Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis

Xi, Pengjiao; Du, Jianying; Liang, Huimin; Han, Jinming; Wu, Zhaoxia; Wang, Haomin; He, Lu; Wang, Qiming; Ge, Haize; Li, Yongmei; Tian, Derun

doi:10.1159/000489746

Cited by 11 publications

(5 citation statements)

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“…Here, we reveal the likely involvement of another kinase cascade, well studied in the contexts of cell growth, metabolism, cancer and polarity ( Shackelford and Shaw, 2009 ) but hitherto unstudied in the context of learning and memory. That this pathway should have a role in learning is perhaps not shocking given the ubiquity of its previously demonstrated roles in 1) axonal development Barnes et al, 2007 ; Shelly et al, 2007 ; 2) synaptic remodeling during aging Samuel et al, 2014 ; 3) regulation of presynaptic neurotransmission Kwon et al, 2016 ; and perhaps most tellingly 4) regulation of glucose metabolism, feeding and obesity through actions in multiple tissues including hypothalamus ( Xi et al, 2018 ; Fei-Wang et al, 2012 ; Claret et al, 2011 ). Given the involvement of hypothalamus in coding of taste palatability, and the connectivity between hypothalamus and gustatory cortex ( Li et al, 2013 ), it is tempting to speculate that the role of Stk11 signaling pathways in feeding may be functionally related to its role in gustatory learning.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

Levitan

Liu

Yang

et al. 2020

eLife

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Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.

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Section: Discussionmentioning

confidence: 99%

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

Levitan

Liu

Yang

et al. 2020

eLife

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“…That this pathway should have a role in learning is perhaps not shocking given its ubiquity and its previously demonstrated roles in axonal specification and dynamics during development (Barnes et al, 2007; Shelly et al, 2007), synaptic remodeling during aging (Samuel et al, 2014), and its ability to regulate axonal function and presynaptic neurotransmission (Kwon et al 2016). In addition, Stk11 and downstream AMP-related kinases have been implicated in regulation of glucose metabolism, feeding and obesity through actions in multiple tissues including hypothalamus (Xi et al, 2018; Fei-Wang et al, 2012; Claret et al, 2011). Given the ability of hypothalamus to encode taste palatability and its connectivity with gustatory cortex (Li et al, 2013), it is tempting to speculate that the role of Stk11 signaling pathways in feeding may be functionally related to its role in gustatory learning.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

Levitan

Liu

Lin

et al. 2019

Preprint

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27Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral 28 amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms 29 are poorly understood, however. We used RNAseq from BLApn to identify learning-30 related changes in Stk11, a kinase with well-studied roles in growth, metabolism and 31 development, but not previously implicated in learning. Deletion of Stk11 restricted to 32 BLApn completely blocks memory when occurring prior to training, but not following it, 33 despite altering neither BLApn-dependent encoding of taste palatability in gustatory 34 cortex, nor transcriptional activation of BLApn during training. Deletion of Stk11 in BLApn 35 also increases their intrinsic excitability. Conversely, BLApn activated by CTA to express 36 the immediate early gene Fos had reduced excitability. BLApn knockout of Fos also 37 increased excitability and impaired learning. These data suggest that Stk11 and Fos 38 expression play key roles in CTA long-term memory formation, perhaps by modulating 39 the intrinsic excitability of BLApn. (149 words) 40 41 103 104 Results 105CTA long-term memory requires BLA transcription 106 In order to determine whether CTA requires new RNA transcription within the BLA, we 107 inhibited transcription by injecting Actinomycin-D (1 µl, 50 ng, bilaterally, Figure 1), a 108 widely used RNA polymerase 2 inhibitor (Alberini, 2009), into the BLA 20 min prior to CTA 109 training, and tested memory 48 hours later. As a control, a separate group of mice 110 received vehicle injection (1 µl of PBS, bilaterally). CTA training consisted of 30 min of 111 access to 0.5% saccharin followed by an intraperitoneal injection of 0.15M LiCl, 2% body 112 weight; (Figure 1-figure supplement 1). A two-way ANOVA comparing vehicle and 113 actinomycin-D injected mice before and after training revealed significant training and 114 129 analysis revealed significant reduction in the consumption of saccharin (CTA vs. Test) for 130 the vehicle group, indicating impairment of learning for the actinomycin-D treated group 131 compared to control mice. As a convergent measure, we also assessed the strength of 132 CTA memory by calculating the relative consumption of saccharin during the test day to 133 that consumed on the training day (Neseliler et al., 2011). The differences between the 134 groups were large (23% in the vehicle group vs. 80 % for the actinomycin D group) and 135 significant. Meanwhile, actinomycin-treated mice were neither impaired in their ability to 136 detect the palatability of saccharin, nor in their drinking behavior-consumption of 137 saccharin during CTA training was similar for the two groups, as was consumption of 138 water 8 hours after the test ( Figure 1E), suggesting that these nonspecific effects cannot 139 account for the memory impairment. Thus, BLA transcription is essential for CTA memory 140 formation. These results extend prior work showing the importance of BLA protein 141 synthesis for CTA memory (Josselyn et al., 2...

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“…It has been confirmed that the activation of AMPK/SIRT1/LXRα and AMPK/STAT1/STING signaling pathways in macrophages can up-regulate the expressions of ABCA1, ABCG1, and SR-B1, promote intracellular cholesterol outflow, reduce lipid accumulation, and ultimately prevent the occurrence of atherosclerosis ( Lin et al, 2015 ; Cai D. et al, 2021 ). Interestingly, LKB1 is the main upstream kinase of AMPK, so it may participate in cellular lipid metabolism by activating AMPK ( Xi et al, 2018 ). Nevertheless, more evidence is needed to evaluate that macrophage LKB1 participates in intracellular lipid outflow and negatively regulates atherosclerotic plaque formation by activating AMPK/SIRT1/LXR α and AMPK/STAT1/STING signaling pathways ( Figure1 ).…”

Section: Introductionmentioning

confidence: 99%

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

et al. 2021

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Liver kinase B1 (LKB1) is known to shape the regulation of macrophage function by participating in multiple processes including cell metabolism, growth, and polarization. However, whether LKB1 also affects the functional plasticity of macrophages in atherosclerosis has not attracted much attention. Abnormal macrophage function is a pathophysiological hallmark of atherosclerosis, characterized by the formation of foam cells and the maintenance of vascular inflammation. Mounting evidence supports that LKB1 plays a vital role in the regulation of macrophage function in atherosclerosis, including affecting lipid metabolism reprogramming, inflammation, endoplasmic reticulum stress, and autophagy in macrophages. Thus, decreased expression of LKB1 in atherosclerosis aggravates vascular injury by inducing excessive lipid deposition in macrophages and the formation of foam cells. To systematically understand the role and potential mechanism of LKB1 in regulating macrophage functions in atherosclerosis, this review summarizes the relevant data in this regard, hoping to provide new ideas for the prevention and treatment of atherosclerosis.

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Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis

Cited by 11 publications

References 63 publications

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

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