Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet

Alli-Shaik, Asfa; Qiu, Beiying; Wee, Sheena; Choi, Hyungwon; Gunaratne, Jayantha; Tergaonkar, Vinay

doi:10.1038/srep25844

Cited by 22 publications

(13 citation statements)

References 69 publications

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“…Previous studies combining phosphoproteomic data and NetPhorest indicated that Akt has an important role for cellular regulation in response to insulin (Alli Shaik et al, ; Vinayagam et al, ), consistent with this study. These studies did not focus on the kinase selectivity of the regulated cellular functions, and this study provides the first evidence for the kinase selectivity of cellular functions regulated by insulin.…”

Section: Discussionsupporting

confidence: 91%

Reconstruction of global regulatory network from signaling to cellular functions using phosphoproteomic data

et al. 2018

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Cellular signaling regulates various cellular functions via protein phosphorylation.Phosphoproteomic data potentially include information for a global regulatory network from signaling to cellular functions, but a procedure to reconstruct this network using such data has yet to be established. In this paper, we provide a procedure to reconstruct a global regulatory network from signaling to cellular functions from phosphoproteomic data by integrating prior knowledge of cellular functions and inference of the kinase-substrate relationships (KSRs). We used phosphoproteomic data from insulin-stimulated Fao hepatoma cells and identified protein phosphorylation regulated by insulin specifically over-represented in cellular functions in the KEGG database. We inferred kinases for protein phosphorylation by KSRs, and connected the kinases in the insulin signaling layer to the phosphorylated proteins in the cellular functions, revealing that the insulin signal is selectively transmitted via the Pi3k-Akt and Erk signaling pathways to cellular adhesions and RNA maturation, respectively. Thus, we provide a method to reconstruct global regulatory network from signaling to cellular functions based on phosphoproteomic data. K E Y W O R D S cellular functions, insulin signaling, network integration, phosphoproteomic data, phosphorylation, systems biology, Trans-omics | 91Genes to Cells KAWATA eT Al. ACKNOWLEDGMENTSWe thank our laboratory members for critically reading this manuscript and for their technical assistance with the experiments. The computational analysis of this work was performed in part with support of the supercomputer system

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Section: Discussionsupporting

confidence: 91%

Reconstruction of global regulatory network from signaling to cellular functions using phosphoproteomic data

et al. 2018

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“…8c ). Moreover, HFD reduces phosphorylation of PDHE1α at Ser293 30 . In fact, both Ser293 and Ser300 resulted significantly less phosphorylated in floxed and H3atKO mice fed HFD (Fig.…”

Section: Resultsmentioning

confidence: 94%

HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning

et al. 2017

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White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.

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“…Excess energy due to a calorie-dense diet or disturbance of lipid metabolism, in humans and animals, is normally stored as fat in WAT that contains very few mitochondria [ 1 , 14 , 15 , 16 ]. Therefore, accumulation of WAT quickly leads to weight gain and even obesity.…”

Section: Introductionmentioning

confidence: 99%

Betaine Supplementation Enhances Lipid Metabolism and Improves Insulin Resistance in Mice Fed a High-Fat Diet

Shen

Tan

et al. 2018

Nutrients

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Obesity is a major driver of metabolic diseases such as nonalcoholic fatty liver disease, certain cancers, and insulin resistance. However, there are no effective drugs to treat obesity. Betaine is a nontoxic, chemically stable and naturally occurring molecule. This study shows that dietary betaine supplementation significantly inhibits the white fat production in a high-fat diet (HFD)-induced obese mice. This might be due to betaine preventing the formation of new white fat (WAT), and guiding the original WAT to burn through stimulated mitochondrial biogenesis and promoting browning of WAT. Furthermore, dietary betaine supplementation decreases intramyocellular lipid accumulation in HFD-induced obese mice. Further analysis shows that betaine supplementation reduced intramyocellular lipid accumulation might be associated with increasing polyunsaturated fatty acids (PUFA), fatty acid oxidation, and the inhibition of fatty acid synthesis in muscle. Notably, by performing insulin-tolerance tests (ITTs) and glucose-tolerance tests (GTTs), dietary betaine supplementation could be observed for improvement of obesity and non-obesity induced insulin resistance. Together, these findings could suggest that inhibiting WAT production, intramyocellular lipid accumulation and inflammation, betaine supplementation limits HFD-induced obesity and improves insulin resistance.

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Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet

Cited by 22 publications

References 69 publications

Reconstruction of global regulatory network from signaling to cellular functions using phosphoproteomic data

Reconstruction of global regulatory network from signaling to cellular functions using phosphoproteomic data

HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning

Betaine Supplementation Enhances Lipid Metabolism and Improves Insulin Resistance in Mice Fed a High-Fat Diet

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