Dataset Information

Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55? Subunit of Phosphoinositide 3-Kinase.

ABSTRACT: Introduction: The Phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in skeletal muscle insulin-stimulated glucose uptake. While whole-body and tissue specific knockout (KO) of individual or combinations of the regulatory subunits of PI3K (p85?, p55?, and p50? or p85?); increase insulin sensitivity, no study has examined whether increasing the expression of the individual regulatory subunits would inhibit insulin action in vivo. Therefore, the objective of this study was to determine whether skeletal muscle-specific overexpression of the p55? regulatory subunit of PI3K impairs skeletal muscle insulin sensitivity, or prevents its enhancement by caloric restriction. Methods: We developed a novel "floxed" mouse that, through the Cre-LoxP approach, allows for tamoxifen (TMX)-inducible and skeletal muscle-specific overexpression of the p55? subunit of PI3K (referred to as, 'p55?-mOX'). Beginning at 10 weeks of age, p55?-mOX mice and their floxed littermates (referred to as wildtype [WT]) either continued with free access to food (ad libitum; AL), or were switched to a calorie restricted diet (CR; 60% of AL intake) for 20 days. We measured body composition, whole-body energy expenditure, oral glucose tolerance and ex vivo skeletal muscle insulin sensitivity in isolated soleus and extensor digitorum longus muscles using the 2-deoxy-glucose (2DOG) uptake method. Results: p55? mRNA and protein expression was increased ?2 fold in muscle from p55?-mOX versus WT mice. There were no differences in energy expenditure, total activity, or food intake of AL-fed mice between genotypes. Body weight, fat and lean mass, tissue weights, and fasting glucose and insulin were comparable between p55?-mOX and WT mice on AL, and were decreased equally by CR. Interestingly, overexpression of p55? did not impair oral glucose tolerance or skeletal muscle insulin signaling or sensitivity, nor did it impact the ability of CR to enhance these parameters. Conclusion: Skeletal muscle-specific overexpression of p55? does not impact skeletal muscle insulin action, suggesting that p85? and/or p50? may be more important regulators of skeletal muscle insulin signaling and sensitivity.

SUBMITTER: Martins VF

PROVIDER: S-EPMC6030672 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55α Subunit of Phosphoinositide 3-Kinase.

Martins Vitor F VF Tahvilian Shahriar S Kang Ji H JH Svensson Kristoffer K Hetrick Byron B Chick Wallace S WS Schenk Simon S McCurdy Carrie E CE

Frontiers in physiology 20180627

<b>Introduction:</b> The Phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in skeletal muscle insulin-stimulated glucose uptake. While whole-body and tissue specific knockout (KO) of individual or combinations of the regulatory subunits of PI3K (p85α, p55α, and p50α or p85β); increase insulin sensitivity, no study has examined whether increasing the expression of the individual regulatory subunits would inhibit insulin action <i>in vivo</i>. Therefore, the objective of t ...[more]

PMID: 29997524

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Project description:Background: The mechanisms responsible for calorie restriction (CR)-induced improvement in insulin sensitivity (IS) have not been fully elucidated. Greater insight can be achieved through deep biological phenotyping of subjects undergoing CR, and integration of big data. Materials and Methods: An integrative approach was applied to investigate associations between change in IS and factors from host, microbiota, and lifestyle after a 6-week CR period in 27 overweight or obese adults (ClinicalTrials.gov: NCT01314690). Partial least squares regression was used to determine associations of change (week 6 - baseline) between IS markers and lifestyle factors (diet and physical activity), subcutaneous adipose tissue (sAT) gene expression, metabolomics of serum, urine and feces, and gut microbiota composition. ScaleNet, a network learning approach based on spectral consensus strategy (SCS, developed by us) was used for reconstruction of biological networks. Results: A spectrum of variables from lifestyle factors (10 nutrients), gut microbiota (10 metagenomics species), and host multi-omics (metabolic features: 84 from serum, 73 from urine, and 131 from feces; and 257 sAT gene probes) most associated with IS were identified. Biological network reconstruction using SCS, highlighted links between changes in IS, serum branched chain amino acids, sAT genes involved in endoplasmic reticulum stress and ubiquitination, and gut metagenomic species (MGS). Linear regression analysis to model how changes of select variables over the CR period contribute to changes in IS, showed greatest contributions from gut MGS and fiber intake. Conclusion: This work has enhanced previous knowledge on links between host glucose homeostasis, lifestyle factors and the gut microbiota, and has identified potential biomarkers that may be used in future studies to predict and improve individual response to weight-loss interventions. Furthermore, this is the first study showing integration of the wide range of data presented herein, identifying 115 variables of interest with respect to IS from the initial input, consisting of 9,986 variables. Clinical Trial Registration: clinicaltrials.gov (NCT01314690).

Dataset Information

Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55? Subunit of Phosphoinositide 3-Kinase.

Publications

Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55α Subunit of Phosphoinositide 3-Kinase.

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