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      Leptin Stimulates Cellular Glycolysis Through a STAT3 Dependent Mechanism in Tilapia


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          We assessed if leptin, a cytokine hormone known to enhance energy expenditure by promoting lipid and carbohydrate catabolism in response to physiologic stress, might directly regulate cellular glycolysis. A transcriptomic analysis of prolactin cells in the tilapia ( Oreochromis mossambicus) pituitary rostral pars distalis (RPD) revealed that recombinant leptin (rtLep) differentially regulates 1,995 genes, in vitro. Machine learning algorithms and clustering analyses show leptin influences numerous cellular gene networks including metabolism; protein processing, transport, and metabolism; cell cycle and the hypoxia response. Leptin stimulates transcript abundance of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase ( gapdh) in a covariate manner to the hypoxic stress gene network. Orthogonal tests confirm that rtLepA dose-dependently increases gapdh gene expression in the RPD along with transcript abundance of 6-phosphofructo-1-kinase ( pfk1), the rate limiting glycolytic enzyme. Functional testing demonstrated that leptin stimulates PFK activity and glycolytic output, while Stattic (a STAT3 blocker) was sufficient to suppress these responses, indicating leptin stimulates glycolysis through a STAT3-dependent mechanism. Leptin also stimulated pfk1 gene expression and lactate production in primary hepatocyte incubations in a similar manner to those shown for the pituitary RPD. This work characterizes a critical metabolic action of leptin to directly stimulate glycolysis across tissue types in a teleost model system, and suggest that leptin may promote energy expenditure, in part, by stimulating glycolysis. These data in a teleost fish, suggest that one of leptin's ancient, highly-conserved functions among vertebrates may be stimulation of glycolysis to facilitate the energetic needs associated with various stressors.

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          Most cited references 60

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          Integration of biological networks and gene expression data using Cytoscape.

          Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.
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            Stattic: a small-molecule inhibitor of STAT3 activation and dimerization.

            Signal transducers and activators of transcription (STATs) are a family of latent cytoplasmic transcription factors that transmit signals from the cell membrane to the nucleus. One family member, STAT3, is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of cancer cell lines and human tumors. Screening of chemical libraries led to the identification of Stattic, a nonpeptidic small molecule shown to selectively inhibit the function of the STAT3 SH2 domain regardless of the STAT3 activation state in vitro. Stattic selectively inhibits activation, dimerization, and nuclear translocation of STAT3 and increases the apoptotic rate of STAT3-dependent breast cancer cell lines. We propose Stattic as a tool for the inhibition of STAT3 in cell lines or animal tumor models displaying constitutive STAT3 activation.
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              The Gene Ontology project in 2008

              The Gene Ontology (GO) project (http://www.geneontology.org/) provides a set of structured, controlled vocabularies for community use in annotating genes, gene products and sequences (also see http://www.sequenceontology.org/). The ontologies have been extended and refined for several biological areas, and improvements to the structure of the ontologies have been implemented. To improve the quantity and quality of gene product annotations available from its public repository, the GO Consortium has launched a focused effort to provide comprehensive and detailed annotation of orthologous genes across a number of ‘reference’ genomes, including human and several key model organisms. Software developments include two releases of the ontology-editing tool OBO-Edit, and improvements to the AmiGO browser interface.

                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                21 August 2018
                : 9
                1Department of Biological Sciences, North Carolina State University , Raleigh, NC, United States
                2Genomics Sciences Laboratory, North Carolina State University , Raleigh, NC, United States
                3Department of Applied Ecology, North Carolina State University , Raleigh, NC, United States
                4Hawaii Institute of Marine Biology, University of Hawaii , Kaneohe, HI, United States
                5Department of Human Nutrition, Food, and Animal Sciences, University of Hawaii at Mānoa , Honolulu, HI, United States
                6University of Hawaii Sea Grant College Program , Honolulu, HI, United States
                Author notes

                Edited by: Gen He, Ocean University of China, China

                Reviewed by: Satoshi Ogawa, Monash University Malaysia, Malaysia; Zhen-Yu Du, East China Normal University, China

                *Correspondence: Russell J. Borski russell_borski@ 123456ncsu.edu

                This article was submitted to Experimental Endocrinology, a section of the journal Frontiers in Endocrinology

                Copyright © 2018 Douros, Baltzegar, Reading, Seale, Lerner, Grau and Borski.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 75, Pages: 12, Words: 8424
                Funded by: National Science Foundation 10.13039/100000001
                Award ID: IOS-1457040
                Funded by: United States Agency for International Development 10.13039/100000200
                Award ID: EPP-A-00-06-000120-00
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: F32DK115031
                Original Research

                Endocrinology & Diabetes

                leptin, prolactin cell, hepatocytes, pituitary, rnaseq, fishes, phosphofructokinase-1


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