Crosstalk of hypothalamic chemerin, histamine, and AMPK in diet-and olanzapine-induced obesity in rats

Samy, Doaa M.; Mostafa, Dalia K.; Abdelmonsif, Doaa A.; Ismail, Cherine A.; Hassaan, Passainte S.

doi:10.1016/j.lfs.2021.119897

Cited by 9 publications

(7 citation statements)

References 40 publications

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“…The active components naringenin, baicalein, and quercetin mentioned above can improve glucolipid metabolism by activating or upregulating the AMPK pathway. A previous study has shown that olanzapine causes obesity and elevated blood glucose by inhibiting the AMPK signaling pathway [53], and targeting AMPKcontaining complexes can prevent metabolic disorders such as olanzapine-induced diabetes [41]. Therefore, ECD exerts its therapeutic effect mainly through the AMPK pathway.Thirteen core targets were selected in the visualization network based on the intersection targets of the active components of ECD, clozapine and olanzapine, and metabolic syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…A study has shown that the ADRA1A gene is associated with weight gain in schizophrenia patients receiving SGAs [54]. Another study also demonstrated that the number of Arg347 alleles for ADRA1Awas significantly associated with an increased risk of metabolic abnormalities [53]. AHR acts as a transcription factor that binds to ligands to upregulate drug metabolizing enzymes and participates in processes such as stem cell differentiation and immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

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Erchen Decoction regulates AMPK pathway in the treatment of metabolic syndrome induced by second-generation antipsychotics based on network pharmacology and molecular docking strategy

Luo

et al. 2023

Preprint

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Erchen Decoction(ECD) has been clinically verified to be effective for treating metabolic syndrome(MetS) induced by second-generation antipsychotics(SGAs). Network pharmacology analysis results exhibited that 129 active components and 221 potential targets of ECD, 1027 targets related to MetS, and 361 targets of clozapine and olanzapine were gained after screening. Then, 79 intersection targets of ECD and MetS were obtained by Venn analysis to construct a PPI network. However, it could not explain the potential target and mechanism of ECD to improve the metabolic disorder caused by SGAs. GO function and KEGG pathway analyses were performed on 23 common targets of ECD, clozapine, olanzapine, and metabolic syndrome, and visualization networks were constructed. The results revealed the potential signaling pathway of ECD for treating drug-induced MetS, especially the AMPK signaling pathway. The visualization network reflects that ADRA1A, AHR, NR3C1, and SLC6A4 may be the core targets. Ultimately, molecular docking results displayed that active components of ECD naringenin, baicalein, and quercetin had a good binding activity with NR3C1 and SLC6A4 targets.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Erchen Decoction regulates AMPK pathway in the treatment of metabolic syndrome induced by second-generation antipsychotics based on network pharmacology and molecular docking strategy

Luo

et al. 2023

Preprint

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“…2,[75][76][77] Tanycytes monitor and respond to the fluctuations of circulating FFAs and induce the production and secretion of intermediate metabolites, hormones, and cytokines. 1,19,20 These factors, such as DPPIV, FGF1, HGF, and VEGF, are transcriptionally regulated by HIF-1a 78 and are involved in energy expenditure, insulin signal transmission, and vascular homeostasis. [79][80][81] In addition, tanycytes release ATP and lactate via monocarboxylate transporters (MCTs), purinergic receptors, and connexin 43 (CX43) channels.…”

Section: Discussionmentioning

confidence: 99%

Saturated fatty acids stimulate cytokine production in tanycytes via the PP2Ac-dependent signaling pathway

