Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms

Salvatore Fusco (), Matteo Spinelli, Sara Cocco, Cristian Ripoli, Alessia Mastrodonato, Francesca Natale, Marco Rinaudo, Giulia Livrizzi and Claudio Grassi ()
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Salvatore Fusco: Fondazione Policlinico Universitario A. Gemelli IRCCS
Matteo Spinelli: Institute of Human Physiology, Università Cattolica del Sacro Cuore
Sara Cocco: Institute of Human Physiology, Università Cattolica del Sacro Cuore
Cristian Ripoli: Fondazione Policlinico Universitario A. Gemelli IRCCS
Alessia Mastrodonato: Institute of Human Physiology, Università Cattolica del Sacro Cuore
Francesca Natale: Institute of Human Physiology, Università Cattolica del Sacro Cuore
Marco Rinaudo: Institute of Human Physiology, Università Cattolica del Sacro Cuore
Giulia Livrizzi: Institute of Human Physiology, Università Cattolica del Sacro Cuore
Claudio Grassi: Fondazione Policlinico Universitario A. Gemelli IRCCS

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants’ brain health via gametic mechanisms susceptible to lifestyle.

Date: 2019
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DOI: 10.1038/s41467-019-12793-3

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