LKB1 alleviates high glucose‑ and high fat‑induced inflammation and the expression of GnRH and sexual precocity‑related genes, in mouse hypothalamic cells by activating the AMPK/FOXO1 signaling pathway

Liu, Hui; Guan, Limei; Zhou, Qing; Huang, Hailong; Xu, Liangpu

doi:10.3892/mmr.2022.12659

Cited by 6 publications

(5 citation statements)

References 25 publications

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“…Activation of brain AMPK in immature female rats substantially deferred puberty [32]. In addition, the expression of p-FOXO1 was markedly downregulated following LKBI overexpression [33]. These ndings demonstrate that the onset of puberty is regulated by phosphorylated proteins.…”

Section: Discussionmentioning

confidence: 68%

Integrative proteomic and phosphoproteomic analysis in the female goat hypothalamus to study the onset of puberty

Zhang

et al. 2023

Preprint

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Background: Puberty marks the end of childhood and achieve sexual maturation and fertility. The role of hypothalamic proteins in regulating puberty onset is unclear. We performed a comprehensive differential proteomics and phosphoproteomics analysis in prepubertal and pubertal goatsto determine the roles of hypothalamic proteins and phosphoproteins during the onset of puberty. Results: We used peptide and posttranslational modifications peptide quantification and statistical analyses, and identified 67 differentially expressed proteins from 5,057 proteins and 576 differentially expressed phosphopeptides from 1574 phosphorylated proteins. Combined proteomic and phosphoproteomics, 759 correlated proteins were identified, of which 5 were differentially expressed only at the protein level, and 201 were only differentially expressed at the phosphoprotein level. Pathway enrichment analyses revealed that the majority of correlated proteins were associated with glycolysis/gluconeogenesis, Fc gamma R-mediated phagocytosis, focal adhesion, GABAergic synapse, and Rap1 signaling pathway. These pathways are related to cell proliferation, neurocyte migration, and promoting the release of gonadotropin-releasing hormone in the hypothalamus. CTNNB1 occupied important locations in the protein-protein interaction network and is involved in focal adhesion. Conclusion: The results demonstrate that the proteins differentially expression only at the protein level or only differentially expressed at the phosphoprotein level and their related signalling pathways are crucial in regulating puberty in goats. These differentially expressed proteins and phosphorylated proteins may constitute the proteomic backgrounds between the two different stages.

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Section: Discussionmentioning

confidence: 68%

Integrative proteomic and phosphoproteomic analysis in the female goat hypothalamus to study the onset of puberty

Zhang

et al. 2023

Preprint

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Section: Discussionmentioning

confidence: 99%

“…One of the interesting interacting partners of Hippo pathway with higher expression in the brain of vgll3*EE individuals was a gene encoding a paralog of Forkhead box protein O1 (foxo1c). In mouse, Foxo1 encodes a transcription factor that participates in regulation of the onset of puberty by affecting the release of GnRH in the hypothalamus (Liu et al 2022), however, such a role has to our knowledge not yet been reported in fish species. Two other interacting partners of the Hippo pathway with potential roles in central regulation of the onset of puberty were kdm5b (jarid1b), which has been shown to be modified epigenetically prior to puberty in the rat brain (Lomniczi et al 2015), and mc4ra, another paralog of Melanocortin 4 receptor (Mc4r) with conserved role in stimulating the central initiation of the puberty (see above).…”

Section: Distinct Interacting Partners Of the Hippo Pathway May Parti...mentioning

confidence: 99%

A salmon fish model reveals genetic signals in brain associated with early maturation

Pashay Ahi,

Verta,

Kurko

et al. 2024

Preprint

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Emerging evidence suggests a link between adiposity and early maturation, potentially impacting hormonal signaling pathways governing puberty timing. Fish models have proven invaluable in studying these processes, given their genetic and physiological similarities to humans. In Atlantic salmon, in addition to being linked with environmental shifts and lipid reserves, the timing of sexual maturation also has a strong genetic basis. A gene encoding a co-factor of Hippo pathway,vgll3, is a major determinant of maturation timing in salmon, and the same gene was found to be associated with maturation timing in humans. Intriguingly,vgll3also inhibits adipogenesis in mice. Recent studies in salmon revealed correlations betweenvgll3genotypes and reproductive axis gene expression, possibly modulated through the Hippo signaling pathway. The Hippo pathway is known for its role in sexual maturation and adipogenesis and responds to environmental cues such as dietary fat and temperature. In this study, we employed a custom gene expression panel in male Atlantic salmon with differentvgll3 early(E) andlate(L) maturation genotypes testing components of this pathway in brain at immature and mature stages. We found increased brain expression of a major Hippo pathway kinase (lats1b) and melanocortin receptor encoding genes (mc4raandmc4rc) in individuals withearly(E) maturation genotypes ofvgll3before maturation development of testes. Moreover, we found components and interacting partners of Hippo pathway showing differential expression in brain of individuals withearly(E) andlate(L)vgll3genotypes prior to maturation. This could indicate extensive and complex roles of Hippo pathway in brain processes required for preparing for [the onset of] maturation at upstream of reproductive axis. This study elucidates molecular mechanisms underpinning early maturation, and for the first time in fish, offering insights into detecting it at molecular level in brain before visible gonadal changes occur.

