MHY2013 Modulates Age-related Inflammation and Insulin Resistance by Suppressing the Akt/FOXO1/IL-1β Axis and MAPK-mediated NF-κB Signaling in Aged Rat Liver

Chronic inflammation is a major risk factor underlying aging and age-associated diseases. It impairs normal lipid accumulation, adipose tissue function, and mitochondrial function, which eventually lead to insulin resistance. Peroxisome proliferator-activated receptors (PPARs) critically regulate gluconeogenesis, lipid metabolism, and the lipid absorption and breakdown process, and PPAR activity decreases in the liver during aging. In the present study, we investigated the ability of 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), synthesized PPARα/PPARβ/PPARγ pan agonist, to suppress the inflammatory response and attenuate insulin resistance in aged rat liver. Six- and 20-month-old rats were divided into 4 groups: young and old rats fed ad libitum; and old rats fed ad libitum supplemented with MHY2013 (1 mg and 5 mg/kg/d for 4 wk). We found that MHY2013 supplementation efficiently downregulated the activity of nuclear factor-κB through JNK/ERK/p38 mitogen-activated protein kinase signaling in the liver of aged rats. In addition, MHY2013 treatment increased hepatic insulin signaling, and the downstream signaling activity of FOXO1, which is negatively regulated by Akt. Downregulation of Akt increases expression of FOXO1, which acts as a transcription factor and increases transcription of interleukin-1β, leading to hepatic inflammation. The major finding of this study is that MHY2013 acts as a therapeutic agent against...
Source: Applied Immunohistochemistry and Molecular Morphology - Category: Chemistry Tags: Research Articles Source Type: research