BESTO mice maintain improved glucose tolerance and enhanced GSIS under a Western-style high-fat diet (HFD)
We observed that both aged BESTO and control male mice had increased body weights (Supplementary Fig. S2A) and statistically significant increases in lipid parameters such as cholesterol, triglycerides, and free fatty acids compared to the young BESTO and control male mice (Supplementary Fig. S3). Although similar differences in lipid profiles were not observed in female mice, we speculated that the increased body weights and blood lipid levels in the aged BESTO mice might contribute to their loss of glucose-responsive phenotypes.
To test this possibility, we placed BESTO and control mice at 2–4 months of age on a HFD containing 42% calories from fat for up to 30 weeks. After 12 weeks of this HFD treatment, BESTO and control mice both reached similar body weights to those of regular chow-fed mice aged 15–18 months (compare Supplementary Fig. S2A and B). While BESTO and control mice did not differ in the extent of the HFD-induced hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hypertriglyceridemia over the course of the HFD treatment (Fig. 4A–E), both male and female BESTO mice still maintained significantly improved glucose tolerance and higher plasma insulin levels 15 min and 30 min post-glucose injection compared to controls after 12 weeks on the HFD (Fig. 5A,B). Even following 30 weeks of HFD treatment, the BESTO mice, which at that point were 9–11 months of age, still showed significantly improved glucose tolerance and enhanced GSIS compared to controls (Supplementary Fig. S4A,B). Additionally, islets from HFD-fed BESTO mice still displayed reduced Ucp2 expression compared to controls, similar to the level of repression observed in islets from young BESTO mice on a regular chow diet (Supplementary Figs S4C and 2). Therefore, although BESTO mice did not differ from controls in HFD-induced weight gain and lipidemia, Sirt1 still improved β cell function under this diabetogenic condition, suggesting that increased body weight and hyperlipidemia alone are not enough to abolish the positive effects of Sirt1 in β cell function.