Transcriptome analysis to investigate the link between obesity and its metabolic complications: type 2 diabetes and NASH

PhD ceremony: Mr. M.G.M. Wolfs, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Transcriptome analysis to investigate the link between obesity and its metabolic complications: type 2 diabetes and NASH

Promotor(s): prof. M.H. Hofker, prof. T.N. Wijmenga

Faculty: Medical Sciences

Throughout the world half a billion people are obese. This epidemic is a tremendous problem, because obesity often induces severe diseases such as type 2 diabetes and Non-Alcoholic SteatoHepatitis (NASH; specific kind of liver inflammation), The obesity epidemic is driven by the new “Western” lifestyle. However, also heritable factors in the DNA (mutations) are important, because they determine whether a person – given the changed lifestyle – is viable to obesity, type 2 diabetes, and/or NASH. This thesis describes research into relations between mutations and the expression of genes (this means to what extent genes are turned “on” or “off”). In particular, relationships between mutations involved in type 2 diabetes, and expression of genes in several tissues - fat, muscle and liver tissue – were investigated. Also, direct relations between expression of genes, and diabetes and NASH were studied.

A major finding is the discovery of a large number of relations between mutations and gene expression. Moreover, six genes (THADA, PTPLB, MEST, CCNE2, NUCB2, ATP2B3) were identified to have a causal role in the onset of type 2 diabetes, and three genes (LEP, RARRES2 en ANGPT2) were found to have expression levels in adipose tissue related to NASH. Finally, in fat tissue, expression levels of genes involved in the immune system were found to be related to diabetes.

Research into the functions of these genes will further increase knowledge about type 2 diabetes and NASH. This is important for the development of new therapies.