Dataset Information

Nyman2012_InsulinSignalling

ABSTRACT: 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.

SUBMITTER: Elin Nyman

PROVIDER: BIOMD0000000423 | BioModels | 2012-07-27

REPOSITORIES: BioModels

ACCESS DATA

Publications

Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes.

Nyman Elin E Fagerholm Siri S Jullesson David D Strålfors Peter P Cedersund Gunnar G

The FEBS journal 20120215 6

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 activati ...[more]

PMID: 22248283

Similar Datasets

Project description:Development of insulin resistance is a key pathogenic component underlying metabolic syndrome and Type 2 diabetes (T2DM). Despite its importance, the molecular mechanisms underlying insulin resistance are poorly understood. Genome-wide association studies for T2DM and other metabolic traits have led to the identification of many candidate SNPs, but the majority of these SNPs are noncoding and determination of associated causal genes and/or specific tissue sites of action have been difficult. Adipocytes are critical regulators of mammalian metabolic homeostasis, with important effects on appetite, satiety, glucose and lipid homeostasis, energy expenditure, blood pressure, and immune function. Although insulin resistance (IR) in skeletal muscle, the major source of glucose disposal, is responsible for the bulk of the hyperglycemia observed in T2DM, muscle IR KO mice are generally healthy, IR also occurs in adipocytes, and inflammation within adipose tissue has been proposed as a primary mediator of IR, resulting in excess release of free fatty acids as well as alterations in adipokine release. Absence of adipose tissue, as observed in various lipodystrophies, or adipocyte-specific knockout of genes such as GLUT4 or insulin receptor, also alter systemic IR and T2DM risk. Transcriptional changes in adipocytes associated with metabolic disease. Despite the importance of adipocytes to metabolic disease, we have a poor understanding of how the adipocyte transcriptome changes in the disease state. Studies investigating transcriptional changes in whole adipose tissue have shown decreases in genes involved in adipogenesis, as well as alterations in inflammation, mitochondrial metabolism, lipid metabolism, detoxification, and insulin signaling. However, the vast majority of these studies use total adipose tissue samples, which does not allow for the exclusive evaluation of gene expression in mature adipocytes due to the substantial number of nonadipocyte cells (immune cells, fibroblasts, endothelial cells, pre-adipocytes, and mesenchymal cells) that also reside in adipose tissue. This is particularly relevant when studying metabolic disorders related to obesity-associated insulin resistance because these conditions are characterized by an increased influx of inflammatory cells into the adipose tissue.

Dataset Information

Nyman2012_InsulinSignalling

Publications

Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure