Related Experiment Video
Updated: Aug 11, 2025
Studying the Hypothalamic Insulin Signal to Peripheral Glucose Intolerance with a Continuous Drug Infusion System into the Mouse Brain
Published on: January 4, 2018
Sitagliptin Ameliorates Creb5/lncRNA ENSMUST00000213271-Mediated Vascular Endothelial Dysfunction in Obese Mice
Yi Zong1, Xiaorui Wang1, Yi Zhang1,2
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
Purpose:
Obesity is mediated by the changes in dyslipidemia, oxidative stress, and inflammation, leading to vascular endothelial dysfunction. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors prevent the development of endothelial dysfunction. However, the underlying mechanism still remains largely unclear. Long non-coding RNAs (lncRNAs), one class of non-coding small RNAs, have been shown to exert a regulatory impact on the endothelial function in obesity. This study aimed to investigate whether the elevation of GLP-1 by a DPP-4 inhibitor sitagliptin improved vascular endothelial function by modulating lncRNAs in obese mice and to clarify the underlying molecular mechanism.
Methods:
Male C57BL/6J mice were fed a high-fat diet for 4 months to induce obesity and some obese mice were treated with sitagliptin for the last 1 month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined using western blot. The differentially expressed lncRNAs were validated using qRT-PCR.
Results:
Obese mice exhibited increased levels of TC and LDL, decreased concentrations of HDL and GLP-1 in plasma, and impaired aortic endothelium-dependent relaxations; such effects could be reversed by sitagliptin. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. Consistent with microarray analysis, qRT-PCR also revealed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and aortic endothelial cells (ECs), which could be down-regulated by sitagliptin. Creb5 silencing reduced lncRNA ENSMUST00000213271 in obese mouse ECs. Knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse ECs. Furthermore, sitagliptin also suppressed Creb5 and lncRNA ENSMUST00000213271 and increased the phosphorylations of AMPK and eNOS in obese mice.
Conclusion:
Creb5/lncRNA ENSMUST00000213271 mediated vascular endothelial dysfunction through inhibiting AMPK/eNOS cascade in obesity. Elevation of GLP-1 by sitagliptin possibly improved endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide new evidence for the benefits of GLP-1 against vasculopathy in obesity.
Insights
Sitagliptin, a GLP-1 enhancer, improves vascular function in obese mice by suppressing Creb5 and lncRNA ENSMUST00000213271, restoring AMPK/eNOS activation. This highlights a new mechanism for treating obesity-related vascular dysfunction.
Area of Science:
- Endocrinology and Metabolism
- Vascular Biology
- Molecular Biology
Background:
- Obesity-induced dyslipidemia, oxidative stress, and inflammation impair vascular endothelial function.
- Glucagon-like peptide-1 (GLP-1) analogues and DPP-4 inhibitors show promise in preventing endothelial dysfunction, but mechanisms are unclear.
- Long non-coding RNAs (lncRNAs) are implicated in regulating endothelial function during obesity.
Purpose of the Study:
- To investigate if sitagliptin, by elevating GLP-1, improves vascular endothelial function in obese mice.
- To determine if sitagliptin modulates lncRNAs in the context of obesity-induced endothelial dysfunction.
- To elucidate the molecular mechanisms underlying sitagliptin's effects on endothelial function in obesity.
Main Methods:
- Obesity was induced in C57BL/6J mice using a high-fat diet.
- Sitagliptin treatment was administered to obese mice for one month.
- Plasma lipid profiles, GLP-1 levels, aortic relaxations, lncRNA expression, and protein signaling pathways (AMPK/eNOS) were analyzed.
Main Results:
- Obese mice displayed dyslipidemia and impaired aortic relaxation, which were reversed by sitagliptin.
- Sitagliptin modulated lncRNA expression profiles in obese mouse aortae.
- Sitagliptin suppressed Creb5 and lncRNA ENSMUST00000213271, restoring AMPK/eNOS activation in obese mice.
Conclusions:
- The Creb5/lncRNA ENSMUST00000213271 axis mediates vascular endothelial dysfunction in obesity by inhibiting the AMPK/eNOS pathway.
- Sitagliptin enhances GLP-1 levels, potentially improving endothelial function by suppressing this axis and reactivating AMPK/eNOS.
- These findings offer new insights into the benefits of GLP-1-based therapies for obesity-related vasculopathy.
Related Concept Videos
01:23Dipeptidyl Peptidase 4 Inhibitors
01:24Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
01:06Oral Hypoglycemic Agents: Glinides
01:26Oral Hypoglycemic Agents: Biguanides and Glitazones
01:20Pathophysiology of Diabetes
Type 1 diabetes is characterized by autoimmune-mediated destruction of pancreatic β cells, with environmental factors potentially triggering this process in genetically susceptible individuals. Despite many not having a family history, certain genes increase susceptibility,...
01:19Oral Hypoglycemic Agents: α-Glucosidase Inhibitors
Acarbose and miglitol are...