Systematic Comparison of High‐Fat Diet– and Streptozotocin‐Induced Prediabetic Obese
C57BL
/
6J
Mouse Models: A Sex‐Based Protocol Optimization Stud
Min Xu, Chao Ke, Yangkun Liu, Wenying Shi, Yang Cao, Zhengyu Li, Yi Xiao, Wei Zhang ABSTRACT
Aims
Animal models of prediabetes (Pre‐DM) are essential for studying metabolic disease and testing therapies, yet high‐fat diet (HFD) and HFD‐plus‐streptozotocin (STZ) protocols vary in feeding duration, STZ dose, and diagnostic criteria and rarely account for sex. We compared five protocols in male and female C57BL/6J mice to find the best balance of duration, cost, and phenotypic stability and to characterize how HFD and HFD‐STZ differ in their effects on glucose and lipid metabolism.
Materials and Methods
Five‐week‐old mice were stratified by sex and assigned to three HFD‐only groups (HFD‐12w, ‐16w, ‐20w) and two STZ groups of differing cumulative dose (HFD‐STZ‐L, ‐H). Body weight, food and energy intake, body fat percentage, fasting blood glucose (FBG), OGTT, ITT, fasting insulin, serum lipids, hepatic Oil Red O, histopathology, liver and kidney safety, and per‐animal cost were assessed.
Results
HFD induced obesity of equal magnitude in both sexes (non‐significant Sex × Diet interactions for body weight and fat mass). Glucose and hepatic‐lipid metabolism showed clear sex dimorphism: in males these deteriorated by Week 12, whereas females required 16 weeks to reach the Pre‐DM threshold, at a higher preset STZ dose. HFD‐STZ‐L matched HFD‐12w in both sexes within a shorter cycle (overall success 73.3%). Notably, STZ reversed the HFD lipid phenotype, synchronously reducing body fat, serum lipids, and hepatic fat in females.
Conclusions
HFD‐STZ‐L is preferred for glucose and β‐cell studies in both sexes; HFD‐12w preserves the intact female obesity phenotype; HFD‐20w is preferred for MASLD studies. Biological sex must be incorporated into model design and phenotype interpretation.