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Lipid-induced monokine cyclophilin-A promotes adipose tissue dysfunction implementing insulin resistance and type 2 diabetes in zebrafish and mice models of obesity

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Abstract

Several studies have implicated obesity-induced macrophage–adipocyte cross-talk in adipose tissue dysfunction and insulin resistance. However, the molecular cues involved in the cross-talk of macrophage and adipocyte causing insulin resistance are currently unknown. Here, we found that a lipid-induced monokine cyclophilin-A (CyPA) significantly attenuates adipocyte functions and insulin sensitivity. Targeted inhibition of CyPA in diet-induced obese zebrafish notably reduced adipose tissue inflammation and restored adipocyte function resulting in improvement of insulin sensitivity. Silencing of macrophage CyPA or pharmacological inhibition of CyPA by TMN355 effectively restored adipocytes’ functions and insulin sensitivity. Interestingly, CyPA incubation markedly increased adipocyte inflammation along with an impairment of adipogenesis, however, mutation of its cognate receptor CD147 at P309A and G310A significantly waived CyPA’s effect on adipocyte inflammation and its differentiation. Mechanistically, CyPA–CD147 interaction activates NF-κB signaling which promotes adipocyte inflammation by upregulating various pro-inflammatory cytokines gene expression and attenuates adipocyte differentiation by inhibiting PPARγ and C/EBPβ expression via LZTS2-mediated downregulation of β-catenin. Moreover, inhibition of CyPA or its receptor CD147 notably restored palmitate or CyPA-induced adipose tissue dysfunctions and insulin sensitivity. All these results indicate that obesity-induced macrophage–adipocyte cross-talk involving CyPA–CD147 could be a novel target for the management of insulin resistance and type 2 diabetes.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

D. B. and S. R. expresses their gratitude to the DBT for the award of Research Fellowship. D. B. and A. S. acknowledges the ‘Research and Innovation Grant (DoRD/RIG/10-73/1592-A)’ from Tezpur University. De. P. acknowledges IIT Ropar and MHRD for his Research Fellowship. We thank Dr. R. Mukhopadhyay, Department of MBBT, Tezpur University, for the gift of THP-1 monocyte cell line and the National Center for Cell Science (NCCS), Pune for providing RAW264.7 macrophage cell line. We are also thankful to the Head, Department of MBBT, Tezpur University, the Head, Department of BME, Indian Institute of Technology Ropar, the Head, Department of Pharmacology and Toxicology, NIPER S.A.S. Nagar, and the Dean, College of Fisheries, Assam Agricultural University for extending the facilities required for the present investigation. Financial support in the form of UGC-SAP-DRS-II, and DST-FIST-I to the Department of MBBT, Tezpur University is also acknowledged.

Funding

This work was supported by the “DBT-Twinning Grant” from the Department of Biotechnology (DBT), New Delhi (Grant number: BT/PR24700/NER/95/819/2017)” to S.D.G. (Tezpur University) and D.P. (IIT Ropar). The SERB-Early Career Research Grant from the Science and Engineering Research Board (SERB), New Delhi (Grant number: ECR/2017/000892) to D.P. also supported this work.

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  1. Dipanjan Banerjee and Debarun Patra contributed equally to this work.

Authors and Affiliations

  1. Metabolic Disease Biology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, 784028, Assam, India

    Dipanjan Banerjee, Archana Sinha & Suman Dasgupta

  2. Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, Punjab, India

    Debarun Patra, Soumyajit Roy & Durba Pal

  3. Department of Aquatic Environment Management, College of Fisheries, Assam Agricultural University, Nagaon, 782103, Assam, India

    Raktim Sarmah, Rajdeep Dutta & Sarada Kanta Bhagabati

  4. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, 160062, India

    Rajat Pant & Kulbhushan Tikoo

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  1. Dipanjan Banerjee
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Contributions

SDG, DP, and DB conceived and designed the experiments. DB, DeP, AS, SR, RP, RS performed the experiments. SDG, DP, KT, DB, and DeP analyzed the data. RS, RD, and SKB developed obese diabetic zebrafish model and helped in experiments. RP and KT developed mice models and helped in experiments. SDG, DP, and DB wrote the manuscript. SDG and DP supervised the study. All authors read and approved the final manuscript. SDG is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Durba Pal or Suman Dasgupta.

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Banerjee, D., Patra, D., Sinha, A. et al. Lipid-induced monokine cyclophilin-A promotes adipose tissue dysfunction implementing insulin resistance and type 2 diabetes in zebrafish and mice models of obesity. Cell. Mol. Life Sci. 79, 282 (2022). https://doi.org/10.1007/s00018-022-04306-1

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