title: Metabolic alterations and increased liver mTOR expression precede the development of autoimmune disease in a murine model of lupus erythematosus.
abstract: Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Vilà
authors.forename: Núria
authors.initials: N
authors.lastname: Roglans
authors.forename: Miguel
authors.initials: M
authors.lastname: Baena
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.forename: Marta
authors.initials: M
authors.lastname: Alegret
authors.forename: Manuel
authors.initials: M
authors.lastname: Merlos
authors.forename: Juan C
authors.initials: JC
authors.lastname: Laguna
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005247:Feeding Behavior; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000097:blood; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000097:blood; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D024821:Metabolic Syndrome / Q000097:blood / Q000150:complications / Q000378:metabolism; D051379:Mice; D011507:Proteinuria / Q000097:blood / Q000150:complications / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D015415:Biomarkers; D016207:Cytokines; D007328:Insulin; D020738:Leptin; D014280:Triglycerides; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases