Botteri, GaiaSalvadó Serra, LaiaGumà i Garcia, Anna MariaLee Hamilton, D.Meakin, Paul J.Montagut, GemmaAshford, MichaelCeperuelo-Mallafré, VictoriaFernández-Veledo, SoniaVendrell, JoanCalderón Domínguez, MaríaSerra i Cucurull, DolorsHerrero Rodríguez, LauraPizarro Delgado, JavierBarroso Fernández, EmmaPalomer Tarridas, Francesc XavierVázquez Carrera, Manuel2020-06-092020-06-092018-03-090026-0495https://hdl.handle.net/2445/164869Objective -secretase/-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sAPP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 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  Co-activator 1 (PGC-1) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1 down-regulation, and fatty acid oxidation were mimicked by soluble APP 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 mRNA levels and by an increase in sAPPplasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPP administration to mice reduced PGC-1 levels and increased inflammation in skeletal muscle and decreased insulin sensitivity. Conclusions Collectively, these findings indicate that the BACE1 product sAPP is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.17 p.application/pdfengcc-by-nc-nd (c) W.B. Saunders, 2018http://creativecommons.org/licenses/by-nc-nd/3.0/esInsulinaFarmacologiaFarmacocinèticaFisiologiaResistència a la insulinaMetabolismeInflamacióReticle endoplasmàticRatolins (Animals de laboratori)InsulinPharmacologyPharmacokineticsPhysiologyInsulin resistanceMetabolismInflammationEndoplasmic reticulumMice (Laboratory animals)info:eu-repo/semantics/article6789542020-06-09info:eu-repo/semantics/openAccess