Endogenous rat CRP. Anti-PLOS ONE | www.plosone.orgDimethyl Fumarate Anti-Inflammatory and Metabolic EffectsFigure 2. Basal and insulin stimulated lipogenesis in SHR-CRP transgenic rats treated with fumaric acid esters (FAE) (N = 6) or placebo (N = 7). FAE treated SHR-CRP transgenic rats showed significantly greater levels of both basal (open bars) and insulin stimulated (solid bars) incorporation of radioactively labeled glucose into adipose tissue lipids when compared to untreated rats. *denotes significant difference compared to untreated controls, P,0.01. doi:10.1371/journal.pone.0101906.ginflammatory effects of FAE treatment appeared to be associated with significantly lower levels of oxidative stress as indicated by significantly lower levels of lipoperoxidation products in tissues. Amelioration of inflammation and oxidative stress in FAE treated rats was associated with less adiposity and ectopic fat accumulation, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. To search for molecular mechanisms associated with antiinflammatory, anti-oxidative, and metabolic effects of FAE, we analyzed gene expression profiles in livers isolated from treated rats versus untreated controls. We focussed on liver because this is the main tissue site of expression of the human CRP transgene. We observed that FAE treatment was associated with downregulated Jak-Stat signaling, Toll-like receptor signaling, chemokine signaling KEGG pathways and with upregulated terpenoid backbone biosynthesis, steroid biosynthesis, and glutathionemetabolism pathways, as well as deregulated mineral absorption pathway. The Jak-Stat signaling pathway is the main intracellular cascade initiated in response to binding of cytokines to their receptors. Jak phosphorylation of Stats is followed by their translocation to the nucleus where they can regulate the expression of specific target genes [8].Prazosin hydrochloride In addition, the JAK2/STAT3 pathway is involved in the early stage of 3T3-L1 adipocyte differention [9].α-Glucosidase Recently, Kang et al.PMID:24268253 [10] demonstrated in 3T3-L1 preadipocytes that DMF may function as an inhibitor of STAT3 and thus DMF is a negative regulator of adipogenic differentiation. These findings are in agreement with reduced adiposity and ectopic fat accumulation in rats treated with FAE. The Toll-like receptor signaling pathway regulates innate immune responses to various exogenous as well as endogenous stimuli by inducing the expression of many factors including pro-inflammatory cytokines, type I interferons, chemokines, and other molecules [11]. Chemokines play important rolesTable 2. Metabolic parameters in SHR-CRP transgenic rats treated with fumaric acid esters (FAE) or placebo.Trait Body weight (g) Relative liver weight (g/100 g BW) Relative epididymal fat weight (g/100 g BW) Plasma trigylcerides (mmol/L) Plasma NEFA (mmol/L) Plasma glucose (mmol/L) Plasma insulin (nmol/L) Plasma adiponectin (ng/mL) Liver triglycerides (nmol/g) Heart triglycerides (nmol/g) Muscle triglycerides (nmol/g) Basal lipolysis NEFA (mmol/g) Adrenaline stimulated lipolysis NEFA (mmol/g) Basal glycogenesis (nmol gl./g/2 h) Insulin stimulated glycogenesis (nmol gl./g/2 h)SHR-CRP placebo 40767 3.8960.12 0.9460.02 1.0860.13 0.3560.03 8.660.4 0.7360.11 8.260.5 25.764.1 1.6260.20 3.1060.17 3.2660.30 5.9160.90 70.8611.9 231.4616.SHR-CRP treated with FAE 405612 3.8860.12 0.7360.05** 1.4260.06* 0.5960.05** 8.460.3 0.7060.06 10.160.5* 14.261.2* 1.6460.13 2.4160.25*.
