Impact of Modulating Leptin Sensitivity on the Transcriptomic Profile of Adult-derived Hypothalamic Mouse Neurons

Overview

Journal Front Mol Neurosci

Date 2025 Feb 7

PMID 39916981

Authors

Ewa Oclon

Artur Gurgul

Tomasz Szmatola

Igor Jasielczuk

Miroslaw Kucharski

Joanna Zubel-Lojek

Dorota Anna Zieba

Affiliations

Soon will be listed here.

Abstract

The modulation of leptin sensitivity in hypothalamic neurons plays a crucial role in metabolic regulation and the development of obesity. Three distinct approaches, exposure to leptin (LEPA), administration of leptin antagonist (LANTA), and treatment with palmitate (PA), were explored in this study to assess their effects on adult-derived mHypoA-2/12 neurons and the resulting transcriptomic signatures. To this end, 3' mRNA-Seq transcriptome analysis was employed, unexpectedly revealing downregulation of key genes associated with the NOD-like receptor signaling pathway (, , , , , , , and ), the C-type lectin receptor signaling pathway (, , , , , , , and ), the NF kappa B signaling pathway (, , , , , , and ), and the IL 17 signaling pathway (, , , , , , and ). These findings help elucidate the molecular mechanisms through which these factors influence leptin sensitivity and provide insights into the pathways implicated in the development of leptin resistance in hypothalamic neurons. The surprising downregulation of these pathways suggests a complex interplay between leptin signaling and the cellular stress response in hypothalamic neurons. This alteration may reflect adaptive mechanisms in response to prolonged leptin or fatty acid exposure. Understanding these dynamics is essential for elucidating the role of hypothalamic inflammation in the progression of leptin resistance and associated metabolic disorders.

References

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Philp L, Rockstroh A, Sadowski M, Fard A, Lehman M, Tevz G . Leptin antagonism inhibits prostate cancer xenograft growth and progression. Endocr Relat Cancer. 2021; 28(5):353-375. DOI: 10.1530/ERC-20-0405. View

Lee E, Lee Z, Song Y . CXCL10 and autoimmune diseases. Autoimmun Rev. 2008; 8(5):379-83. DOI: 10.1016/j.autrev.2008.12.002. View

Johnson K, Aurubin C, Jondle C, Lange P, Tarakanova V . Interferon Regulatory Factor 7 Attenuates Chronic Gammaherpesvirus Infection. J Virol. 2020; 94(24). PMC: 7925175. DOI: 10.1128/JVI.01554-20. View

Dodt M, Roehr J, Ahmed R, Dieterich C . FLEXBAR-Flexible Barcode and Adapter Processing for Next-Generation Sequencing Platforms. Biology (Basel). 2014; 1(3):895-905. PMC: 4009805. DOI: 10.3390/biology1030895. View

Fang X, Jiang S, Wang J, Bai Y, Kim C, Blake D . Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity. Mol Psychiatry. 2021; 26(6):2299-2315. PMC: 8272726. DOI: 10.1038/s41380-020-01004-x. View

Zhao Y, Xu D, Jiang Y, Zhang L . Dual functions of interferon regulatory factors 7C in Epstein-Barr virus-mediated transformation of human B lymphocytes. PLoS One. 2010; 5(3):e9459. PMC: 2831998. DOI: 10.1371/journal.pone.0009459. View

Chen S, Hsiao C, Chen Y, Hong C, Lin J, Yang C . Interleukin-4 inhibits the hypothalamic appetite control by modulating the insulin-AKT and JAK-STAT signaling in leptin mutant mice. Environ Toxicol. 2024; 39(7):3980-3990. DOI: 10.1002/tox.24264. View

Ge S, Son E, Yao R . iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data. BMC Bioinformatics. 2018; 19(1):534. PMC: 6299935. DOI: 10.1186/s12859-018-2486-6. View

10.

Wang X, Ge A, Cheng M, Guo F, Zhao M, Zhou X . Increased hypothalamic inflammation associated with the susceptibility to obesity in rats exposed to high-fat diet. Exp Diabetes Res. 2012; 2012:847246. PMC: 3401545. DOI: 10.1155/2012/847246. View

11.

Ye L, Jia G, Li Y, Wang Y, Chen H, Yu L . C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation. J Neuroinflammation. 2021; 18(1):159. PMC: 8286609. DOI: 10.1186/s12974-021-02167-2. View

12.

Liu T, Zhang L, Joo D, Sun S . NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017; 2. PMC: 5661633. DOI: 10.1038/sigtrans.2017.23. View

13.

Zieba D, Biernat W, Szczesna M, Kirsz K, Barc J, Misztal T . Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes. Int J Mol Sci. 2020; 21(12). PMC: 7348850. DOI: 10.3390/ijms21124238. View

14.

Mayer C, Belsham D . Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5' monophosphate-activated protein kinase activation. Endocrinology. 2009; 151(2):576-85. DOI: 10.1210/en.2009-1122. View

15.

Zieba D, Szczesna M, Klocek-Gorka B, Molik E, Misztal T, Williams G . Seasonal effects of central leptin infusion on secretion of melatonin and prolactin and on SOCS-3 gene expression in ewes. J Endocrinol. 2008; 198(1):147-55. DOI: 10.1677/JOE-07-0602. View

16.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

17.

Zhou Y, Rui L . Leptin signaling and leptin resistance. Front Med. 2013; 7(2):207-22. PMC: 4069066. DOI: 10.1007/s11684-013-0263-5. View

18.

Williams L . Hypothalamic dysfunction in obesity. Proc Nutr Soc. 2012; 71(4):521-33. DOI: 10.1017/S002966511200078X. View

19.

Dalvi P, Nazarians-Armavil A, Tung S, Belsham D . Immortalized neurons for the study of hypothalamic function. Am J Physiol Regul Integr Comp Physiol. 2011; 300(5):R1030-52. DOI: 10.1152/ajpregu.00649.2010. View

20.

Souza-Almeida G, DAvila H, Almeida P, Luna-Gomes T, Liechocki S, Walzog B . Leptin Mediates Neutrophil Migration: Involvement of Tumor Necrosis Factor-Alpha and CXCL1. Front Immunol. 2018; 9:111. PMC: 5808117. DOI: 10.3389/fimmu.2018.00111. View