebo, and studied these subjects with MRI. We concluded that liraglutide and possibly other GLP-1 receptor agonists can be a good strategy to reduce the volume of visceral adipose tissue. This reduction was accompanied by a significant improvement of glycemic control. Lastly, we provided evidence that liraglutide does not improve cardiac function and myocardial tissue characteristics and thus does not improve diabetic cardiomyopathy. In addition, in another study, we studied the mechanism behind GLP-1 receptor agonism induced weight loss and concluded that liraglutide induces weight loss in humans by decreasing energy intake rather than by activating brown adipose tissue or increasing energy expenditure. Show less
Rozendaal, Y.J.W.; Wang, Y.N.; Hilbers, P.A.J.; Riel, N.A.W. van 2019
BackgroundA positive energy balance is considered to be the primary cause of the development of obesity-related diseases. Treatment often consists of a combination of reducing energy intake and... Show moreBackgroundA positive energy balance is considered to be the primary cause of the development of obesity-related diseases. Treatment often consists of a combination of reducing energy intake and increasing energy expenditure. Here we use an existing computational modelling framework describing the long-term development of Metabolic Syndrome (MetS) in APOE3L.CETP mice fed a high-fat diet containing cholesterol with a human-like metabolic system. This model was used to analyze energy expenditure and energy balance in a large set of individual model realizations.ResultsWe developed and applied a strategy to select specific individual models for a detailed analysis of heterogeneity in energy metabolism. Models were stratified based on energy expenditure. A substantial surplus of energy was found to be present during MetS development, which explains the weight gain during MetS development. In the majority of the models, energy was mainly expended in the peripheral tissues, but also distinctly different subgroups were identified.In silico perturbation of the system to induce increased peripheral energy expenditure implied changes in lipid metabolism, but not in carbohydrate metabolism. In silico analysis provided predictions for which individual models increase of peripheral energy expenditure would be an effective treatment.ConclusionThe computational analysis confirmed that the energy imbalance plays an important role in the development of obesity. Furthermore, the model is capable to predict whether an increase in peripheral energy expenditure - for instance by cold exposure to activate brown adipose tissue (BAT) - could resolve MetS symptoms. Show less
Obesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a... Show moreObesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a combination of known and unknown risk factors. Since effective long-term treatment strategies are currently lacking, the search for additional risk factors and development of targeted treatment strategies to combat these (cardio)metabolic diseases is warranted. An attractive approach seems to be activation of energy-combusting brown adipose tissue (BAT), which can result in increased energy expenditure and improvement in glucose and lipid metabolism. In this thesis, we aimed to address two key objectives: 1) unravelling the underlying mechanisms that could explain the increased predisposition for metabolic disease in the South Asian population, and 2) identifying novel pharmacological strategies that activate BAT and increase energy expenditure in risk populations, including South Asians and individuals with overweight and prediabetes. The studies described in this thesis have highlighted some novel factors, such as endocannabinoids and angiopoitein-like-protein-4, that might in part explain to unbeneficial metabolic phenotype of South Asians. In addition, novel potential therapeutic strategies were identified to combat metabolic disease, such as treatment with a β3-adrenergic receptor agonist and a dipeptidyl-peptidase-4 inhibitor. Show less
Vroegrijk, I.O.C.M.; Diepen, J.A. van; Berg, S. van den; Westbroek, I.; Keizer, H.; Gambelli, L.; ... ; Voshol, P.J. 2011
