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

Gaia  Botteri; Laia  Salvadó; Anna  Gumà; D. Lee Hamilton; Paul J. Meakin; Gemma Montagut; Michael L. J. Ashford; Victoria  Ceperuelo-Mallafré; Sonia  Fernández-Veledo; Joan  Vendrell; María  Calderón-Dominguez; Dolors  Serra; Laura  Herrero; Javier  Pizarro; Emma  Barroso; Xavier  Palomer; Manuel  Vázquez-Carrera

doi:10.1016/j.metabol.2018.03.005

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

Gaia Botteri, Laia Salvadó, Anna Gumà, D. Lee Hamilton, Paul J. Meakin, Gemma Montagut , Michael L. J. Ashford, Victoria Ceperuelo-Mallafré, Sonia Fernández-Veledo, Joan Vendrell, María Calderón-Dominguez, Dolors Serra, Laura Herrero, Javier Pizarro, Emma Barroso, Xavier Palomer, Manuel Vázquez-Carrera (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

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Abstract

Objective: β-secretase/β-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 APPβ (sAPPβ), 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 sAPPβ 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 γ Co-activator 1α (PGC-1α) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1α down-regulation, and fatty acid oxidation were mimicked by soluble APPβ 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-1α mRNA levels and by an increase in sAPPβ plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPβ administration to mice reduced PGC-1α levels and increased inflammation in skeletal muscle and decreased insulin sensitivity.

Conclusions: Collectively, these findings indicate that the BACE1 product sAPPβ is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.

Original language	English
Pages (from-to)	59-75
Number of pages	17
Journal	Metabolism
Volume	85
Early online date	9 Mar 2018
DOIs	https://doi.org/10.1016/j.metabol.2018.03.005
Publication status	Published - Aug 2018

Keywords

BACE1
CREB
NF-κB
PGC-1α
insulin resistance
palmitate
sAPPβ

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Endocrinology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.metabol.2018.03.005

Author Accepted ManuscriptAccepted author manuscript, 2.78 MB

Cite this

Botteri, G., Salvadó, L., Gumà, A., Hamilton, D. L., Meakin, P. J., Montagut , G., Ashford, M. L. J., Ceperuelo-Mallafré, V., Fernández-Veledo, S., Vendrell, J., Calderón-Dominguez, M., Serra, D., Herrero, L., Pizarro, J., Barroso, E., Palomer, X., & Vázquez-Carrera, M. (2018). The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling. Metabolism, 85, 59-75. https://doi.org/10.1016/j.metabol.2018.03.005

@article{7195734796e34833a418b583dbe815d8,

title = "The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling",

abstract = "Objective: β-secretase/β-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 APPβ (sAPPβ), 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 sAPPβ 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 γ Co-activator 1α (PGC-1α) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1α down-regulation, and fatty acid oxidation were mimicked by soluble APPβ 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-1α mRNA levels and by an increase in sAPPβ plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPβ administration to mice reduced PGC-1α levels and increased inflammation in skeletal muscle and decreased insulin sensitivity.Conclusions: Collectively, these findings indicate that the BACE1 product sAPPβ is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver. ",

keywords = "BACE1, CREB, NF-κB, PGC-1α, insulin resistance, palmitate, sAPPβ",

author = "Gaia Botteri and Laia Salvad{\'o} and Anna Gum{\`a} and Hamilton, {D. Lee} and Meakin, {Paul J.} and Gemma Montagut and Ashford, {Michael L. J.} and Victoria Ceperuelo-Mallafr{\'e} and Sonia Fern{\'a}ndez-Veledo and Joan Vendrell and Mar{\'i}a Calder{\'o}n-Dominguez and Dolors Serra and Laura Herrero and Javier Pizarro and Emma Barroso and Xavier Palomer and Manuel V{\'a}zquez-Carrera",

note = "This study was partly supported by funds from the Spanish Ministerio de Econom{\'i}a y Competitividad (SAF2012-30708 and SAF2015-64146-R to MVC, SAF2013-45887-R to LH, SAF2014-52223-C2-1-R to DS, SAF2015-65019-R to SFV and PI14/00228 to JV), the Generalitat de Catalunya (2014SGR-13 to MVC and 2014SGR465 to DS), Diabetes UK Grants (Grant nos. 08/0003681 and 12/0004458 to MLJA), European Union ERDF funds, and the European Foundation for the Study of Diabetes (EFSD)/JanssenRising Star and L{\textquoteright}Or{\'e}al-UNESCO “For Women in Science” research fellowships to LH. CIBER de Diabetes y Enfermedades Metab{\'o}licas Asociadas (CIBERDEM) is an Instituto de Salud Carlos III project (Grant CB07/08/0003 to MVC and CB07/08/0012 to JV). CIBER Fisiopatolog{\'i}a de la Obesidad y la Nutrici{\'o}n (CIBEROBN) (Grant CB06/03/0001 granted to DS). GB was supported by a FPI grant from the Spanish Ministerio de Econom{\'i}a y Competitividad. SFV acknowledges support from the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigaci{\'o}n Sanitaria (FIS) cofinanced by the ERDF. We would like to thank the University of Barcelona{\textquoteright}s Language Advisory Service for revising the manuscript.",

