title: Age-related autocrine diabetogenic effects of transgenic resistin in spontaneously hypertensive rats: gene expression profile analysis.
abstract: Increased circulating levels of resistin have been proposed as a possible link between obesity and insulin resistance; however, many of the potential metabolic effects of resistin remain to be investigated, including systemic versus local resistin action. We investigated potential autocrine effects of resistin on lipid and glucose metabolism in 2- and 16-mo-old transgenic spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin under control of the aP2 promoter. To search for possible molecular mechanisms, we compared gene expression profiles in adipose tissue in 6-wk-old transgenic SHR versus control rats, before development of insulin resistance, by digital transcriptional profiling using high-throughput sequencing. Both young and old transgenic rats showed moderate expression of the resistin transgene in adipose tissue but had serum resistin levels similar to control SHR and undetectable levels of transgenic resistin in the circulation. Young transgenic rats exhibited mild glucose intolerance. In contrast, older transgenic rats displayed marked glucose intolerance in association with near total resistance of adipose tissue to insulin-stimulated glucose incorporation into lipids (6 ± 2 vs. 77 ± 19 nmol glucose·g(-1)·2 h(-1), P < 0.00001). Ingenuity Pathway Analysis of differentially expressed genes revealed calcium signaling, Nuclear factor-erythroid 2-related factor-2 (NRF2)-mediated oxidative stress response, and actin cytoskeletal signaling canonical pathways as those most significantly affected. Analysis using DAVID software revealed oxidative phosphorylation, glutathione metabolism, pyruvate metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling as top Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These results suggest that with increasing age autocrine effects of resistin in fat tissue may predispose to diabetes in part by impairing insulin action in adipose tissue.
authors.affiliation: Institute of Physiology, Czech Academy of Sciences, 14220 Prague 4, Czech Republic. pravenec@biomed.cas.cz
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Václav
authors.initials: V
authors.lastname: Zídek
authors.forename: Vladimír
authors.initials: V
authors.lastname: Landa
authors.forename: Miroslava
authors.initials: M
authors.lastname: Simáková
authors.forename: Petr
authors.initials: P
authors.lastname: Mlejnek
authors.forename: Jan
authors.initials: J
authors.lastname: Silhavy
authors.forename: Martina
authors.initials: M
authors.lastname: Maxová
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdová
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Seda
authors.initials: S
authors.lastname: Eminaga
authors.forename: Joshua
authors.initials: J
authors.lastname: Gorham
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wang
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Kurtz
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D051381:Rats; D011918:Rats, Inbred SHR; D055647:Rats, Transgenic; D052243:Resistin / Q000235:genetics / Q000378:metabolism*
chemical_list: D052243:Resistin