title: Effects of MHY908, a New Synthetic PPARα/γ Dual Agonist, on Inflammatory Responses and Insulin Resistance in Aged Rats.
abstract: Insulin resistance is common with aging and is associated with the inflammatory response in both humans and rodents. A number of peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists have been tested for their abilities to attenuate insulin resistance and type 2 diabetes. However, there is no study on the effects of PPARα/γ dual agonists on inflammation and insulin resistance during aging. In the present study, we investigated the ability of 2-[4-(5-chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908), a newly synthesized novel PPARα/γ dual agonist, to suppress the inflammatory response and attenuate insulin resistance in aged rats. Twenty-month-old rats were divided into four groups: ad libitum fed, ad libitum fed supplemented with MHY908 (1 mg and 3 mg/kg/day for 4 weeks), and 40% calorie restricted. Six-month-old ad libitum fed rats were used as an age control. The aged rats supplemented with MHY908 showed reduced serum glucose, triglyceride, and insulin levels, as well as reduced liver triglyceride levels. MHY908 brought about a reduction in endoplasmic reticulum stress and activation of the c-Jun N-terminal kinase in the livers of aged rats, which consequently improved insulin signaling. In the kidneys of aged rats, the efficacy of MHY908 as a potent anti-inflammatory agent was shown by its suppression of NF-κB activation through inhibition of the Akt/IκB kinase signaling pathway. Therefore, the major finding of this study is that MHY908 acts as a therapeutic agent against age-related inflammation associated with insulin resistance by activating PPARα and PPARγ, thus attenuating endoplasmic reticulum stress.
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Min Hi
authors.initials: MH
authors.lastname: Park
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Min Jo
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Eun Kyeong
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: An
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio.
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.affiliation: Molecular Inflammation Research Center for Aging intervention (MRCA), College of Pharmacy, Pusan National University, Busan, Republic of Korea. hyjung@pusan.ac.kr.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma
keywords: Aging; ER stress; Inflammation; Insulin resistance.; MHY908; PPARα/γ