Host Genetic Background Affects the Brain Weight Influenced by Obesity and Diabetes Development in Collaborative Cross Mice

The population is increasingly obese, which is linked to the emergence of numerous health issues. Numerous risk factors are present along with the metabolic syndrome. Genetic components, environmental factors, and psychosocial impacts are some of the causes that contribute to obesity. Increases in diabetes mellitus, coronary heart disease, some malignancies, and sleep-related breathing issues have all been linked to an increase in obese cases. Type 2 diabetes (T2D) mellitus due to obesity has been shown to cause brain alterations that may lead to cognitive impairment. A correlation between T2D and an increased risk for neurodegenerative diseases such as dementia, Parkinson’s disease (PD), and Alzheimer’s disease (AD) was observed. Thus, understanding the connection between these diseases may aid in halting or delaying their prevalence. In this report, we studied the impact of a high-fat diet (HFD) on the development of obesity and diabetes and its effect on brain weight. In the two experimental groups, an evaluation was conducted on a cohort of 143 mice from eight different collaborative Cross (CC) mouse lines. For the entire 12 weeks experiment period, the mice were kept on either the high-fat diet (HFD) or chow diet (CHD). Throughout the experiment, the body weight of each mouse was recorded on weeks zero, 6, and 12, while the host's response to a glucose load and clearance was measured using the intraperitoneal glucose tolerance test (IPGTT) at two time points, week 6 and 12. These results were then converted to the area under the curve (AUC) values. At week 12, mice were culled, their brains were removed, and then evaluated. The results have revealed that HFD has a different impact on obesity and T2D development, as well as on brain weight among the different CC lines, and varies depending on the sex. Finally, we applied machine learning (ML) approaches to explore aspects of brain weight changes, using sex, diet, initial body weight, and area under the curve (AUC) as an indicator for T2D development and severity at weeks 6 and 12 at the end-stage of the experiment, while variation in efficiency exists between different host genetic backgrounds. This emphasizes a personalized/precision medicine approach. Altogether, it illustrates the power of the CC mice in identifying susceptible genes to personalized/precision of co and multimorbidity of T2D and obesity in future studies.