ESPE Abstracts (2014) 82 P-D-1-2-69

Activation of Insulin/IGF1 Signaling Could Increase Hypothalamic Lipid Anabolism in Non-Diabetic IRS2-Deficient Mice

Vicente Barriosa,b, Eva Baquedanoa,b, Sandra Canellesa,b, Águeda González-Rodríguezc,d, Emma Burgos-Ramose, Julie A Chowena,b, Laura M Fragoa,b, Ángela M Valverdec,d & Jesús Argentea,b

aEndocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; bCentro de Investigación Biomédica en Red de Fisiopatología Obesidad y Nutrición, Madrid, Spain; cInstituto de Investigaciones Biomédicas Alberto Sols, CSIC/Universidad Autónoma de Madrid, Madrid, Spain; dCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain; eMolecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

Background: Insulin/IGF1 signaling plays a critical role in central glucose bioavailability and lipid metabolism. An increase in glucose disposal can generate reducing agents through the pentose-phosphate pathway necessary for the synthesis of free fatty acids (FFA). Disturbances in lipid synthesis are related to the appearance of insulin resistance and diabetes. The insulin receptor substrate 2 (IRS2) deficient mice (IRS2−/−) is an excellent model to study the development of diabetes as a high proportion of them present an abrupt increase in glycemia, showing similarities with type 1 diabetes. However, the molecular mechanisms involved in the onset of diabetes in IRS2−/−mice remain to be elucidated.

Objective and hypotheses: We hypothesized that alterations in insulin/IGF1 signaling could be related to the incidence of diabetes in IRS2−/−mice. Thus, we analyzed the changes in hypothalamic signaling and its relationship with hypothalamic lipid synthesis in this model.

Method: We studied 18 mice including controls (C), non-diabetic IRS2−/− (ND) and diabetic IRS2−/− (D) mice. We analyzed serum concentrations of FFA by a colorimetric method, insulin and IGF1 by enzymoimmunoassay, insulin/IGF1 signaling by multiplexed bead immunoassay and immunoprecipitation/western blot and enzymes involved in glucose oxidation and lipid anabolism by western blot.

Results: Serum insulin was increased in both D and ND, with higher levels in ND, whereas IGF1 and FFA concentrations were augmented only in ND mice. Hypothalamic levels of glucose transporter 2, IGF1 receptor, IRS1 and association of p85 subunit of PI3 kinase to IRS1 were augmented only in ND mice. Among the studied enzymes, acetyl-CoA carboxylase was inhibited in D mice, whereas levels of malic enzyme and fatty acid synthase were increased in the hypothalamus of ND mice.

Conclusion: Increased hypothalamic insulin/IGF1 signaling might be a triggering factor for the occurrence of diabetes in IRS2−/−mice.