Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders.
Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders.
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DOI：
10.1016/j.cmet.2021.12.023
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发表时间：
2022-02-01
期刊：
影响因子：
29
通讯作者：
Claret M
中科院分区：
文献类型：
--
作者：
Ramírez S;Haddad-Tóvolli R;Radosevic M;Toledo M;Pané A;Alcolea D;Ribas V;Milà-Guasch M;Pozo M;Obri A;Eyre E;Gómez-Valadés AG;Chivite I;Van Eeckhout T;Zalachoras I;Altirriba J;Bauder C;Imbernón M;Garrabou G;Garcia-Ruiz C;Nogueiras R;Soto D;Gasull X;Sandi C;Brüning JC;Fortea J;Jiménez A;Fernández-Checa JC;Claret M
肥胖和2型糖尿病与认知功能障碍有关。由于下丘脑与能量平衡控制和记忆障碍有关，我们假设该脑区的特定神经元处于新陈代谢和认知的交界处。由于神经类固醇前体孕烯醇酮在下丘脑的产生缺陷，小鼠的急性肥胖饮食管理损害了识别记忆。下丘脑POMC中Star缺失对孕烯醇酮合成的遗传干扰，而不是AgRP神经元，独立于代谢障碍而恶化识别记忆。我们的数据表明，孕烯醇酮对认知功能的影响是通过POMC神经元上的自分泌机制来调节的，从而影响海马长时程增强。在代谢不健康的肥胖患者中，中枢孕烯醇酮与认知的相关性也得到了证实。我们的数据揭示了POMC神经元衍生神经类固醇在认知中的一个意想不到的作用。这些结果为研究POMC神经元生物学的新方面提供了框架的基础，并暗示了认知障碍。急性西方饮食损害记忆性能，这一点被孕烯醇酮孕烯醇酮合成干预POMC神经元导致认知功能障碍逆转POMC孕烯醇酮通过海马体机制调节记忆功能不健康肥胖者脑脊液中孕烯醇酮与认知评分Ramírez等人相关。研究表明，在代谢性疾病的背景下，下丘脑孕烯醇酮水平降低与认知能力下降有关。POMC神经元衍生的孕烯醇酮是认知的关键中介，但不是新陈代谢的关键介质，通过海马体机制发挥作用。这些结果确定了POMC神经元衍生的孕烯醇酮在记忆表现中的一个意想不到的作用。
Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone’s effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders. Acute western diet impairs memory performance, which is reversed by pregnenolone Pregnenolone synthesis interference in POMC neurons causes cognitive dysfunction POMC pregnenolone mediates memory function via hippocampal mechanisms Pregnenolone in the CSF of individuals with unhealthy obesity correlates with cognitive score Ramírez et al. show that reduced hypothalamic pregnenolone levels, in the context of metabolic diseases, are associated with cognitive deterioration. POMC neuron-derived pregnenolone is a key mediator of cognition, but not metabolism, acting via hippocampal mechanisms. These results identify an unsuspected role for POMC neuron-derived pregnenolone in memory performance.
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影响因子：
20.3
作者：
Jais A;Brüning JC
通讯作者：
Brüning JC
影响因子：
8.1
作者：
Lam BYH;Cimino I;Polex-Wolf J;Nicole Kohnke S;Rimmington D;Iyemere V;Heeley N;Cossetti C;Schulte R;Saraiva LR;Logan DW;Blouet C;O'Rahilly S;Coll AP;Yeo GSH
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影响因子：
8.8
作者：
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Spetter MS
影响因子：
64.5
作者：
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通讯作者：
MAYFORD, M
影响因子：
29
作者：
Koenner, A. Christine;Janoschek, Ruth;Bruening, Jens C.
通讯作者：
Bruening, Jens C.