Liu,

Wang,

Zhao

et al. 2023

J Cereb Blood Flow Metab

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The hypothalamic tanycytes are crucial for free fatty acids (FFAs) detection, storage, and transport within the central nervous system. They have been shown to effectively respond to fluctuations in circulating FFAs, thereby regulating energy homeostasis. However, the precise molecular mechanisms by which tanycytes modulate lipid utilization remain unclear. Here, we report that the catalytic subunit of protein phosphatase 2 A (PP2Ac), a serine/threonine phosphatase, is expressed in tanycytes and its accumulation and activation occur in response to high-fat diet consumption. In vitro, tanycytic PP2Ac responds to palmitic acid (PA) exposure and accumulates and is activated at an early stage in an AMPK-dependent manner. Furthermore, activated PP2Ac boosts hypoxia-inducible factor-1α (HIF-1α) accumulation, resulting in upregulation of an array of cytokines. Pretreatment with a PP2Ac inhibitor, LB100, prevented the PA-induced elevation of vascular endothelial growth factor (VEGF), fibroblast growth factor 1 (FGF1), hepatocyte growth factor (HGF), and dipeptidyl peptidase IV (DPPIV or CD26). Our results disclose a mechanism of lipid metabolism in tanycytes that involves the activation of PP2Ac and highlight the physiological significance of PP2Ac in hypothalamic tanycytes in response to overnutrition and efficacious treatment of obesity.

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“…The inhibition of H1R is considered to be involved in the high risk of weight gain of several atypical antipsychotics via activation of AMPK signalling [ 65 ]. Indeed, both clozapine and olanzapine (high-affinity H1R antagonists [ 65 , 66 ]) induced weight gain was compensated by H1R agonist via suppression of AMPK signalling [ 68 , 69 , 70 ], whereas lurasidone (low binding affinity to H1R) suppresses AMPK signalling in the hypothalamus [ 34 ]. Although we could not identify the expression of histamine H1R in the astroglial plasma membrane, therefore, the suppressive effects of Brex on astroglial AMPK signalling cannot deny being over-evaluated due to the lack of expression of H1R in astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Brexpiprazole Reduces 5-HT7 Receptor Function on Astroglial Transmission Systems

Fukuyama

Motomura

Okada

2022

IJMS

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Several atypical antipsychotics exert mood-stabilising effects via the modulation of various monoamine receptors and intracellular signallings. Recent pharmacodynamic studies suggested that tripartite synaptic transmission can contribute to the pathophysiology of schizophrenia and mood disorders, their associated cognitive impairment, and several adverse reactions to atypical antipsychotics. Therefore, to explore the mechanisms underlying the antidepressive mood-stabilising and antipsychotic effects of brexpiprazole (Brex), we determined the effects of subchronic administration of therapeutically relevant concentrations/doses of Brex on the protein expression of 5-HT receptors, connexin43, cAMP levels, and intracellular signalling in cultured astrocytes and rat hypothalamus using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. Subchronic administration of a therapeutically relevant concentration of Brex (300 nM) downregulated both 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors, in addition to phosphorylated Erk (pErk), without affecting phosphorylated Akt in the astroglial plasma membrane. Subchronic administration of 300 nM Brex decreased and increased phosphorylated AMPK and connexin43, respectively, in the astroglial cytosol fraction. A therapeutically relevant concentration of Brex acutely decreased the astroglial cAMP level, whereas, under the inhibition of 5-HT1AR, Brex did not affect astroglial cAMP levels. However, the 5-HT7R-agonist-induced increased astroglial cAMP level was inhibited by Brex. In contrast to the in vitro study, systemic subchronic administration of effective doses of Brex (3 and 10 mg/kg/day for 14 days) increased the cAMP level but did not affect phosphorylated AMPK in the rat hypothalamus. These results suggest several complicated pharmacological features of Brex. Partial 5-HT1AR agonistic action predominates in the low range of therapeutically relevant concentrations of Brex, whereas in the high range, 5-HT7R inverse agonist-like action is overlapped on the 5-HT1A agonistic action. These unique suppressive effects of Brex on 5-HT7R play important roles in the clinical features of Brex regarding its antidepressive mood-stabilising actions.

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Crosstalk of hypothalamic chemerin, histamine, and AMPK in diet-and olanzapine-induced obesity in rats

Cited by 9 publications

References 40 publications

Erchen Decoction regulates AMPK pathway in the treatment of metabolic syndrome induced by second-generation antipsychotics based on network pharmacology and molecular docking strategy

Erchen Decoction regulates AMPK pathway in the treatment of metabolic syndrome induced by second-generation antipsychotics based on network pharmacology and molecular docking strategy

Saturated fatty acids stimulate cytokine production in tanycytes via the PP2Ac-dependent signaling pathway

Brexpiprazole Reduces 5-HT7 Receptor Function on Astroglial Transmission Systems

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