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“…The cAMP signaling pathway can regulate the levels of testosterone synthesis–related proteins 60 . Kinase B1 alleviates the expression of GnRH and sexual precocity–related genes by activating the FoxO1 signaling (FoxO family) pathway 61 . Figure 6A shows that the active ingredients act principally on targets PIK3CA, HSD11B1, CYP19A1, AR, PTGS2, CDK2, NR3C1, and MMP2, affecting primary pathways such as pathways in cancer, neuroactive ligand–receptor interaction, cAMP, endocrine resistance, and FoxO signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…60 Kinase B1 alleviates the expression of GnRH and sexual precocity-related genes by activating the FoxO1 signaling (FoxO family) pathway. 61…”

Section: Molecular Docking Validationmentioning

confidence: 99%

Integrated multicomponent analysis based on ultra‐high‐performance liquid chromatography coupled with quadrupole‐Exactive Orbitrap mass spectrometry and network pharmacology to elucidate the effective constituents and potential mechanism of Zhibai Dihuang pill in treating childhood precocious puberty

Zhang,

Yang,

Wulu

et al. 2024

Rapid Comm Mass Spectrometry

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RationaleChildhood precocious puberty (CPP) is a common pediatric endocrine disorder with significant associated risks. Zhibai Dihuang pill (ZBDHP), a classic recipe of the Qing dynasty with its efficacy of nourishing yin and clearing heat, can downregulate the expression of ESR1 in the uterus and ovaries, thereby inhibiting CPP. However, as of now, the main active ingredients and pharmacological mechanisms of ZBDHP remain unclear.MethodsA comprehensive approach was proposed using ultra‐high‐performance liquid chromatography coupled with quadrupole‐Exactive Orbitrap mass spectrometry (UHPLC‐Q‐Exactive Orbitrap‐MS) and network pharmacology to explore the potentially active constituents of ZBDHP and reveal the underlying mechanisms against CPP. Molecular docking was used to verify the possible mechanisms.ResultsA total of 214 constituents derived were identified via UHPLC‐Q‐Exactive Orbitrap‐MS, and 12 of them were definitely characterized using reference standards. Subsequently, compounds tetrahydropalmatine, alisol C, 25‐anhydroalisol A 11‐acetate, hispidone, cavidine, alisol E, melianone, neogitogenin, denudatin B, and 16β‐hydroperoxyalisol B with related targets PIK3CA, HSD11B1, CYP19A1, AR, PTGS2, CDK2, NR3C1, MMP2, MMP1, and MAPK1 were regarded as key components and targets for ZBDHP treating CPP using the compound–target–pathway network. Besides, the results revealed that the pathways conduced obviously to therapeutic efficacy, including pathways in cancer, neuroactive ligand–receptor interaction, and cyclic adenosine monophosphate（cAMP） signaling pathways. Molecular docking indicated that PIK3CA, HSD11B1, and CYP19A1 exhibited high affinities to corresponding compounds. Overall, the study determined the multicomponent, multitarget, and multipathway mechanisms of ZBDHP against CPP.ConclusionsThis study provided a new method for exploring the chemical constituents and pharmacology mechanism of traditional Chinese medicine.

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LKB1 alleviates high glucose‑ and high fat‑induced inflammation and the expression of GnRH and sexual precocity‑related genes, in mouse hypothalamic cells by activating the AMPK/FOXO1 signaling pathway

Cited by 6 publications

References 25 publications

Integrative proteomic and phosphoproteomic analysis in the female goat hypothalamus to study the onset of puberty

Integrative proteomic and phosphoproteomic analysis in the female goat hypothalamus to study the onset of puberty

A salmon fish model reveals genetic signals in brain associated with early maturation

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