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Animal Models

Hypothalamic long noncoding RNA AK044061 is involved in the development of dietary obesity in mice

International Journal of Obesity volume 45, pages 2638–2647 (2021)Cite this article

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Abstract

Background

Long noncoding RNAs (lncRNAs) have been implicated in various important biological processes, however, its role in energy balance and obesity remains largely unknown.

Methods

Differentially expressed lncRNAs in the hypothalamus of diet-induced obesity (DIO) mice versus chow-fed mice were identified by RNA sequencing. Lentivirus-mediated overexpression and knockdown of a novel lncRNA, AK044061, were used to assess its role in energy balance and the development of DIO. RNA immunoprecipitation (RIP) and pull down assays were carried out to analyze the interaction between lncRNA AK044061 and RelA, an NF-κB subunit.

Results

LncRNA AK044061 was upregulated in the hypothalamus of DIO mice. Acute intracerebroventricular (i.c.v.) infusion of glucose reduced the expression of lncRNA AK044061, whereas an overnight of fasting enhanced its expression. RNA in situ hybridization data showed that AK044061 was expressed in the neurons of the arcuate nucleus (ARC). Lentivirus-mediated overexpression of AK044061 in ARC cells, or in the neurons of the ARC nucleus led to an obesity-like phenotype and related metabolic disorders. Furthermore, knockdown of lncRNA AK044061 in Agouti-related peptide (AgRP)-expressing neurons mitigated DIO and its related metabolic dysregulations. In mechanism, we showed that lncRNA AK044061 was associated with RelA and could enhance the NF-κB reporter activity. The effect of lncRNA AK044061 on energy balance is mediated by NF-κB.

Conclusions

Our findings suggest that excessive lncRNA AK044061 in the ARC nucleus leads to energy imbalance and obesity. LncRNA AK044061 expressed in the AgRP neurons is important in the development of dietary obesity in mice.

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Fig. 1: Dysregulation of hypothalamic lncRNA AK044061 in diet-induced obesity mice.
Fig. 2: Overexpression of lncRNA AK044061 in the ARC nucleus leads to an obesity-like phenotype and related metabolic dysregulations.
Fig. 3: Overexpression of AK044061 in the ARC neurons leads to an obesity-like phenotype and related metabolic comorbidities.
Fig. 4: lncRNA AK044061 expressed in AgRP neurons is crucial in DIO development.
Fig. 5: RelA mediates the effect of lncRNA AK044061 on energy balance.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81573146 and 91539125 to G.Z., 31822030 to A.Y.G., 31801113 to Q.Z.), the Young Thousand Talents Program of China and the Natural Science Foundation of Hubei Province (2019CFB591 to Z.M.).

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Authors and Affiliations

  1. Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Juan Li, Jinlie Long & Guo Zhang

  2. Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Juan Li & Guo Zhang

  3. Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Qiong Zhang & An-Yuan Guo

  4. Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore, Singapore

    Hongyuan Shen

  5. School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China

    Zhaowu Ma

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Contributions

JL and JLL designed and performed the experiments, and analyzed the data. QZ and HS analyzed the data and provided technical support. GZ conceived the study. GZ, ZM and AYG designed the experiments, analyzed the data and wrote the paper. All authors commented on the paper.

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Correspondence to An-Yuan Guo, Zhaowu Ma or Guo Zhang.

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Li, J., Long, J., Zhang, Q. et al. Hypothalamic long noncoding RNA AK044061 is involved in the development of dietary obesity in mice. Int J Obes 45, 2638–2647 (2021). https://doi.org/10.1038/s41366-021-00945-9

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