year = "2018",

month = aug,

doi = "10.1016/j.metabol.2018.03.005",

language = "English",

volume = "85",

pages = "59--75",

journal = "Metabolism",

issn = "0026-0495",

publisher = "W.B. Saunders",

}

Botteri, G, Salvadó, L, Gumà, A, Hamilton, DL, Meakin, PJ, Montagut , G, Ashford, MLJ, Ceperuelo-Mallafré, V, Fernández-Veledo, S, Vendrell, J, Calderón-Dominguez, M, Serra, D, Herrero, L, Pizarro, J, Barroso, E, Palomer, X & Vázquez-Carrera, M 2018, 'The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling', Metabolism, vol. 85, pp. 59-75. https://doi.org/10.1016/j.metabol.2018.03.005

TY - JOUR

T1 - The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling

AU - Botteri, Gaia

AU - Salvadó, Laia

AU - Gumà, Anna

AU - Hamilton, D. Lee

AU - Meakin, Paul J.

AU - Montagut , Gemma

AU - Ashford, Michael L. J.

AU - Ceperuelo-Mallafré, Victoria

AU - Fernández-Veledo, Sonia

AU - Vendrell, Joan

AU - Calderón-Dominguez, María

AU - Serra, Dolors

AU - Herrero, Laura

AU - Pizarro, Javier

AU - Barroso, Emma

AU - Palomer, Xavier

AU - Vázquez-Carrera, Manuel

N1 - This study was partly supported by funds from the Spanish Ministerio de Economía y Competitividad (SAF2012-30708 and SAF2015-64146-R to MVC, SAF2013-45887-R to LH, SAF2014-52223-C2-1-R to DS, SAF2015-65019-R to SFV and PI14/00228 to JV), the Generalitat de Catalunya (2014SGR-13 to MVC and 2014SGR465 to DS), Diabetes UK Grants (Grant nos. 08/0003681 and 12/0004458 to MLJA), European Union ERDF funds, and the European Foundation for the Study of Diabetes (EFSD)/JanssenRising Star and L’Oréal-UNESCO “For Women in Science” research fellowships to LH. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an Instituto de Salud Carlos III project (Grant CB07/08/0003 to MVC and CB07/08/0012 to JV). CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (Grant CB06/03/0001 granted to DS). GB was supported by a FPI grant from the Spanish Ministerio de Economía y Competitividad. SFV acknowledges support from the Miguel Servet tenure-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigación Sanitaria (FIS) cofinanced by the ERDF. We would like to thank the University of Barcelona’s Language Advisory Service for revising the manuscript.

PY - 2018/8

Y1 - 2018/8

N2 - Objective: β-secretase/β-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 APPβ (sAPPβ), 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 sAPPβ 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 γ Co-activator 1α (PGC-1α) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1α down-regulation, and fatty acid oxidation were mimicked by soluble APPβ 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-1α mRNA levels and by an increase in sAPPβ plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPβ administration to mice reduced PGC-1α levels and increased inflammation in skeletal muscle and decreased insulin sensitivity.Conclusions: Collectively, these findings indicate that the BACE1 product sAPPβ is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.

AB - Objective: β-secretase/β-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 APPβ (sAPPβ), 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 sAPPβ 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 γ Co-activator 1α (PGC-1α) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1α down-regulation, and fatty acid oxidation were mimicked by soluble APPβ 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-1α mRNA levels and by an increase in sAPPβ plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPβ administration to mice reduced PGC-1α levels and increased inflammation in skeletal muscle and decreased insulin sensitivity.Conclusions: Collectively, these findings indicate that the BACE1 product sAPPβ is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.

KW - BACE1

KW - CREB

KW - NF-κB

KW - PGC-1α

KW - insulin resistance

KW - palmitate

KW - sAPPβ

UR - http://www.scopus.com/inward/record.url?scp=85053081687&partnerID=8YFLogxK

U2 - 10.1016/j.metabol.2018.03.005

DO - 10.1016/j.metabol.2018.03.005

M3 - Article

C2 - 29526536

SN - 0026-0495

VL - 85

SP - 59

EP - 75

JO - Metabolism

JF - Metabolism

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

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BACE1 and Endothelial Dysfunction in Diabetes (Project Grant scheme)

Targeting the Aspartic Protease BACE1 for Inhibition in Order to Increase Hypothalamic Leptin Sensitivity and Reverse Obesity

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

BACE1 and Endothelial Dysfunction in Diabetes (Project Grant scheme)

Targeting the Aspartic Protease BACE1 for Inhibition in Order to Increase Hypothalamic Leptin Sensitivity and Reverse Obesity

Cite this