Administration of kynurenic acid reduces hyperlipidemia-induced inflammation and insulin resistance in skeletal muscle and adipocytes.

Abstract

Kynurenic acid (KA), an endogenous product of L-tryptophan metabolism in the kynurenine pathway, regulates adipose tissue energy homeostasis and inflammation. However, its role in palmitate-induced insulin resistance and detailed underlying mechanisms in skeletal muscles and adipose tissues are unclear. Herein, we report that KA ameliorated palmitate-induced inflammation and insulin resistance in differentiated C2C12 and 3T3-L1 cell lines as well as soleus skeletal muscle and subcutaneous adipose tissues in mice. Palmitate-induced inflammatory markers, such as nuclear factor κB translocation, inhibitory κBα phosphorylation, pro-inflammatory cytokine expression, and impaired insulin signaling, were markedly attenuated by KA both in vitro and in vivo. KA significantly increased AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 6 (SIRT6) expressions in C2C12 myocytes and 3T3-L1 adipocytes and skeletal muscle and adipose tissues of mice. siRNA-mediated AMPK or SIRT6 inhibition significantly mitigated the suppressive effects of KA on palmitate-induced inflammation and insulin resistance. KA significantly stimulated expression of genes involved in fatty acid oxidation in C2C12 myocytes and skeletal muscle of mice. Moreover, KA inhibits lipogenesis in 3T3-L1 adipocytes. AMPK or SIRT6 siRNA markedly reversed these changes. The siRNA targeting Gpr35 abrogated the effects of KA on AMPK phosphorylation in C2C12 myocytes and 3T3-L1 adipocytes, except SIRT6 expression. It has therefore been shown that KA could potentially alleviate inflammation and insulin resistance in skeletal muscle and adipose tissues through Gpr35/AMPK and SIRT6-mediated pathways.

• Authors: Tae Woo Jung, Jinwoo Park, Jaw Long Sun, Sung Ho Ahn, A M Abd El-Aty, Ahmet Hacimuftuoglu, Hyoung-Chun Kim, Jae-Han Shim, SungShik Shin, Ji Hoon Jeong
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 518 Pg. 110928 (12 01 2020) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 32702471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Kynurenic Acid

Topics

• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism, pathology)
• Animals
• Cells, Cultured
• Diet, High-Fat
• Hyperlipidemias (complications, drug therapy, metabolism, pathology)
• Inflammation (etiology, prevention & control)
• Insulin Resistance
• Kynurenic Acid (administration & dosage, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Skeletal (drug effects, metabolism, pathology)
• Signal Transduction (drug effects)