Genes participating in fatty liver and type 2 diabetes

Contact persons: Dr. Wenke Jonas, Dr. Heike Vogel, Heja Aga-Barfknecht, Markus Jähnert, Dr. Pascal Gottmann, Dr. Thilo Speckmann

Funding: German Center for Diabetes Research (DZD)

In order to identify obesity and diabetes genes and to clarify the pathomechanisms of the disease, we use two obese, insulin-resistant mouse models, which differ in their diabetes susceptibility. In addition, we use lean mice. The New Zealand obese (NZO) mouse is a diabetes-prone mouse that suffers from the metabolic syndrome. This syndrome is characterized by obesity, insulin resistance, hypertension and dyslipidemia and leads to a type 2 diabetes-like phenotype that is associated with the failure and loss of beta cells. The C57BL/6-ob/ob mouse (B6-ob/ob) is also extremely obese and insulin-resistant, but is protected against hyperglycemia. The lean mouse strains C57BL/6 (B6) and DBA also differ in terms of their susceptibility to type 2 diabetes, which, however, only becomes apparent on an obese background.

Basically, we use two approaches to identify new disease genes. In the first approach, the genomes of the NZO mouse were mixed with those of the lean diabetes-resistant B6 or the lean and diabetes-susceptible DBA mouse by generating backcross populations. The offspring were characterized with regard to their genetics and phenotype, allowing linkage analyzes for the identification of chromosomal regions (quantitative trait loci, QTL). These QTL carry genes that e.g. affect body weight, liver fat or blood glucose concentration. Up to now, we have discovered 15 responsible disease genes using positional cloning - a combination of breeding and bioinformatics methods (Fig. 1). Among them are Ifgga2 and Ifgga4, two neighboring genes that encode immune-associated GTPases and influence the amount of fat in the liver. The loss of only one base in the binding site of the transcription factor FOXO1 in an enhancer region reduces the expression of both genes, which leads to the development of fatty liver. Functional studies have shown that overexpression of Ifgga2 and Ifgga4 in liver cells as well as in the liver of mice significantly reduced their fat content. This occurred by inducing lipophagy – a special form of autophagy – which is specific for the breakdown of lipids. The family of immune-associated GTPases also plays a role in humans, since patients with a non-alcoholic fatty liver (NAFLD) express the orthologue gene IRGM to a lower degree than healthy people.

In the second approach, we focus on genes from islets of Langerhans, organs within the pancreas that release important hormones of glucose meabolism (insulin, glucagon). We compare pathological changes in islets of Langerhans in the diabetes-prone NZO and the diabetes-resistant B6-ob/ob mice, which were subjected to a specific dietary regime. A genome-wide expression analysis of the islets of both mouse strains before and two days after feeding a diabetogenic diet showed more than 1000 differentially expressed genes. Among them, we discovered a significant enrichment of close to 400 genes annotated to cilia function. More than 80 of these cilia genes exhibited also an altered expression in islets of patients with type 2 diabetes. In fact, we observed that NZO islets carry less cilia than B6-ob/ob islands. Further functional analysis had shown that islet cells disassemble their cilia after carbohydrate feeding and trigger cell division as a result. The inhibition of one important cilia gene, the Kif3a, led to a reduced formation of cilia and a decrease in islet cell division in both humans and mice.