Abstract
Rosiglitazone is an agonist of peroxisome proliferator-activated receptor- (PPAR-) γ that is principally associated with insulin action. The exact mechanisms underlying its insulin-sensitizing action are still not fully elucidated. It is well known that adiponectin mostly secreted in adipose tissue is an insulin sensitizer. Here, we found that treatment of Otsuka Long-Evans Tokushima Fatty (OLETF) rats with rosiglitazone (3 mg/kg, once daily, by oral gavage for 33 weeks) attenuated the increase in fasting plasma insulin concentrations and the index of the homeostasis model assessment of insulin resistance along with the age growth and glucose concentrations during an oral glucose tolerance test. In addition, the increase in plasma alanine aminotransferase activity, concentrations of fasting plasma nonesterified fatty acids and triglyceride, and hepatic triglyceride content was also suppressed. The hepatic protein expression profile revealed that rosiglitazone increased the downregulated total protein expression of insulin receptor substrate 1 (IRS-1) and IRS-2. Furthermore, the treatment suppressed the upregulated phosphorylation of IRS-1 at Ser307 and IRS-2 at Ser731. The results indicate that rosiglitazone ameliorates hepatic and systemic insulin resistance, hepatic inflammation, and fatty liver. Mechanistically, rosiglitazone suppressed hepatic protein overexpression of both phosphorylated nuclear factor- (NF-) κBp65 and inhibitory-κB kinase-α/β, a transcription factor that primarily regulates chronic inflammatory responses and the upstream NF-κB signal transduction cascades which are necessary for activating NF-κB, respectively. More importantly, rosiglitazone attenuated the decreases in adipose adiponectin mRNA level, plasma adiponectin concentrations, and hepatic protein expression of adiponectin receptor-1 and receptor-2. Thus, we can draw the conclusion that rosiglitazone elicits an adiponectin-mediated insulin-sensitizing action at the adipose tissue-liver axis in obese rats. Our findings may provide new insights into the mechanisms of action of rosiglitazone.
Highlights
Insulin resistance is the cord that runs through various modern chronic illnesses, of which obesity, dyslipidemia, hypertension, type 2 diabetes, nonalcoholic fatty liver diseases, and cardiovascular disease are included [1]
The results indicate that rosiglitazone ameliorates hepatic and systemic insulin resistance, hepatic inflammation, and fatty liver
The thiazolidinediones (TZDs) are agonists of peroxisome proliferator-activated receptor- (PPAR-) γ, a nuclear Journal of Diabetes Research transcription factor principally associated with insulin action, lipid and glucose metabolism, and energy homeostasis [2, 3]
Summary
Insulin resistance is the cord that runs through various modern chronic illnesses, of which obesity, dyslipidemia, hypertension, type 2 diabetes, nonalcoholic fatty liver diseases, and cardiovascular disease are included [1]. The liver, adipose tissue, and skeletal muscle are the main insulintargeted organs. The insulin resistance in the liver, skeletal muscle, and adipose tissue plays an important role in systemic insulin resistance. Large amounts of studies have shown that TZDs improve insulin sensitivity in various animal models with insulin resistance and patients with type 2 diabetes [2]. Rosiglitazone is one of the currently used TZDs/PPAR-γ agonists in the treatment of type 2 diabetes. It has been demonstrated that rosiglitazone improves insulin resistance in most tissues, such as adipose tissue [4] and tissues of the skeletal muscle [5], liver [6], myocardium [7], blood vessel [8], and kidney [9]. There is, still an important but unresolved question associated with the direct targets and action mechanisms of the TZD
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