期刊
METABOLISM-CLINICAL AND EXPERIMENTAL
卷 85, 期 -, 页码 59-75出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.metabol.2018.03.005
关键词
BACE1; CREB; insulin resistance; NF-kappa B; palmitate; PGC-1 alpha; SAPP beta
资金
- Spanish Ministerio de Economia y Competitividad [SAF2012-30708, SAF2015-64146-R, SAF2013-45887-R, SAF2014-52223C2-1-R, SAF2015-65019-R, PI14/00228]
- Generalitat de Catalunya [2014SGR-13, 2014SGR465]
- Diabetes UK Grants [08/0003681, 12/0004458]
- European Union ERDF funds
- European Foundation for the Study of Diabetes (EFSD)/Janssen-Rising Star
- L'Oreal-UNESCO For Women in Science
- Institute de Salud Carlos III project [CB07/08/0003, CB07/08/0012]
- CIBER Fisiopatologia de la Obesidad y la Nutrition (CIBEROBN) [CB06/03/0001]
- FPI grant from the Spanish Ministerio de Economia y Competitividad
- Miguel Servet tenure -track program from the Fondo de Investigation Sanitaria (FIS) - ERDF [CP10/00438, CPI116/00008]
- MRC [MR/K003291/1] Funding Source: UKRI
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.
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