Administration of kynurenic acid reduces hyperlipidemia-induced inflammation and insulin resistance in skeletal muscle and adipocytes
- Authors
- Jung, Tae Woo; Park, Jinwoo; Sun, Jaw Long; Ahn, Sung Ho; El-Aty, A.M. Abd; Hacimuftuoglu, Ahmet; Kim, Hyoung-Chun; Shim, Jae-Han; Shin, SungShik; Jeong, Ji Hoon
- Issue Date
- Dec-2020
- Publisher
- Elsevier Ireland Ltd
- Keywords
- Adipose tissues; AMP-Activated protein kinase; Inflammation; Insulin resistance; Kynurenic acid; Sirtuin 6; Skeletal muscle
- Citation
- Molecular and Cellular Endocrinology, v.518
- Journal Title
- Molecular and Cellular Endocrinology
- Volume
- 518
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/47500
- DOI
- 10.1016/j.mce.2020.110928
- ISSN
- 0303-7207
1872-8057
- 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. © 2020 Elsevier B.V.
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