Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle.
OBJECTIVE
Fenofibrate (FF) is commonly used clinically as a lipid-lowering drug, but whether it participates in endoplasmic reticulum (ER) stress and decreases inflammation in skeletal muscle is still unknown. The aim of this study is to determine whether FF treatment reduces insulin resistance (IR) by alleviating ER stress and downstream inflammation in skeletal muscle tissues and cells.


METHODS
Female SD rats were randomly divided into groups receiving the standard chow diet (SCD), a high-fat diet (HFD), or HFD plus FF (HFD+FF). The rats in the latter two groups were subjected to a standard HFD for 20weeks, then the HFD+FF rats were administered FF (30mg/kg once daily via gavage) for another 8weeks. Whole-body IR, expression of peroxisome proliferator-activated receptor α (PPARα), ER stress-related genes, and inflammatory genes in the soleus muscle were assessed. The differentiated C2C12 myotubes were treated with palmitic acid or pretreated with fenofibric acid or 4-phenylbutyric acid (4-PBA), etomoxir, and the expression of ER stress, beta-oxidation-related genes, inflammatory genes, Toll-like receptor 4 (TLR4), and insulin-signaling-related molecules were determined.


RESULTS
Eight weeks of FF treatment attenuated HFD-induced IR by decreased tribbles 3 (TRB3) expression, ER stress and inflammation in skeletal muscle. FA pretreatment markedly inverted the PA-induced expression of TLR4 and downstream inflammatory genes, activated ER stress, improved β-oxidation and insulin signaling in differentiated myotube cells.


CONCLUSIONS
FF treatment significantly improved HFD-induced IR in skeletal muscle and PA-induced IR in myotube cells, which may be related to reduced ER stress-induced inflammation.
Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Fang
F
Dai
Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Tian
T
Jiang
Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Ying-Ying
YY
Bao
Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei 230032, China.
Guan-Jun
GJ
Chen
Department of Medical Laboratory, Anhui Provincial Hospital, Hefei 230001, China.
Li
L
Chen
Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: aynfmkqz87@163.com.
Qiu
Q
Zhang
Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei 230032, China; The Comprehensive Laboratory, Anhui Medical University, Hefei 230032, China. Electronic address: wwwdluyx@sina.com.
Yun-Xia
YX
Lu
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019308:Palmitic Acid; D011345:Fenofibrate
2-deoxyglucose (PubChem CID: 439268); 4-phenylbutyric acid (PubChem CID:4775); Endoplasmic reticulum stress; Etomoxir (PubChem CID: 23675376); Fenofibrate; Fenofibrate (PubChem CID: 3339); Fenofibric acid (PubChem CID: 64929); Inflammation; Insulin resistance; Lipids; Palmitic acid (PubChem CID:985); Skeletal muscle; Tunicamycin (PubChem CID: 16220051)