Alleviation of high-fat diet-induced atherosclerosis and glucose intolerance by a novel GLP-1 fusion protein in ApoE−/− mice

Abstract

We have previously constructed an engineered anti-diabetic fusion protein using glucagon-like peptide-1 and the globular domain of adiponectin. Herein, we evaluated the therapeutic effects of this fusion protein (GAD) on high-fat diet (HFD)-fed ApoE(-/-) mice. The lipid-lowering effect of GAD was determined in C57BL/6 mice using a lipid tolerance test. The effects of GAD on HFD-induced glucose intolerance, atherosclerosis, and hepatic steatosis were evaluated in HFD-fed ApoE(-/-) mice using glucose tolerance test, histological examinations and real-time quantitative PCR. The anti-inflammation activity of GAD was assessed in vitro on macrophages. GAD improved lipid metabolism in C57BL/6 mice. GAD treatment alleviated glucose intolerance, reduced blood lipid level, and attenuated atherosclerotic lesion in HFD-fed ApoE(-/-) mice, which was associated with a repressed macrophage infiltration in the vessel wall. GAD treatment also blocked hepatic macrophage infiltration and prevented hepatic inflammation. GAD suppressed lipopolysaccharide-triggered inflammation responses on macrophages, which can be abolished by H89, an inhibitor of protein kinase A. These findings demonstrate that GAD is able to generate a variety of metabolic benefits in HFD-fed ApoE(-/-) mice and indicate that this engineered fusion protein is a promising lead structure for anti-atherosclerosis drug discovery.

Extra‐Virgin Olive Oil with Natural Phenolic Content Exerts an Anti‐Inflammatory Effect in Adipose Tissue and Attenuates the Severity of Atherosclerotic Lesions in Ldlr−/−.Leiden Mice

“…[30] A study in ApoE−/− mice demonstrated that GAD, a fusion protein derived from glucagon-like peptide-1 and the globular domain of adiponectin, was capable of attenuating HFDinduced atherosclerosis which was associated with a repressed macrophage infiltration in the vessel wall. [31] In addition, another study also in ApoE−/− mice provided evidence that perivascular adipose tissue-derived adiponectin protects against carotid atherosclerosis by promoting macrophage autophagy in vascular tissue. [32] Consistent with these previous studies, our data showed that HFD-EVOO mice, which exhibited the greatest levels of adiponectin in visceral white adipose tissue, presented reduced atherosclerotic lesions with a very low count of monocyte/macrophage compared with HFD-L and HFD-OL mice.…”

“…There is growing experimental evidence highlighting the direct protective role of adiponectin in cardiovascular disease . A study in ApoE −/− mice demonstrated that GAD, a fusion protein derived from glucagon‐like peptide‐1 and the globular domain of adiponectin, was capable of attenuating HFD‐induced atherosclerosis which was associated with a repressed macrophage infiltration in the vessel wall . In addition, another study also in ApoE −/− mice provided evidence that perivascular adipose tissue–derived adiponectin protects against carotid atherosclerosis by promoting macrophage autophagy in vascular tissue .…”

Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism

“…Further, liraglutide treatment seemed to prevent and stabilize early onset atherosclerotic vascular disease partially through GLP-1R-dependent mechanisms but had no significant effect on the progression of late onset, high-burden atherosclerotic disease [38]. Recently, treatment with engineered fusion proteins constituted by GLP-1 fused to the globular domain of adiponectin has been reported to reduce atherosclerosis and glucose intolerance in ApoEÀ/À mice fed a highfat diet [39]. To the best of our knowledge, there are no published studies assessing specifically the role of GLP-2 on atherosclerosis processes or plaque vulnerability.…”