Hepatic adenylate cyclase 3 is upregulated by Liraglutide and subsequently plays a protective role in insulin resistance and obesity

Abstract

Objective: Recent studies have demonstrated that adenylate cyclase 3 (AC3) has a protective role in obesity. This gene resides at the pathway with glucagon-like peptide (GLP)-1. Liraglutide is a GLP-1 analog and has independent glucose and body weight (BW)-reducing effects. In the present study, we aimed to examine whether hepatic AC3 activity was regulated by Liraglutide and to further understand the effect of AC3 in reduction of BW and insulin resistance.

Subjects: The diabesity and obese mice were induced from db/db and C57BL/6 J mice, respectively, by high-fat diet. Liraglutide (0.1 mg kg(-1) per 12 h) was given to the mice twice daily for 12 weeks. C57BL/6 J mice fed with chow diet and obese or diabesity mice treated with saline were used as the controls. Hepatic AC3 gene expression at mRNA and protein levels was analyzed with real-time reverse transcription-PCR and western blot. Fasting blood glucose and serum insulin levels were measured and followed insulin resistance index (HOMA-IR) was evaluated according to the homeostasis model assessment.

Results: After administration of Liraglutide, BW and HOMA-IR in obese and diabesity mice were decreased, whereas hepatic AC3 mRNA and protein expression levels were upregulated. The AC3 gene expression was negatively correlated with BW, HOMA-IR and the area ratio of hepatic fat deposition in the liver.

Conclusions: The present study thus provides the evidence that hepatic AC3 gene expression is upregulated by Liraglutide. The reduction of BW and improvement of insulin resistance with Liraglutide may be partially explained by AC3 activation.

Figure 1

Body weight, fasting blood glucose and serum insulin levels in mice before and after Liraglutide treatment. The changes of body weight (g), fasting blood glucose and serum insulin levels in mice before and after Liraglutide treatment are summarized in a–c, respectively. HOMA-IR index is represented in d. **P<0.001 versus the control group before Liraglutide treatment; ^¤¤P<0.001 test between O+S and O+L; ^##P<0.001 between DO+S and DO+L; ^¤P<0.05 and ^#P<0.05. Abbreviations: Cont, the control group of non-diabetic and lean mice; O+S, obese mice with saline; O+L, obese with Liraglutide treatment; DO+S, diabesity mice with sline; DO+L, diabesity mice with Liraglutide treatment.

Figure 2

AC3 gene expression at mRNA and protein levels in the liver before and after Liraglutide treatment. AC3 gene expression at mRNA and protein levels in liver tissues of mice before and after Liraglutide treatment was shown in a and b, respectively. The image from western blotting experiments is represented in c. **P<0.001 versus the control group before Liraglutide treatment; ^¤P<0.05 and ^¤¤P<0.001 tests between O+S and O+L, while ^##P<0.001 between DO+S and DO+L. Abbreviations: Cont, the control group of non-diabetic and lean mice; O+S, obese mice with saline; O+L, obese with Liraglutide treatment; DO+S, diabesity mice with sline; DO+L, diabesity mice with Liraglutide treatment.