<b><i>Introduction:</i></b> Pioglitazone is a thiazolidinedione oral antidiabetic agent. This study aimed to investigate the effects of pioglitazone as insulin sensitizer on β-arrestin2 signaling in classical insulin target tissues. <b><i>Methods:</i></b> Experiments involved three groups of mice; the first one involved mice fed standard chow diet for 16 weeks; the second one involved mice fed high-fructose, high-fat diet (HFrHFD) for 16 weeks; and the third one involved mice fed HFrHFD for 16 weeks and received pioglitazone (30 mg/kg/day, orally) in the last four weeks of feeding HFrHFD. <b><i>Results:</i></b> The results showed significant improvement in the insulin sensitivity of pioglitazone-treated mice as manifested by significant reduction in the insulin resistance index. This improvement in insulin sensitivity was associated with significant increases in the β-arrestin2 levels in the adipose tissue, liver, and skeletal muscle. Moreover, pioglitazone significantly increased β-arrestin2 signaling in all the examined tissues as estimated from significant increases in phosphatidylinositol 4,5 bisphosphate and phosphorylation of Akt at serine 473 and significant decrease in diacylglycerol level. <b><i>Conclusion:</i></b> To the best of our knowledge, our work reports a new mechanism of action for pioglitazone through which it can enhance the insulin sensitivity. Pioglitazone increases β-arrestin2 signaling in the adipose tissue, liver, and skeletal muscle of HFrHFD-fed mice.

Insulin resistance is a metabolic disorder associated with a wide array of cardiovascular complications. This study aimed to investigate the effect of oleic acid on a dietary model of insulin resistance in mice using high fructose high fat diet (HFrHFD) focusing on the role of β-arrestin signaling in the adipose tissue. Insulin resistance was induced by feeding mice high fructose high fat diet (HFrHFD) for 16 weeks. Oleic acid (40 mg/kg/day) was orally administered for 4 weeks starting at week 13. At the end of experiment, survival curve, body weights (BW), fasting blood glucose, serum insulin and insulin resistance (IR) were measured. Furthermore, adipose tissue levels of β-arrestin2, phosphatidyl inositol 4,5 bisphosphate (PIP2), diacyl glycerol (DAG) and phospho serine 473 of protein kinase B (pS473 Akt) were measured. Results showed that, oleic acid significantly increased survival percentage, BW and fasting blood glucose level compared to HFrHFD fed mice. On the other hand, oleic acid significantly reduced serum insulin level while slightly reduced IR compared to HFrHFD fed mice. In addition, oleic acid significantly increased β-arrestin2, PIP2 and pS473 Akt levels while significantly decreased DAG level in the adipose tissue. In conclusion, although oleic acid significantly improved survival curve and β-arrestin signaling in the adipose tissue, it worsened fasting blood glucose level in HFrHFD fed mice. An effect that may be attributed to reduced insulin secretion without comparable improvement in insulin resistance

This study aimed to investigate the acute effects of oleic acid (OA) on glucose homeostasis in mice fed a standard chow diet (SCD) and a high-fructose, high-fat diet (HFrHFD); moreover, the role of free fatty acid receptor 1 (FFAR1) was evaluated. The mice in the two groups were further divided into three subgroups as follows: control, OA (40 mg/kg), and OA + GW1100 (0.4 mg/kg, selective FFAR1 blocker). After a 16-week feeding period, the mice received the drugs via intraperitoneal (i.p.) injection followed by an i.p. glucose tolerance test (IPGTT) 30 min later. After 3 days, the mice received the same drugs to examine the effects of the drugs on the hepatic levels of phosphatidylinositol-4,5-bisphosphate (PIP2) and diacylglycerol (DAG). OA in the SCD-fed mice significantly increased the blood glucose level (48%, P < 0.001) after 30 min of glucose load compared to that in the control group, but did not affect the levels of PIP2 and DAG. Pre-injection with GW1100 significantly decreased the area under the curve of the IPGTT (28%, P < 0.05) in the SCD group compared to that in the SCD + OA group. OA reduced the blood glucose level (35%, P < 0.001) after 120 min of glucose load in the HFrHFD-fed mice; in addition, it increased hepatic PIP2 (160%, P < 0.01) and decreased hepatic DAG (60%, P < 0.001) levels. Pre-injection with GW1100 blocked the effects of OA on hepatic PIP2 and DAG without affecting the glucose tolerance. In conclusion, OA acutely impaired the glucose tolerance in the SCD-fed mice by acting on FFAR1 but did not improve it in the HFrHFD-fed mice.