The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling

Objective: beta-sectetase/beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APP beta) (sAPP beta), contribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells. Materials/Methods: Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1(-/-)mice and mice treated with sAPP beta and adipose tissue and plasma from obese and type 2 diabetic patients. Results: We show that BACE1 inhibition or knockdown attenuates palmitate-induced endoplasmic reticulum (ER) stress, inflammation, and insulin resistance and prevents the reduction in Peroxisome Proliferator-Activated Receptor gamma Co-activator 1 alpha (PGC-1 alpha) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1 alpha down-regulation, and fatty acid oxidation were mimicked by soluble APP beta in vitro. BACE1 expression was increased in subcutaneous adipose tissue of obese and type 2 diabetic patients and this was accompanied by a decrease in PGC-1 alpha mRNA levels and by an increase in sAPP beta plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPP beta administration to mice reduced PGC-1 alpha levels and increased inflammation in skeletal muscle and decreased insulin sensitivity. Conclusions: Collectively, these findings indicate that the BACE1 product sAPP beta is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver. (C) 2018 Elsevier Inc. All rights reserved.