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PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism.
Diabetologia. 2014 Oct; 57(10):2126-35.D

Abstract

AIM/HYPOTHESIS

Endoplasmic reticulum (ER) stress, which is involved in the link between inflammation and insulin resistance, contributes to the development of type 2 diabetes mellitus. In this study, we assessed whether peroxisome proliferator-activated receptor (PPAR)β/δ prevented ER stress-associated inflammation and insulin resistance in skeletal muscle cells.

METHODS

Studies were conducted in mouse C2C12 myotubes, in the human myogenic cell line LHCN-M2 and in skeletal muscle from wild-type and PPARβ/δ-deficient mice and mice exposed to a high-fat diet.

RESULTS

The PPARβ/δ agonist GW501516 prevented lipid-induced ER stress in mouse and human myotubes and in skeletal muscle of mice fed a high-fat diet. PPARβ/δ activation also prevented thapsigargin- and tunicamycin-induced ER stress in human and murine skeletal muscle cells. In agreement with this, PPARβ/δ activation prevented ER stress-associated inflammation and insulin resistance, and glucose-intolerant PPARβ/δ-deficient mice showed increased phosphorylated levels of inositol-requiring 1 transmembrane kinase/endonuclease-1α in skeletal muscle. Our findings demonstrate that PPARβ/δ activation prevents ER stress through the activation of AMP-activated protein kinase (AMPK), and the subsequent inhibition of extracellular-signal-regulated kinase (ERK)1/2 due to the inhibitory crosstalk between AMPK and ERK1/2, since overexpression of a dominant negative AMPK construct (K45R) reversed the effects attained by PPARβ/δ activation.

CONCLUSIONS/INTERPRETATION

Overall, these findings indicate that PPARβ/δ prevents ER stress, inflammation and insulin resistance in skeletal muscle cells by activating AMPK.

Authors+Show Affiliations

Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Diagonal 643, 08028, Barcelona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25063273

Citation

Salvadó, Laia, et al. "PPARβ/δ Prevents Endoplasmic Reticulum Stress-associated Inflammation and Insulin Resistance in Skeletal Muscle Cells Through an AMPK-dependent Mechanism." Diabetologia, vol. 57, no. 10, 2014, pp. 2126-35.
Salvadó L, Barroso E, Gómez-Foix AM, et al. PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia. 2014;57(10):2126-35.
Salvadó, L., Barroso, E., Gómez-Foix, A. M., Palomer, X., Michalik, L., Wahli, W., & Vázquez-Carrera, M. (2014). PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia, 57(10), 2126-35. https://doi.org/10.1007/s00125-014-3331-8
Salvadó L, et al. PPARβ/δ Prevents Endoplasmic Reticulum Stress-associated Inflammation and Insulin Resistance in Skeletal Muscle Cells Through an AMPK-dependent Mechanism. Diabetologia. 2014;57(10):2126-35. PubMed PMID: 25063273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. AU - Salvadó,Laia, AU - Barroso,Emma, AU - Gómez-Foix,Anna Maria, AU - Palomer,Xavier, AU - Michalik,Liliane, AU - Wahli,Walter, AU - Vázquez-Carrera,Manuel, Y1 - 2014/07/26/ PY - 2014/05/14/received PY - 2014/06/26/accepted PY - 2014/7/27/entrez PY - 2014/7/27/pubmed PY - 2015/7/7/medline SP - 2126 EP - 35 JF - Diabetologia JO - Diabetologia VL - 57 IS - 10 N2 - AIM/HYPOTHESIS: Endoplasmic reticulum (ER) stress, which is involved in the link between inflammation and insulin resistance, contributes to the development of type 2 diabetes mellitus. In this study, we assessed whether peroxisome proliferator-activated receptor (PPAR)β/δ prevented ER stress-associated inflammation and insulin resistance in skeletal muscle cells. METHODS: Studies were conducted in mouse C2C12 myotubes, in the human myogenic cell line LHCN-M2 and in skeletal muscle from wild-type and PPARβ/δ-deficient mice and mice exposed to a high-fat diet. RESULTS: The PPARβ/δ agonist GW501516 prevented lipid-induced ER stress in mouse and human myotubes and in skeletal muscle of mice fed a high-fat diet. PPARβ/δ activation also prevented thapsigargin- and tunicamycin-induced ER stress in human and murine skeletal muscle cells. In agreement with this, PPARβ/δ activation prevented ER stress-associated inflammation and insulin resistance, and glucose-intolerant PPARβ/δ-deficient mice showed increased phosphorylated levels of inositol-requiring 1 transmembrane kinase/endonuclease-1α in skeletal muscle. Our findings demonstrate that PPARβ/δ activation prevents ER stress through the activation of AMP-activated protein kinase (AMPK), and the subsequent inhibition of extracellular-signal-regulated kinase (ERK)1/2 due to the inhibitory crosstalk between AMPK and ERK1/2, since overexpression of a dominant negative AMPK construct (K45R) reversed the effects attained by PPARβ/δ activation. CONCLUSIONS/INTERPRETATION: Overall, these findings indicate that PPARβ/δ prevents ER stress, inflammation and insulin resistance in skeletal muscle cells by activating AMPK. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/25063273/PPARβ/δ_prevents_endoplasmic_reticulum_stress_associated_inflammation_and_insulin_resistance_in_skeletal_muscle_cells_through_an_AMPK_dependent_mechanism_ L2 - https://doi.org/10.1007/s00125-014-3331-8 DB - PRIME DP - Unbound Medicine ER -