MiR-3064 in Epicardial Adipose-Derived Exosomes Targets Neuronatin to Regulate Adipogenic Differentiation of Epicardial Adipose Stem Cells

Abstract

Backgroud: The metabolism of epicardial adipose tissue (EAT) is closely related to coronary atherosclerotic heart disease (CAHD), but the specific mechanism is not fully understood. In this study, we investigated the effects of EAT microenvironment on adipose metabolism from the viewpoint of EAT-derived exosomes and epicardial adipose stem cells (EASCs).Methods: EAT samples from CAHD patients and non-CAHD patients were collected to obtain exosomes via tissue culture. MiRNA sequencing was performed to analyze differences in miRNA expression in exosomes between groups. Luciferase reporter assay was then performed to verify the miRNA target gene. EAT was digested by collagenase to obtain EASCs, which were induced to mature adipocytes in vitro. Immunochemical staining and western blotting were performed to detect protein expression levels.Results: The results showed that CAHD patients had higher levels of EASCs in EAT, and no significant difference in the adipogenic differentiation ability of EASCs was observed between CAHD and non-CAHD patients in vitro. This indicates that the EAT microenvironment is a key factor affecting the adipogenic differentiation of EASCs. The EAT-derived exosomes from CAHD patients inhibited adipogenic differentiation of EASCs in vitro. Sequencing analysis showed that miR-3064-5p was highly expressed in EAT-derived exosomes in CAHD patients, and its inhibitor could improve the adipogenic differentiation of EASCs. Luciferase reporter assay results showed that the target gene of miR-3064-5p is neuronatin (Nnat). Nnat remained silent in EASCs and was less expressed in EAT of CAHD patients.Conclusion: Abovementioned results suggest that Nnat is the key to regulating the adipogenic differentiation of EASCs, and miR-3064-5p in EAT-derived exosomes can inhibit the expression of Nnat by targeting its mRNA, thereby affecting the adipogenic differentiation of EASCs.

Association between metformin treatment and coronary artery inflammation based on pericoronary adipose tissue attenuation in type 2 diabetes mellitus patients

“…PCAT refers to the part of epicardial fat that directly contacts the coronary arteries, facilitating bidirectional conduction between them and playing a crucial role in coronary atherosclerosis. 35 , 36 , 37 PCAT attenuation, as determined by coronary CTA, has been identified as an indicator of coronary inflammation. Our study consistently found that LAD‐PCAT was significant in all adjusted models of multiple linear regression.…”

Tilianin alleviates lipid deposition and fibrosis in mice with nonalcoholic steatohepatitis by activating the PPARα/Nnat axis

“…Nnat regulates the adipogenic differentiation of preadipocytes, thereby improving adipose tissue metabolism. It is also a therapeutic target for atherosclerosis (Yang et al, 2019(Yang et al, , 2021. Nnat is considered an important regulator of glucose homeostasis and normal lipid metabolism under physiological conditions (Asahara, 2018;Gburcik et al, 2013).…”

Adropin Carried by Reactive Oxygen Species-Responsive Nanocapsules Ameliorates Renal Lipid Toxicity in Diabetic Mice

“…43 A recent study showed that Nnat regulates the normal fat metabolism of the epicardial adipose tissue. 44 In highfat diet-fed mice, Nnat was proved as a SERCA uncoupler in cells and may function in adaptive thermogenesis. 45 However, the role of Nnat in glycorenal lipid metabolism has not been reported yet.…”

“…The deletion of Nnat reduces basal and insulin-stimulated glucose uptake and glycogen synthesis without affecting the insulin signal, and, therefore, it is an important regulator of white adipocyte browning and metabolic substrate treatment . A recent study showed that Nnat regulates the normal fat metabolism of the epicardial adipose tissue . In high-fat diet-fed mice, Nnat was proved as a SERCA uncoupler in cells and may function in adaptive thermogenesis .…”