Dimethyl itaconate attenuates palmitate-induced insulin resistance in skeletal muscle cells through the AMPK/FGF21/PPARδ-mediated suppression of inflammation.

Abstract

AIM:

Itaconate (ITA), a derivative of the tricarboxylic acid cycle, has been documented to have a direct antimicrobial effect by inhibiting isocitrate lyase and suppressing proinflammatory cytokines in LPS-treated macrophages. However, the effects of dimethyl ITA (DITA), a membrane-permeable derivative of ITA, on insulin signaling and inflammation in skeletal muscle in an obese state remain to be elucidated. Thus, this study was designed to investigate the effects of DITA on the impairment of insulin signaling and inflammation in palmitate-treated C2C12 myocytes.

MATERIALS AND METHODS:

Western blotting was used to determine the expression of insulin signaling associated genes, inflammatory markers, fibroblast growth factor 21 (FGF21), and PPARδ expression, as well as AMPK phosphorylation in mouse skeletal muscle cells. Secreted proinflammatory cytokine levels were detected by enzyme-linked immunosorbent assay. Insulin signaling was assessed by glucose uptake assay.

KEY FINDINGS:

Treating C2C12 myocytes with DITA attenuated palmitate-induced aggravation of insulin signaling markers, such as insulin receptor substrate-1 (IRS-1) and Akt phosphorylation and inflammatory markers, such as NFκB and IκB phosphorylation. AMPK phosphorylation, as well as PPARδ and myokine FGF21 expression, were enhanced in C2C12 myocytes by DITA treatment. siRNA-mediated suppression of AMPK or FGF21 expression abolished the effects of DITA on insulin resistance and inflammation in palmitate-treated C2C12 myocytes.

SIGNIFICANCE:

In sum, DITA suppresses inflammation through the AMPK/FGF21/PPARδ signaling, thereby alleviating insulin resistance in palmitate-treated C2C12 myocytes. The current study appears to be an essential basis for performing animal experiments to develop insulin resistance therapeutics.

• Authors: Seung Yeon Park, Hyun Jung Lee, Jin-Ho Song, Yong Kyoo Shin, A M Abd El-Aty, Amer Ramadan, A Hacimuftuoglu, Ji Hoon Jeong, Tae Woo Jung
• Journal: Life sciences (Life Sci) Vol. 287 Pg. 120129 (Dec 15 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 34774619 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• PPAR delta
• Palmitates
• Succinates
• fibroblast growth factor 21
• dimethyl itaconate
• Fibroblast Growth Factors
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Animals
• Cell Line
• Dose-Response Relationship, Drug
• Fibroblast Growth Factors (antagonists & inhibitors, metabolism)
• Inflammation (metabolism)
• Insulin Resistance (physiology)
• Mice
• Muscle Fibers, Skeletal (drug effects, metabolism)
• PPAR delta (antagonists & inhibitors, metabolism)
• Palmitates (toxicity)
• Succinates (pharmacology)