Investigating metabolic disease in human induced pluripotent stem cells : apidocyte size, insulin signaling and hepatic lipids

Friesen, M. (2018)

Doctoral Thesis

Metabolic disease has become pandemic in the developed world. Given our lack of understanding of its molecular pathology, we are often unable to diagnose patients before they reach an irreversible state of diabetes or cardiovascular disease. Much research has been done on the role of insulin signaling in metabolic disease, as well as the resultant disturbed lipid homeostasis present in cardiovascular disease and atherosclerosis. Here we add to existing work by developing new tools and sketching out the pathology of dysregulated adipose insulin signaling.
We discuss the mechanism of lipodystrophy by using adipocytes differentiated from patient-derived iPSCs. These cells mimic the clinical phenotype and hint at mechanism that reduced patients’ adipose tissue mass. In mice we find that if we knock out the adipose insulin receptor, there is disrupted adipose and liver metabolism. There is a protection from diet-induced obesity, but a dramatically reduced lifespan. We also establish a relationship between obesity and inflammation by transcriptomically assessing obese human adipocytes. We find that an immune factor is responsible for lipid droplet formation and content.
Lastly, we develop a new differentiation and purification strategy for iPSC-derived hepatocytes, which we employ to in vitro model a SNP that protects against cardiovascular disease.

• Insulin resistance
• Cardiovascular disease
• Insulin
• Type 2 Diabetes
• Hepatocyte
• Adipocyte
• iPSC
• Stem cell differentiation

• All authors: Friesen, M.
• Supervisor: Mummery, C.L.; Cowan, C.
• Committee: Hoeben, R.C.; Slagboom, P.; Koning, E.J.P. de; Water, B. van de; Huylebroeck, D.F.E.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2018-09-05
• ISBN (print): 9789090311241