Background Chronic alcoholic liver disease is associated with hepatic insulin resistance, dysregulated lipid metabolism with increased toxic lipid (ceramide) accumulation, lipid peroxidation, and oxidative and endoplasmic reticulum (ER) stress. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that can restore hepatic insulin responsiveness in both alcohol and non-alcohol-related steatohepatitis. Herein, we demonstrate that treatment with a PPAR-δ agonist enhances insulin signaling and reduces the severities of ER stress and ceramide accumulation in an experimental model of ethanol-induced steatohepatitis. Methods Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle or PPAR-δ agonist twice weekly by i.p. injection. Results Ethanol-fed rats developed steatohepatitis with inhibition of signaling through the insulin and insulin-like growth factor-1 receptors, and Akt activated pathways. Despite continued ethanol exposure, PPAR-δ agonist co-treatments increased Akt activation, reduced multiple molecular indices of ER stress and steatohepatitis. Conclusions These results suggest that PPAR-δ agonist rescue of chronic alcoholic liver disease is mediated by enhancement of insulin signaling through Akt/metabolic pathways that reduce lipotoxicity and ER stress.

Background-Fetal alcohol spectrum disorder (FASD) is associated with deficits in cerebellar function that can persist through adolescence. Previous studies demonstrated striking inhibition of insulin and insulin-like growth factor (IGF) signaling in ethanol-exposed cerebella.

Background. Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are associated with impaired insulin and IGF signaling, which is needed for neuronal growth, survival, and plasticity. We characterized effects of the L-165,041 PPAR-δ agonist insulin sensitizer on cerebellar structure and function in relation to insulin/IGF and neurotrophin signaling in an FASD model. Methods. On postnatal days (P) 2, 4, 6, and 8, rat pups were administered (i.p.) 2 g/kg of ethanol or saline; and on P5, P7, P9, and P11, they were treated with saline or L-165,041. Rotarod tests assessed motor function. Cerebella were studied biochemically. Results. Ethanol-impaired motor function and signaling through the insulin receptor and Akt were abrogated by PPAR-δ agonist treatments, whereas neurotrophin expression was unaffected. Conclusions: PPAR-δ agonists may help normalize cerebellar function in FASD by supporting insulin signaling through cell survival pathways, but additional approaches are needed to restore neurotrophin expression for neuronal plasticity.