Liraglutide prevents hypoadiponectinemia-induced insulin resistance and alterations of gene expression involved in glucose and lipid metabolism

Abstract

Liraglutide is a glucagonlike peptide (GLP)-1 analog that reduces blood glucose levels, increases insulin secretion and improves insulin sensitivity through mechanisms that are not completely understood. Therefore, we aimed to evaluate the metabolic impact and underlying mechanisms of liraglutide in a hypoadiponectinemia and high-fat diet (HFD)-induced insulin resistance (IR) model. Adiponectin gene targeting was achieved using adenovirus-transduced RNAi and was used to lower plasma adiponectin levels. Liraglutide (1 mg/kg) was given twice daily for 8 wks to HFD-fed apolipoprotein (Apo)E⁻/⁻ mice. Insulin sensitivity was examined by a hyperinsulinemic-euglycemic clamp. Gene mRNA and protein expressions were measured by quantitative real-time polymerase chain reaction (PCR) and Western blot, respectively. Administration of liraglutide prevented hypoadiponectinemia-induced increases in plasma insulin, free fatty acids, triglycerides and total cholesterol. Liraglutide also attenuated hypoadiponectinemia-induced deterioration in peripheral and hepatic insulin sensitivity and alterations in key regulatory factors implicated in glucose and lipid metabolism. These findings demonstrated for the first time that liraglutide could be used to rescue IR induced by hypoadiponectinemia and HFD via regulating gene and protein expression involved in glucose and lipid metabolism.

Figure 1

Experimental protocol. (A) IVGTT. (B) Hyperinsulinemic-euglycemic clamps.

Figure 2

Acrp30 knockdown in HFD-fed ApoE^−/− mice. Mice were injected with adeno-viruses expressing either shGFP or shAcrp30. A subgroup of the mice was injected with liraglutide at a dose of 1 mg/kg twice daily. (A) Relative Acrp30 mRNA levels in adipose tissues. (B) Plasma Acrp30 levels. (C) Acrp30 protein levels in adipose tissues.

Figure 3

IVGTT. (A–E) Glucose curves in four groups. (F–J) Insulin curves in four groups. Values are presented as means ± SE; *P < 0.05, ^#P < 0.01.

Figure 4

Real-time RT-PCR and Western immunoblot analysis of hepatic PEPCK and GLUT-1. (A) PEPCK mRNA expression. (B) GLUT-1 mRNA expression. (C) PEPCK protein level graphs show the averages ± SD for each parameter obtained (n = 6 mice per group).

Figure 5

Effects of liraglutide on gene expression involved in TG and fatty acid metabolism in adipose tissues. (A) HSL mRNA expression. (B) PPARγ mRNA expression. (C) FAS mRNA expression. (D) ACC mRNA expression. (E) SCD1 mRNA expression. (F) PPARγ and HSL protein levels. Graphs show the average ± SEM for each parameter obtained (n = 6 mice per group).

Figure 6

Effects of liraglutide on gene expression involved in cholesterol metabolism in liver. (A) INSIG-2 mRNA expression. (B) HMGCR mRNA expression. (C) PPARα mRNA expression. (D) LDLr mRNA expression. (E) SREBP-2 mRNA expression.