ABSTRACT Aims/hypothesis Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of toxic amyloid peptides and is highly expressed in the brain, but also to a lesser extent in major peripheral organs such as muscle and liver. In contrast, BACE2 is mainly expressed in peripheral tissues and is enriched in pancreatic beta cells, where it regulates beta- cell function and mass. Previous reports demonstrated that loss of BACE1 function decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice, whereas mice lacking Bace2 exhibit reduced blood glucose levels, improved intraperitoneal glucose tolerance and increased beta-cell mass. Impaired glucose homeostasis and insulin resistance are hallmarks of type 2 diabetes and have been implicated in Alzheimer’s disease. Therefore, we tested the contribution of the individual BACE isoforms to those metabolic phenotypes by placing Bace1 knockout (KO), Bace2 KO, Bace1/2 double knockout (dKO) and wild-type (WT) mice on a high-fat high-cholesterol diet (HFD) for 16 weeks. Methods Bace1 KO ( n = 18), Bace2 KO ( n = 18), Bace1/2 dKO ( n = 18) and WT C57BL/6N mice ( n = 54) were fed a HFD for 16 weeks (age 9–25 weeks). Body composition was measured before initiation of the HFD and after 11 weeks of HFD. Oral glucose tolerance and insulin sensitivity tests were performed after 12 and 13 weeks of HFD, respectively, and full blood chemistry was analyzed after 16 weeks of HFD. The effects of subchronic BACE1/2 inhibition were assessed by administration of 10 mg/kg/day of the dual BACE1/2 inhibitor MBi-3 in a HFD fed to C57BL/6N mice for 3 weeks. Results Bace1 KO and Bace1/2 dKO mice showed decreased body weight and improved glucose tolerance and insulin resistance vs. WT mice. Conversely, Bace2 KO mice did not show any significant differences in body weight, glucose tolerance or insulin resistance under our experimental conditions. Finally, subchronic MBi-3–mediated BACE1/2 inhibition in mice in conjunction with a HFD resulted in a modest improvement of glucose tolerance. Conclusions/interpretation Our data indicate that lack of BACE1 – but not BACE2 – function contributes mainly to the metabolic phenotypic changes observed in Bace1/2 dKO mice, suggesting that inhibition of BACE1 has the greater role (vs. BACE2) in any potential improvements in metabolic homeostasis. HIGHLIGHTS Insulin resistance may develop in the brains of patients with Alzheimer’s disease (83/85 characters) BACE1 and BACE2 may play a role in glucose homeostasis and insulin sensitivity (80/85 characters) Body weight in mice decreased with Bace1 KO and Bace1/2 KO but not Bace2 KO alone (83/85 characters) Bace1 and Bace1/2, but not Bace2, KO improved glucose tolerance/insulin resistance (84/85 characters) Improved metabolic homeostasis may follow loss of BACE1 rather than BACE 2 activity (85/85 characters)

BACE1 – but not BACE2 – function is critical for metabolic disorders induced by high-fat diets in C57BL/6N mice