Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders

• DOI: 10.1016/j.cmet.2021.12.023
• Publication Date: 2022-02-01T15:40:36Z
• Authors: Sara Ramírez; Roberta Haddad-Tó...; Marija Radosevic; Miriam Toledo; Adriana Pané; Daniel Alcolea; Vicent Ribas; Maria Milà-Guasch; Macarena Pozo; Arnaud Obri; Elena Eyre; Alicia G. Gómez-V...; Iñigo Chivite; Tomas Van Eeckhout; Ioannis Zalachoras; Jordi Altirriba; Corinna Bauder; Mónica Imbernón; Gloria Garrabou; Carmen Garcia-Ruiz; Rubén Nogueiras; David Soto; Xavier Gasull; Carmen Sandi; Jens C. Brüning; Juan Fortea; Amanda Jiménez; José C. Fernández...; Marc Claret
• Keywords: proopiomelanocortin; cognition; metabolic disorder; obesity; Pro-Opiomelanocortin; Trastorns del metabolisme; animal cell; obesogenic diet; Recognition memory; Mice; cognitive defect; energy metabolism; animal; hypothalamus; long term potentiation; mental performance; cell population; pregnenolone; 2. Zero hunger; clinical article; diabetes; Hipotàlem; C57BL mouse; non insulin dependent diabetes mellitus; adult; metabolically unhealthy obese; Diabetes; Trastorns de la memòria; Mitochondria; 3. Good health; mitochondria; female; Disorders of metabolism; Pregnenolone; Memory disorders; neurosteroid; hormone synthesis; Cognitive function; nerve cell; recognition; neurosteroids; Neurosteroids; steroidogenic acute regulatory protein; insulin; Stard1; ketamine; animal experiment; Hypothalamus; recognition memory; xylazine; cerebrospinal fluid; Article; animal tissue; in vivo study; cholesterol side chain cleavage; male; Metabolic Diseases; autocrine signaling; Animals; Humans; controlled study; human; Obesity; insulin signaling; cognitive function; cerebrospinal fluid analysis; mouse; nonhuman; POMC neurons; gene deletion; animal model; Mice, Inbred C57BL; Diabetes Mellitus, Type 2; cerebrospinal fluid level; metabolism

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control memory disorders, we hypothesized that specific neurons this brain region at interface of metabolism cognition. Acute obesogenic diet administration mice impaired recognition due to defective production neurosteroid precursor pregnenolone hypothalamus. Genetic interference synthesis by Star deletion hypothalamic POMC, but not AgRP neurons, deteriorated independently metabolic disturbances. Our data suggest pregnenolone's effects on function were mediated via an autocrine mechanism POMC influencing hippocampal long-term potentiation. The relevance central cognition was also confirmed metabolically unhealthy patients obesity. reveal unsuspected role for neuron-derived neurosteroids These results provide basis a framework investigate new facets neuron biology implications disorders.