Prompted by metabolic phenotypes of FoxO1 KODAT mice seen only in stress conditions such as glucose and insulin tolerance tests (GTT and ITT), we next challenged the mice with high-fat diet (HFD) to investigate the role of FoxO1 in DA neurons in metabolic stress condition. Interestingly, FoxO1 KODAT mice on HFD showed significantly less weight gain compared to WT littermates (Fig. 3a and Supplementary Fig. 2l). Less weight gain under HFD in FoxO1 KODAT mice was associated with reduced total fat mass (Fig. 3b). Furthermore, HFD-fed FoxO1 KODAT mice showed significantly decreased blood glucose, insulin and leptin levels (Fig. 3c–e). In addition, GTT and ITT revealed an enhanced glucose and insulin sensitivity in FoxO1 KODAT mice compared to their WT littermates (Fig. 3f,g and Supplementary Fig. 2m). These results illustrate that FoxO1 in DA neurons plays an important role not only in glucose/insulin homoeostasis but also in body weight regulation, especially under HFD condition.
