Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model
EntityUAM. Departamento de Pediatría; Centro de Biología Molecular Severo Ochoa (CBM)
PublisherThe Company of Biologists Ltd.
10.1242/dmm.023515Disease Models & Mechanisms 9 (2016): 573-583
ISSN1754-8403 (print); 1754-8411 (online)
Funded byThis work was supported by the Ministerio de Ciencia e Innovación [BFU2011- 27492 and BFU2014-51836-C2-2-R to J.A.C.; and SAF2012-33283 to A.M.V.]; Fondo de Investigación Sanitaria [PI1302195 to J.A.]; Centro de Investigación Biomédica en Red de Fisiopatologı́a de Obesidad y Nutrición (CIBEROBN); and Centro de Investigación Biomédica en Red Diabetes y Enfermedades asociadas (CIBERDEM), Instituto de Salud Carlos III, and Fundación de Endocrinologı́a y Nutrición.
ProjectGobierno de España. BFU2011- 27492; Gobierno de España. BFU2014-51836-C2-2-R; Gobierno de España. SAF2012-33283
SubjectsApoptosis; Cell death; Diabetes; Hypothalamus; IRS2; Oxidative stress; Medicina
Rights© 2016. The Company of Biologists Ltd
Insulin receptor substrate-2-deficient (IRS2-/-) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2-/- mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2-/- mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2-/- mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, nondiabetic IRS2-/- mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus
Google Scholar:Baquedano, Eva - Burgos-Ramos, Emma - Canelles, Sandra - González-Rodrı́guez, Águeda - Chowen, Julie Ann - Argente Oliver, Jesús - Barrios, Vicente - Valverde, Ángela M. - Frago Fernández, Laura María
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