ESPE Abstracts (2016) 86 P-P1-444

Neonatal Overfeeding Alters Hepatic Insulin Sensitivity During Lactation and Leads to Long-term Insulin Resistance and Fatty Liver in Mice: Key Role of Mogat1

Marta Ramon-Krauela, Thais Pentinata, Judith Cebriàa, Maria Vilàa, Ricky Pérez-Wienesea, Susana Kalkob, Uwe Tietgec, Torsten Ploschc, Ruben Diaza & Josep Jimenez-Chillarona

aHospital Sant Joan de Déu, Barcelona, Spain; bHospital Clínic-IDIBAPS, Barcelona, Spain; cGroningen University, Groningen, The Netherlands

Background: Excessive energy intake and rapid weight gain early in life are associated with obesity, type 2 diabetes, hepatic steatosis and other features of the metabolic syndrome. The monoacylglycerol acyltransferase (MGAT) is an enzyme involved in an alternative pathway for triglyceride (TAG) synthesis and storage. It has been recently proposed to have potential implications in the pathogenesis of hepatic insulin resistance (IR).

Objective: To understand the mechanisms that contribute to i) the development of early IR and ii) the long-term programming of metabolic disease in a mouse model of childhood obesity.

Method: Here we used a mouse model of model of neonatal overnutrition (ON) and accelerated growth that develops obesity, IR, glucose intolerance and hepatic steatosis with aging. To gain insight about the mechanisms that lead to IR and steatosis, we performed gene expression profiling (Affymetrix) in livers from Control and ON Mice.

Results: Gene expression profiling uncovered that the Ontology with highest significance was the Lipid Biosynthetic Pathway. Strikingly, Mogat1 ranked with highest significance in this list. We confirmed Mogat1 up-regulation in liver samples from 4–6 month old ON mice. Importantly, Mogat1 was already elevated in livers of lactating 15-day-old ON mice. Furthermore we found no changes on other pathways that could contribute to lipid synthesis and storage in the liver (synthesis de novo, oxidation or VLDL transport). Mogat1 catalyzes the conversion of Monoacylglycerol to DAG, which activates PKCε that in turn contributes to IR. In agreement, we found that Mogat1 over expression resulted in DAG hepatic accumulation and higher PKCε activation in ON mice.

Conclusion: Mogat1 might be a key player in the development of IR and hepatic steatosis. Therefore, targeting MGAT activity in the liver might be a novel potential strategy to improve hepatic insulin sensitivity.