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Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes

ABSTRACT: This dataset includes mRNA sequencing data obtained from 4T1 cells, either from in vitro cell culture, or clonogenic assay from brain, or primary tumor treated with exosomes from insulin sensitive (IS) or induslin resistant (IR) adipocytes; and 4T1 cells cultured in vitro and treated with miR-145a-3p. Exosomal small RNA from IS and IR aidpocytes derived exsomes were also included. RNA was extracted and sequenced to investigate differential gene expression and associated biological pathways. The aim of the study is to elucidate how insulin resistance in adipocytes influences gene expression, cancer aggressiveness and metastasis. Data include raw and processed mRNA sequencing files from replicates for each condition.

ORGANISM(S): Mus musculus

PROVIDER: GSE286275 | GEO | 2025/06/16

REPOSITORIES: GEO

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Project description:This model is from the article: Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes. Nyman E, Fagerholm S, Jullesson D, Strålfors P, Cedersund G. FEBS J. 2012 Jan 16. 22248283 , Abstract: Insulin signaling through insulin receptor (IR) and insulin receptor substrate-1 (IRS1) is important for insulin control of target cells. We have previously demonstrated a rapid and simultaneous overshoot behavior in the phosphorylation dynamics of IR and IRS1 in human adipocytes. Herein, we demonstrate that in murine adipocytes a similar overshoot behavior is not simultaneous for IR and IRS1. The peak of IRS1 phosphorylation, which is a direct consequence of the phosphorylation and the activation of IR, occurs earlier than the peak of IR phosphorylation. We used a conclusive modeling framework to unravel the mechanisms behind this counter-intuitive order of phosphorylation. Through a number of rejections, we demonstrate that two fundamentally different mechanisms may create the reversed order of peaks: (i) two pools of phosphorylated IR, where a large pool of internalized IR peaks late, but phosphorylation of IRS1 is governed by a small plasma membrane-localized pool of IR with an early peak, or (ii) inhibition of the IR-catalyzed phosphorylation of IRS1 by negative feedback. Although (i) may explain the reversed order, this two-pool hypothesis alone requires extensive internalization of IR, which is not supported by experimental data. However, with the additional assumption of limiting concentrations of IRS1, (i) can explain all data. Also, (ii) can explain all available data. Our findings illustrate how modeling can potentiate reasoning, to help draw nontrivial conclusions regarding competing mechanisms in signaling networks. Our work also reveals new differences between human and murine insulin signaling. Database The mathematical model described here has been submitted to the Online Cellular Systems Modelling Database and can be accessed at http://jjj.biochem.sun.ac.za/database/nyman/index.html free of charge.

Project description:Aims/Hypothesis. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Methods. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain- or loss of LMO3 expression, respectively. Results. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. Lmo3 expression in eWAT significantly improved glucose clearance and insulin sensitivity in diet-induced obesity, paralleled by increased serum adiponectin. On a molecular level, LMO3 expression in eWAT increased pathways indicative of adipogenesis and PPARg signaling as well as mitochondrial activity, paralleled by a suppression of adipose tissue fibrosis. In vitro, Lmo3 expression in 3T3-L1 adipocytes increased insulin-stimulated GLUT4 translocation and glucose uptake as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. LMO3 overexpression promoted, while silencing of LMO3 suppressed, mitochondrial oxidative capacity in human mature adipocytes. Conclusions. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose tolerance, insulin sensitivity and adiponectin secretion. Together with increased PPARγ activity, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity.

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Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes

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