Identification of new candidate genes for insulin sensitivity and insulin resistance in the Berlin Fat Mouse

• Applicant: Dr. Deike Hesse-Wilting
• Subject Area: Endocrinology, Diabetology, Metabolism ; Nutritional Sciences ; Animal Breeding, Animal Nutrition, Animal Husbandry
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396456925

• Final Report Year: 2024

Final Report Abstract

The worldwide increase in type 2 diabetes is alarming: according to the World Health Organization, 8.5% of the adult population is affected. The results of this project offer additional approaches to the development of new therapeutic and preventive strategies. This research project investigates the genetic causes and mechanisms leading to the development of type 2 diabetes and insulin resistance. By using special mouse models, the Berlin Fat Mouse Inbred Lines (BFMI), new genes and gene variants responsible for these diseases are to be identified. Objectives and Results; 1. Fine Mapping of Causal Gene Loci: Through crossbreeding experiments and genetic analyses, genomic regions responsible for differences in insulin sensitivity were identified. The study of the Berlin Fat Mouse sublines BFMI861-S1 and BFMI861-S2, which show significant differences in insulin sensitivity, enabled a detailed analysis of these differences. 2. Identification of the Causal Tissue: The analysis of metabolically relevant tissues revealed that gonadal fat tissue plays a central role in the Berlin Fat Mouse. The expression of specific genes such as Plg and Acat2, which are important for fat cell storage and fat metabolism, was significantly altered in the fat tissue. 3. Functional Characterization of Candidate Genes: Genes such as Bbs7 and Acat2 were verified and identified as important candidates for insulin resistance and body weight. These genes influence fat metabolism and insulin sensitivity, leading to new approaches for researching and treating type 2 diabetes. 4. Temporal and Diet-Dependent Analysis: The investigation of gene expression and body weight over various time periods and under different dietary conditions showed that certain genomic regions affect the insulin sensitivity of the Berlin Fat Mouse in a time- and dietdependent manner. An example is the gene Sun2, which plays a key role in carbohydrate metabolism. The findings from this project contribute significantly to the understanding of the genetic foundations of type 2 diabetes and insulin resistance. This is of great importance as it enables the development of personalized therapeutic approaches. By identifying new genetic markers, at-risk individuals can be detected early and treated specifically to prevent or delay the onset of diabetes. Additionally, the identified genes offer new targets for the development of medications that specifically address the molecular causes of the disease. Overall, this research project makes a further contribution to the complex fight against type 2 diabetes and towards improving the quality of life for those affected.

Publications

• Die Fettleber der Berliner Fettmaus assoziiert mit einem Locus auf Chromosom 8. Diabetologie und Stoffwechsel. Georg Thieme Verlag KG.
  Hesse, D.; Delpero, M.; Freiberg, A.; Dresen, S.; Arends, D. & Brockmann, G.
  
• Identification of four novel QTL linked to the metabolic syndrome in the Berlin Fat Mouse. International Journal of Obesity, 46(2), 307-315.
  Delpero, Manuel; Arends, Danny; Sprechert, Maximilian; Krause, Florian; Kluth, Oliver; Schürmann, Annette; Brockmann, Gudrun A. & Hesse, Deike
  
• QTL mapping in an advance intercross line of the Berlin Fat Mouse identifies candidate genes for the metabolic syndrome. Diabetologie und Stoffwechsel. Georg Thieme Verlag KG.
  Delpero, M.; Arends, D.; Hesse, D. & brockmann, G.
  
• 58th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia, 65(S1), 1-469.
  Deike Hesse, Manuel Delpero, Maximilian Sprechert, Danny Arends & Gudrun Brockmann
  
• One region on chromosome 17 is associated with plasma and pancreatic insulin content in an obese mouse model. Diabetologie und Stoffwechsel, 17(S 01), S66-S66.
  Delpero, Manuel; Arends, Danny; Sprechert, Maximilian; Brockmann, Gudrun & Hesse, Deike
  
• QTL-mapping in the obese Berlin Fat Mouse identifies additional candidate genes for obesity and fatty liver disease. Scientific Reports, 12(1).
  Delpero, Manuel; Arends, Danny; Freiberg, Aimée; Brockmann, Gudrun A. & Hesse, Deike
  
• A deleterious mutation in Acat2 promotes ectopic liver fat storage by disturbing Acetyl-CoA metabolism in adipose tissue of the Berlin Fat Mouse. International Mammalian Genome Conference (IMGC 2023), Tsukuba, Japan
  Deike Hesse
  
• A deleterious mutation in Acat2 promotes ectopic liver fat storage by disturbing cholesterol metabolism in adipose tissue of the Berlin Fat Mouse. Diabetologie und Stoffwechsel, 18(S 01), S22-S22.
  Hesse-Wilting, Deike; Sprechert, Maximilian; Delpero, Manuel; Freiberg, Aimée; Korkuc, Paula; Arends, Danny & Brockmann, Gudrun A.
  
• Identification of additional body weight QTLs in the Berlin Fat Mouse BFMI861 lines using time series data. Scientific Reports, 14(1).
  Delpero, Manuel; Korkuć, Paula; Arends, Danny; Brockmann, Gudrun A. & Hesse, Deike