c-Jun N-terminal Kinase 1 ablation protects against metabolic-induced hippocampal cognitive impairments

Busquets, Oriol; Ettcheto, Miren; Eritja, Àuria; Espinosa-Jiménez, Triana; Verdaguer, Ester; Olloquequi, Jordi; Beas‐Zárate, Carlos; Castro-Torres, Rubén Darío; Casadesús, Gemma; Auladell, Carme; Bulló, Mònica; Folch, Jaume; Camins, Antoni

doi:10.1007/s00109-019-01856-z

Cited by 10 publications

(15 citation statements)

References 49 publications

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“…Chang et al reported that these mice showed growing degeneration of axonal and dendritic processes (visible in 8-month-old animals), jointly with progressive learning impairment and motor defects [41,45,46]. Our research group observed no behavioral alterations when testing 9-month-old Jnk1 -/animals using the novel object recognition test [34].…”

Section: Jnks Have Specific Functions Jnk1 Is Essential For Proper Cmentioning

confidence: 44%

“…Finally, mice knockout of Jnk1, or mice treated with an engineered retrovirus that exclusively inhibited JNK1 in adult-born granule cells, displayed an increase in immature neurons in the dentate gyrus of the hippocampus, an effect that has been correlated with a reduction in depressive-like behaviors [33]. Our results provide evidence that a lack of Jnk1 in mice offers neuroprotection against excitability and the cognitive impairments induced with high fat diets (HFD) [34].…”

Section: The Jnks Signaling Cascadementioning

confidence: 69%

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Involvement of JNK1 in Neuronal Polarization During Brain Development

Castro-Torres

Busquets

Parcerisas

et al. 2020

Cells

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The c-Jun N-terminal Kinases (JNKs) are a group of regulatory elements responsible for the control of a wide array of functions within the cell. In the central nervous system (CNS), JNKs are involved in neuronal polarization, starting from the cell division of neural stem cells and ending with their final positioning when migrating and maturing. This review will focus mostly on isoform JNK1, the foremost contributor of total JNK activity in the CNS. Throughout the text, research from multiple groups will be summarized and discussed in order to describe the involvement of the JNKs in the different steps of neuronal polarization. The data presented support the idea that isoform JNK1 is highly relevant to the regulation of many of the processes that occur in neuronal development in the CNS.

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Section: Jnks Have Specific Functions Jnk1 Is Essential For Proper Cmentioning

confidence: 44%

Section: The Jnks Signaling Cascadementioning

confidence: 69%

Involvement of JNK1 in Neuronal Polarization During Brain Development

Castro-Torres

Busquets

Parcerisas

et al. 2020

Cells

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“…In fact, other teams have reported that the downregulation of JNK1 leads to a heightened control of metabolic activity both in the periphery and central tissues, coupled with a resistance of the animals to the negative effects of fat-enriched diets (Sabio et al 2009 , 2010 ; Becattini et al 2016 ; Mohammad et al 2018 ). In our own report, we demonstrated for the first time the beneficial effects of this loss of function of JNK1 in multiple biomarkers of cognitive function in the hippocampus of mice (Busquets et al 2019b ). As for JNK3, there are not many published reports on its role in metabolism.…”

Section: Introductionmentioning

confidence: 86%

“…Male 9 months-of-age wild-type C57BL6/J (WT), Mapk8 −/− (JNK1; Jnk1 −/− ) and Mapk10 −/− (JNK3; Jnk3 −/− ) mice were used in this study (Dong et al 1998 ). They were fed either control (CT) or HFD (45% fat content) ad libitum (Busquets et al 2019b , c ). Diet specifications were as described in Busquets et al ( 2017 ).…”

Section: Methodsmentioning

confidence: 99%

JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function

Busquets

Espinosa-Jiménez

Ettcheto

et al. 2022

Mol Med

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Background and aim The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. Methods Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP‑ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. Results Our studies demonstrated that HFD in Jnk3−/− lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. Conclusions Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD.

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“…Cultured tanycytes respond to inflammatory stimulation with bacterial lipopolysaccharides by increasing protein levels of phosphorylated JNK1 [79], suggesting that JNK1 may play a role in the cellular stress response in different brain cell types. Moreover, whole-body Jnk1-knockout mice are protected against HFD-induced hippocampal cognitive impairment and reduced astrocyte and microglial reactivity [80]. Many other non-metabolic actions have been found for JNK isoforms in the brain, including hippocampal neurogenesis [81], depression and anxiety [82].…”

Section: Hypothalamic Jnks In Non-neuronal Cellsmentioning

confidence: 99%

Brain JNK and metabolic disease

Nogueiras

Sabio

2020

Diabetologia

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Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain. Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic-pituitary-thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology. Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance.

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c-Jun N-terminal Kinase 1 ablation protects against metabolic-induced hippocampal cognitive impairments

Cited by 10 publications

References 49 publications

Involvement of JNK1 in Neuronal Polarization During Brain Development

Involvement of JNK1 in Neuronal Polarization During Brain Development

JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function

Brain JNK and metabolic disease

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