Leiden University Scholarly Publications

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Eenige, R. van (2023)

Targeting adipose tissue to improve cardiometabolic health

Doctoral Thesis
Cardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol and lipid accumulation. Despite available effective cholesterol lowering medication, considerable risk for recurrent vascular events remains. This residual risk is at least in part explained by high blood lipid levels. The research described in this thesis revealed novel therapeutic strategies that improve lipid metabolism and reduce atherosclerosis development in mice. Inhibition of the endocannabinoid system was found to be an effective strategy, as well as concomitant activation of two incretin hormone receptors, namely those for GIP and GLP1. For combined GIP/GLP1 receptor agonism we additionally showed strongly attenuated hepatic steatosis. We were also able to identify additional targets to attenuate hyperlipidemia by studying the mechanisms underlying the strong day-night rhythm...Show moreCardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol and lipid accumulation. Despite available effective cholesterol lowering medication, considerable risk for recurrent vascular events remains. This residual risk is at least in part explained by high blood lipid levels. The research described in this thesis revealed novel therapeutic strategies that improve lipid metabolism and reduce atherosclerosis development in mice. Inhibition of the endocannabinoid system was found to be an effective strategy, as well as concomitant activation of two incretin hormone receptors, namely those for GIP and GLP1. For combined GIP/GLP1 receptor agonism we additionally showed strongly attenuated hepatic steatosis. We were also able to identify additional targets to attenuate hyperlipidemia by studying the mechanisms underlying the strong day-night rhythm of brown adipose tissue, which is a lipid combusting tissue. In this thesis, I also stress the importance of the choice in animal model when studying lipid-modifying interventions, and describe the development of the software tool RandoMice which can be used to improve the quality of preclinical studies by creating well-balanced experimental groups.
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Atherosclerosis
Brown adipose tissue
Cardiovascular disease
Circadian/diurnal rhythms
Endocannabinoid system
Incretin system
Lipids
Lipoproteins
Metabolism
Randomization
All authors
Eenige, R. van
Supervisor
Rensen, P.C.N.
Co-supervisor
Kooijman, S.; Boon, M.R.
Committee
Meijer, O.C.; Stelt, M. van der; Shiri-Sverdlov, R.; Sluis, A.J.A. van der
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2023-06-27
ISBN (print)
9789464830385

Funding

Sponsorship
Financial support by the Netherlands Association for the Study of Obesity (NASO) for the publication of this thesis is gratefully acknowledged