Dataset Information

Human adipose insulin resistance

ABSTRACT: Adipocytes play a major role in whole body fuel homeostasis. Integrated proteomic analysis of adipose from insulin resistant versus healthy humans or mice or in 3T3-L1 adipocytes revealed defects in the mevalonate/coenzyme Q (CoQ) biosynthesis pathway as a unifying feature of adipocyte insulin resistance. CoQ was decreased selectively in mitochondria in all insulin resistant conditions and this was associated with a selective increase in mitochondrial oxidative stress. CoQ supplementation lowered mitochondrial oxidative stress and reversed insulin resistance in vitro and in vivo. Decreasing mitochondrial CoQ by genetic or pharmacological means caused insulin resistance by increasing mitochondrial oxidants from complex II. Our data suggest that loss of mitochondrial CoQ is a proximal driver of mitochondrial oxidative stress and insulin resistance. These findings may explain why statin use is associated with insulin resistance, and suggest that mitochondrial CoQ may be an effective therapeutic target for treating insulin resistance in humans.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Adipose Tissue

DISEASE(S): Insulin Insensitivity

SUBMITTER: Daniel Fazakerley

LAB HEAD: David James

PROVIDER: PXD006891 | Pride | 2018-02-09

REPOSITORIES: Pride

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			Action	DRS
	170206_QEHF_BenP_DanFaz_Adipose_20633.raw	Raw
	170206_QEHF_BenP_DanFaz_Adipose_21202.raw	Raw
	170206_QEHF_BenP_DanFaz_Adipose_21230.raw	Raw
	170206_QEHF_BenP_DanFaz_Adipose_21246.raw	Raw
	170206_QEHF_BenP_DanFaz_Adipose_21286.raw	Raw

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Project description:Smith2013 - Regulation of Insulin Signalling by Oxidative Stress The model describes insulin signalling (in rodent adipocytes), which includes in addition to the core pathway, the transcriptional feedback through the Forkhead box type O (FOXO) transcription factor and interaction with oxidative stress. This model is described in the article: Computational modelling of the regulation of Insulin signalling by oxidative stress. Smith GR, Shanley DP. BMC Syst Biol. 2013 May 24;7:41. Abstract: BACKGROUND: Existing models of insulin signalling focus on short term dynamics, rather than the longer term dynamics necessary to understand many physiologically relevant behaviours. We have developed a model of insulin signalling in rodent adipocytes that includes both transcriptional feedback through the Forkhead box type O (FOXO) transcription factor, and interaction with oxidative stress, in addition to the core pathway. In the model Reactive Oxygen Species are both generated endogenously and can be applied externally. They regulate signalling though inhibition of phosphatases and induction of the activity of Stress Activated Protein Kinases, which themselves modulate feedbacks to insulin signalling and FOXO. RESULTS: Insulin and oxidative stress combined produce a lower degree of activation of insulin signalling than insulin alone. Fasting (nutrient withdrawal) and weak oxidative stress upregulate antioxidant defences while stronger oxidative stress leads to a short term activation of insulin signalling but if prolonged can have other effects including degradation of the insulin receptor substrate (IRS1) and FOXO. At high insulin the protective effect of moderate oxidative stress may disappear. CONCLUSION: Our model is consistent with a wide range of experimental data, some of which is difficult to explain. Oxidative stress can have effects that are both up- and down-regulatory on insulin signalling. Our model therefore shows the complexity of the interaction between the two pathways and highlights the need for such integrated computational models to give insight into the dysregulation of insulin signalling along with more data at the individual level.A complete SBML model file can be downloaded from BIOMODELS (https://www.ebi.ac.uk/biomodels-main) with unique identifier MODEL1212210000.Other files and scripts are available as additional files with this journal article and can be downloaded from https://github.com/graham1034/Smith2012_insulin_signalling. This model is hosted on BioModels Database and identified by: BIOMD0000000474 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Human adipose insulin resistance

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