Dataset Information

Sex and Insulin Resistance Define a Cell Autonomous Supernetwork of Protein Phosphorylation

ABSTRACT: Insulin resistance is an important factor in the pathophysiology of many metabolic disorders. The aim of this study was to uncover the cell autonomous determinants of insulin resistance using induced pluripotent stem cell (iPSC)-derived myoblasts (iMyos). Here, we found that iMyos from insulin resistant non-diabetic individuals show impaired insulin signaling, defective insulin-stimulated glucose uptake and glycogen synthase activity compared to insulin sensitive individuals. Global phosphoproteomic analysis uncovered a large network of altered protein phosphorylations in insulin resistance, mostly outside the canonical insulin-signaling cascade. More surprisingly, we observed striking differences in the phosphoproteomic signature from male versus female subjects, including changes in DNA and RNA processing, GTPase signaling, and SUMOylation/ubiquitination. These findings unravel cell autonomous mechanisms underlying insulin resistance and demonstrate a previously unrecognized supernetwork of cell signaling differences in males and females that must be considered in understanding the molecular basis of sex-based differences in normal physiology and disease.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Myoblast

DISEASE(S): Type 2 Diabetes Mellitus,Disease Free

SUBMITTER: Ashokkumar Jayavelu

LAB HEAD: Prof.Matthias Mann

PROVIDER: PXD022637 | Pride | 2021-11-03

REPOSITORIES: Pride

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Publications

Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex.

Haider Nida N Lebastchi Jasmin J Jayavelu Ashok Kumar AK Batista Thiago M TM Pan Hui H Dreyfuss Jonathan M JM Carcamo-Orive Ivan I Knowles Joshua W JW Mann Matthias M Kahn C Ronald CR

The Journal of clinical investigation 20211101 21

Insulin resistance is present in one-quarter of the general population, predisposing these people to a wide range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using induced pluripotent stem cell-derived (iPSC-derived) myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type 2 diabetic iMyos revealed critical sites of conserved altered ...[more]

PMID: 34506305

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Project description:We show that roscovitine; a cyclin-dependent kinases inhibitor; given to mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation and fibrosis. It also restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that Roscovitine induced a limited set of proteins associated with lipid metabolism, fatty acid oxidation metabolism and adipose tissue remodeling but suppressed expression of a larger array of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. Furthermore, the phosphoproteome analysis identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases [e.g., CDKs and MAPKs], AGC kinases [e.g., S6K and PKC isoforms], and CAMK kinases [e.g., SIK1 and SIK2]). Pathway enrichment analysis of annotated kinase-substrate pairs showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and phosphatidylcholine and creatine biosynthesis are enriched following roscovitine treatment. The increased creatine pathways combined with more active mitochondria in eWAT may contribute to roscovitine-induced weight loss. Surprisingly, we found that unlike for eWAT, roscovitine led to up regulation of large sets of proteins and phosphosites in brown adipose tissue (BAT). Analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups (AGC kinases [e.g., PKD1 and PKA] and CMGC kinases [e.g., CDKs and MAPKs]. Among the top enriched pathways of kinase-substrate pairs were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling, suggesting that roscovitine led to a metabolically more active BAT. Overall, roscovitine treatment led to restoration of mitochondrial activity in BAT and eWAT suppressed by HFD, likely accounting for enhanced energy expenditure and weight loss.

Dataset Information

Sex and Insulin Resistance Define a Cell Autonomous Supernetwork of Protein Phosphorylation

Publications

Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex.

Similar Datasets

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