Exenatide reverses dysregulated microRNAs in high-fat diet-induced obese mice

Lee, Ihn Suk; Park, Ki Cheol; Yang, Keum‐Jin; Choi, Hyunsu; Jang, Yi Sun; Lee, Jong Min; Kim, Hye Soo

doi:10.1016/j.orcp.2015.07.011

Cited by 11 publications

(6 citation statements)

References 51 publications

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“…A prior observation of diminished expression of miR-199a in early ischemia in isolated porcine cardiomyocytes[52] is also consistent with our observed tissue level changes, perhaps acting via increases in cardiac Hif-1α expression. Previous studies have demonstrated that GLP-1 mimetics induce miR expression changes in various non-cardiac tissues [35, 61]. However, our study is the first to demonstrate GLP-1-induced miR expression changes in myocardium, and that those effects differ considerably depending on obesity status.…”

Section: Discussionmentioning

confidence: 39%

“…These changes in miRs thus mimic the different physiological changes and responses to ischemia/reperfusion that occur in response to exendin-4 in lean and obese swine, suggesting that they may be contributing to the pathophysiological changes. Growing evidence suggests that GLP-1 receptor activation alters DNA transcription in addition to the expected direct signaling effects [35, 61], suggesting the potential for a relatively unexplored mechanism through which GLP-1 may impart direct and/or indirect effects. Further investigation into the mechanisms of GLP-1 mimetic-induced transcriptome changes are needed.…”

Section: Discussionmentioning

confidence: 99%

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Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

et al. 2016

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This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miR) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-min coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca2+ binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion.

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Section: Discussionmentioning

confidence: 39%

Section: Discussionmentioning

confidence: 99%

Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

et al. 2016

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“…In an experimental mouse model of high fat diet induced obesity, Lee et al demonstrated that exenatide, another GLP-1 receptor agonist, ameliorates serum levels of miRNA-375, reflecting the improvement in insulin sensitivity. Thus, they concluded that miRNA-375 can be useful as a biomarker for monitoring the response to exenatide treatment, indicating changes in insulin sensitivity [31].…”

Section: Mirna-375: Diagnostic and Prognostic Implicationsmentioning

confidence: 99%

Is miRNA-375 a promising biomarker for early detection and monitoring of patients with type 2 diabetes?

Patoulias¹

2018

Arch Med Sci Atheroscler Dis

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miRNAs are small, non-coding RNAs, functioning as negative suppressors of target gene expression. A significant proportion of the transcriptome is subject to miRNA modulation. A single miRNA determines the expression of hundreds of genes, while miRNAs are relatively stable in biological fluids. Thus, they have attracted scientific interest regarding their use as biomarkers for several diseases. miRNA-375 mainly influences β-cell function and insulin secretion. Several studies, primarily experimental, have assessed its role as a biomarker in type 2 diabetes, while recently obtained human evidence supports this potential role. Besides its diagnostic potential, miRNA-375 may also have therapeutic implications. In view of the growing epidemic of type 2 diabetes, there is an unmet need for identification of biomarkers for early recognition and monitoring of these patients. Long-term, prospective human studies are required to elucidate whether miRNA-375 can evolve as a key player in diagnosis and prognosis of type 2 diabetes.

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“…Several studies have shown that some key miR-NAs contributed to pancreatic β cells in GLP-1 agonist-treated diabetic rodents and patients, such as miR-7 [22], miR-9 [22], miR-375 [22][23][24], miR-27a [25], miR-139-5p [26], miR-132 [27], miR-212 [27]. However, the effect of GLP-1 agonists or DPP-4 inhibitors on the diabetic cardiovascular system is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Vildagliptin, a dipeptidyl peptidase-4 inhibitor, attenuated endothelial dysfunction through miRNAs in diabetic rats

et al. 2021

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Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors have various cellular effects that are associated with vascular protection. Here, we examined whether vildagliptin protected endothelial function in diabetic rats and explored the involved mechanism. Material and methods: Experimental diabetic rats were obtained by feeding a high-fat diet and administering an intraperitoneal injection of streptozotocin. Rats were randomly divided into four groups: controls (CON), diabetes (DM), diabetes + low dose of vildagliptin (Lvil, 10 mg/kg/day), and diabetes + high dose of vildagliptin (Hvil, 20 mg/kg/day). The metabolic parameters, endothelial function, and whole miRNA expression were measured. Results: After a 12-week treatment, vildagliptin-treated rats showed a significant reduction in blood glucose and blood lipid levels. Moreover, vildagliptin recovered aortic endothelial function in diabetic rats. We identified 31 miRNAs that were differentially expressed in the Hvil group compared with the diabetic group. Importantly, through miRNA target biological function and pathway analysis, we found that vildagliptin activated miR-190-5p to inhibit Ccl2 expression and inhibited miR-134-5p and miR-375-3p to increase Bdnf and Pdk1 expression in the aorta. Conclusions: Our present study indicates that vildagliptin can recover endothelial function in diabetic rats. Anti-inflammatory and anti-apoptosis mechanisms and endothelial moderation may be the intervention targets of vildagliptin to protect the cardiovascular system through miRNA regulation.

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Exenatide reverses dysregulated microRNAs in high-fat diet-induced obese mice

Cited by 11 publications

References 51 publications

Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

Is miRNA-375 a promising biomarker for early detection and monitoring of patients with type 2 diabetes?

Vildagliptin, a dipeptidyl peptidase-4 inhibitor, attenuated endothelial dysfunction through miRNAs in diabetic rats

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