Genotype-by-diet interactions determine susceptibility and resistance in T2D mouse models [Islet 2]

ABSTRACT: Genetic and lifestyle factors greatly impact the development of metabolic diseases including Type 2 Diabetes (T2D). It is an ongoing challenge to determine how these factors and their interplay specifically contribute to risk of T2D. Mouse models allow precise control of environment and genetic replication, and mouse strains fed an unhealthy diet show variable signs of metabolic dysfunction ranging from overt diabetes to diet-induced obesity to complete resistance. When fed a high-fat high-sugar (HFHS) diet, NZO/HlLtJ (NZO) mice become severely obese and many become diabetic, C57BL/6J (B6J) mice develop obesity but seldom overt diabetes, and CAST/EiJ (CAST) mice are resistant to obesity and glucose intolerance. We present deep molecular and metabolic profiling of these three genetically diverse mouse strains fed control (low fat, no sugar) and HFHS diets to define inherited aspects of metabolism that may impact diabetes risk. Transcriptomic analysis of eight tissues revealed significant tissue-specific molecular variability underpinning the metabolic differences across strains. The most distinct diet responses were observed in adipose and pancreas. In adipose tissue, differences in immunometabolism, lipid metabolism, and oxidative phosphorylation pathways parallel the susceptibility to obesity and diabetes across strains. In pancreatic islets, there was inflammation associated with HFHS diet in NZO mice that is expected to contribute to beta cell dysfunction. Taken together, physiological and molecular profiling of these genetically diverse mouse strains provides a foundation for deeper understanding the molecular basis of individual differences in susceptibility to metabolic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE235481 | GEO | 2023/12/31

REPOSITORIES: GEO