Chronic hyperinsulinemia induced miR-27b is linked to adipocyte insulin resistance by targeting insulin receptor

Abstract

Defect in insulin signaling leads to the development of insulin resistance followed by type 2 diabetes. Exploiting our previously developed physiological chronic hyperinsulinemia (CI)-mediated insulin resistance (IR) model, we wanted to understand how miRNAs contribute to the development of IR. Amongst the identified and validate miRNAs, the expression of miR-27b was found to be highly upregulated during CI-induced IR in 3T3-L1 adipocytes. We also validated the expression of miR-27b in CI-induced IR in human mesenchymal stem cell (hMSC)-derived adipocytes and in vivo high fat diet (HFD)-induced IR mice model. Bioinformatics target prediction softwares and luciferase reporter assay identified insulin receptor (INSR) as one of a prime target of miR-27b. Lentiviral mediated overexpression of miR-27b impairs insulin signaling by modulating INSR expression that in turn led to decreased glucose uptake in both 3T3-L1 and hMSC-derived adipocytes. Conversely, inhibition of miR-27b reversed CI-mediated suppression of target protein INSR and improved phosphorylation of Akt, a nodal protein of insulin signaling that is impaired by CI treatment. Lentiviral mediated overexpression of miR-27b in in vivo C57BL/6 mice impaired whole body glucose tolerance and adipose tissue insulin sensitivity. Furthermore, inhibition of miR-27b in HFD-induced insulin resistance mice model improved glucose tolerance and adipose tissue insulin sensitivity by increasing the expression of its target gene INSR in eWAT. Thus, our results indicate that miR-27b functions as a prime modulator of CI-induced IR via regulating the expression of INSR. KEY MESSAGES: miR-27b is upregulated in different in vitro and in vivo models of insulin resistance. miR-27b directly suppresses the expression of INSR by targeting 3'UTR of INSR. Modulation of miR-27b expression regulates insulin sensitivity by targeting INSR.

Pervasive Small RNAs in Cardiometabolic Research: Great Potential Accompanied by Biological and Technical Barriers

“…Other groups have also reported key roles for miR-27 in cholesterol homeostasis, including regulation of low-density lipoprotein receptor (LDLR) and ATP-binding cassette transfer protein A1 (ABCA1), key membrane proteins in cholesterol uptake and efflux, respectively (20,21). miR-27b has also recently been found to control key genes within glucose pathways, including regulation of the insulin receptor (INSR) in adipocytes (22). Over time, miRNAs have repeatedly proven to be critical regulators of metabolism, and the success in miRNA biology is likely a direct result of investigators having access to predesigned reagents and databases as well as a canonical mechanism of function that hypotheses and models can be applied to.…”

“…Recently, we reported that cholesterol homeostasis regulator of miRNA expression (CHROME), a primate-specific lncRNA, serves as a ceRNA and regulates cholesterol metabolism through binding to and suppressing miR-27b-3p, miR-33a/b-5p, and miR-128-3p (7). All three of these miRNAs have previously been reported to regulate specific genes that likely contribute to glucose metabolism (21,22,(32)(33)(34). CHROME is a remarkable example of an lncRNA that has the capacity to sequester and inhibit the activity of multiple key metabolic miRNAs and thus likely control a substantial number of critical important genes for cholesterol and glucose homeostasis to achieve a higher level of posttranscriptional regulatory control.…”

Autofermentation of Chamomile Ligulate Flowers Promote Antitumor Effects in vitro

“…16 Earlier research has shown content of free apigenin is much lower than content of its bound forms. 17 However, from the biological point of view, high concentration of free apigenin in chamomile extracts is of great importance. An increase of its content in starting plant material and further in extracts is very notable task and different method for hydrolysis of apigenin glycosides into aglycone have been reported in the literature.…”

HPLC/PDA/ESI-MS/MS analysis of chamomile decoction and mechanism of its protective effects on aspirin-induced small bowel injuries

“…10,11 The main therapeutic effects of chamomile due to its antioxidant properties are anti-inammatory, anxiolytic, sedative and especially digestive. 12 Indeed, chamomile has been widely used in the treatment of the majority of gastrointestinal diseases such as atulence, indigestion, nausea, vomiting, 13 gastric ulcer 10 and diarrhea. 14 Chamomile is generally safe for consumption, although patients are hypersensitive to ragweed.…”

“…14 Chamomile is generally safe for consumption, although patients are hypersensitive to ragweed. 13 In the present investigation we evaluated the chemical composition of chamomile decoction extract (CDE), as well as the relationship between histological injuries, inammation and oxidative stress induced by aspirin intoxication, and the protection offered by CDE administration. 386950), TBA (PubChem CID: 5759), TCA (PubChem CID: 23681045), beta-D-2-deoxyribose (PubChem CID: 439576), GSH (PubChem CID: 124886), BHT (PubChem CID: 31404), diethyl ether (PubChem CID: 3283) and NaCl (PubChem CID: 5234) were purchased from Sigma-Aldrich Co. (Germany).…”