Effect of TNF-Alpha on Caveolin-1 Expression and Insulin Signaling During Adipocyte Differentiation and in Mature Adipocytes

Objective: Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. Methods: The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. Results: miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Conclusions: Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression.

Section: Introductionmentioning

confidence: 99%

Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression

Dou

Wang

Sun

et al. 2017

“…IR is characterized by a decrease in insulin signaling [14]. Although it is widely accepted that low-grade chronic inflammation is an important factor in the pathogenesis of IR [15, 16], the molecules and mechanisms that regulate inflammation and the IR process in T2D are not fully understood. However, non-coding RNAs were implicated in the regulation of these processes [17-20].…”

Section: Introductionmentioning

confidence: 99%

Aberrant Expression of Long Non-Coding RNAs in Newly Diagnosed Type 2 Diabetes Indicates Potential Roles in Chronic Inflammation and Insulin Resistance

Wang

Zhang

et al. 2017

Background/Aims: Long non-coding RNAs (lncRNAs) have emerged as key players in several biological processes and complex diseases. The risk of type 2 diabetes (T2D) is determined by a combination of environmental factors and genetic susceptibility. The purpose of this study was to identify aberrant lncRNAs involved in T2D pathogenesis. Methods: Microarray analysis was performed using whole blood samples from patients newly diagnosed with T2D and healthy controls. Pathway and Gene Ontology (GO) analyses were utilized to annotate the target genes. Coding non-coding co-expression (CNC) analysis was performed to construct a co-expression network. Results: We found 55 lncRNAs and 202 mRNAs were differentially expressed in the T2D group compared to the healthy control group. Pathway and GO analyses demonstrated that dysregulated mRNAs were mainly associated with immune regulation, inflammation, and insulin resistance, whereas CNC analysis identified 10 pairs of co-expressed lncRNA-mRNAs in our patient cohort (R > 0.99). Furthermore, expression of the top three upregulated lncRNAs in the T2D group was correlated with measures of glycometabolism (P < 0.05). Conclusion: This study identified aberrantly expressed lncRNAs and mRNAs in Han Chinese patients with T2D, and demonstrated that dysregulated lncRNAs may have roles in T2D pathogenesis through regulation of inflammation and insulin resistance.

“…The vessels also supply progenitor cells that can differentiate into preadipocytes and vascular endothelial cells [7]. Besides, activated endothelial cells in adipose tissue produce multifarious cytokines and growth factors regulating adipogenesis, which is the main part of adipose tissue plasticity[9, 10]. To adapt to the changes in volume and metabolic rate of adipose tissue, adipose vasculature requires constant modulation by several angiogenic regulators.…”

Section: Introductionmentioning

confidence: 99%

Cold Exposure Differentially Stimulates Angiogenesis in BAT and WAT of Mice: Implication in Adrenergic Activation

Luo¹,

Jia²,

Luo

et al. 2017

Background/Aims: To characterize the temporal profile of cold-induced angiogenesis in brown and white adipose tissues of mice in vivo and the temporal changes of angiogenic factors in primary mice brown (BA) and white adipocytes (WA) treated with β₃-adrenoceptor agonist (CL316,243) in vitro. Methods: 8-week old male C57BL/6J mice were individually housed in conventional cages under cold exposure (4°C) for 1, 2, 3, 4 and 5 days. Interscapular brown adipose tissue (iBAT), inguinal subcutaneous (sWAT) and epididymal white adipose tissues (eWAT) were harvested for immunohistochemical and gene expression analysis. In vitro, primary mice BA and WA treated with or without CL316,243 were harvested for gene expression and protein secretion analysis. Results: A combination of morphological and genetic (Vegfa, Vegfr2, Hif-1α, Pai1 and Pedf) analyses demonstrated depot-specific angiogenesis in response to cold exposure. Upon CL316,243 treatment, angiogenic factors (Vegfa, Vegfr2, Hif-1α, Pai1 and Pedf) and secreted protein VEGFA were transiently increased in both BA and WA. Conclusion: Our results show that iBAT is highly responsive to cold-induced angiogenesis that is mainly supported by sWAT with a lesser extent by eWAT. Moreover, the angiogenesis is a transient process with the angiogenic factors may work in an autocrine/paracrine manner.