The PPARα/γ dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats

Abstract

1 The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipidlowering effect is mediated through its activation of PPARa. 2 Chiglitazar is a PPARa/g dual agonist.3 The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4 Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5 Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARa, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6 These data suggest that PPARa/g coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARg agonists.

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

“…Chiglitazar (33), a PPAR / agonist, by suppressing the expression of genes for the key gluconeogenic enzymes PEPCK and G-6-Pase and upregulating mRNA expression of genes involved in NEFA oxidation, demonstrated to reduce insulin resistance and to improve glucose tolerance and lipid profiles in monosodium L-glutamate obese rats [273]. Unfortunately, this study does not report data on liver fibrosis.…”

Glycolytic and Mitochondrial Metabolism in Pancreatic Islets from MSG-Treated Obese Rats Subjected to Swimming Training

“…Studies have shown that successful beta cell adaptation to insulin resistance includes increasing beta cell mass via hypertrophy and/or hyperplasia [30]. However, few studies have been conducted to evaluate the endocrine characteristics of the pancreas in MSG-treated obese rats, and the data that have been reported are contradictory [22,31]. The proliferation of pancreatic islets is modulated by parasympathetic vagal activity [32].…”

Uteroplacental insufficiency and reducing litter size alters skeletal muscle mitochondrial biogenesis in a sex-specific manner in the adult rat

“…This could perhaps be indicative of onset of hepatic insulin resistance, as reported in a previous study (35), which has yet to affect whole body insulin resistance or glucose tolerance. Although the use of HOMA as a measurement of insulin resistance in rodent studies is quite common (14,27), it is also controversial (38) and better suited to larger cohorts. Nevertheless, our finding of elevated HOMA in the Restricted female rats suggests that alterations in insulin sensitivity could be occurring in our model of restriction that might be more readily detected by more sensitive measures such as a euglycemic hyperinsulinemic clamp.…”