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Animal Models

Temporal immmunometabolic profiling of adipose tissue in HFD-induced obesity: manifestations of mast cells in fibrosis and senescence

International Journal of Obesity volume 43, pages 1281–1294 (2019)Cite this article

Subjects

Abstract

Background/Objectives:

Chronic low-grade inflammation/meta-inflammation in adipose tissue leads to obesity-associated metabolic complications. Despite growing understanding, the roles of immune cell subsets, their interrelationship, and chronological events leading to progression of obesity-associated insulin resistance (IR) remains unclear.

Methods:

We carried out temporal immunometabolic profiling of adipose tissue from C57BL/6 mice fed a high-fat diet (HFD) for 4, 8, 12, 16, and 20 weeks. We used clodronate sodium liposomes (CLODs) to deplete macrophages and disodium cromoglycate sodium liposomes (DSCGs) to stabilize mast cells.

Results:

In the temporal HFD settings, mice showed progressive glucose intolerance, insulin resistance, and adipose tissue senescence. Histochemistry analysis of epididymal white adipose tissue (eWAT) using picro-sirius red and Masson’s trichrome staining showed extensive collagen deposition in the 16th and 20th weeks. Flow cytometry analysis of the stromal vascular fraction (SVF) from eWAT revealed T-cell subsets as early-phase components and pro-inflammatory macrophages, as well as mast cells as the later phase components during obesity progression. In our therapeutic strategies, macrophage depletion by CLOD and mast stabilization by DSCG attenuated obesity, adipose tissue fibrosis, and improved whole-body glucose homeostasis. In addition, mast cell stabilization also attenuated senescence (p53 and X-gal staining) in eWAT, signifying the role of mast cells over macrophages during obesity.

Conclusion:

New-generation mast cell stabilizers can be exploited for the treatment of obesity-associated metabolic complications.

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Acknowledgements

We are grateful for the excellent instrumental and technical support from institutional SAIF division. This manuscript bears CSIR-CDRI communication number 9735.

Funding

This study was supported by CSIR-CDRI Network project: “Towards holistic understanding of complex diseases: Unraveling the threads of complex disease (THUNDER) Project No: BSC0102. DK, SP, and AS are supported by SRF-CSIR fellowship, New Delhi. KS, SR, and AG are supported by SRF-UGC, New Delhi. SV is supported by SRF-ICMR, New Delhi. SG is supported by DBT-JRF fellowship, New Delhi.

Author contribution

DK and ANG conceptualized the idea. DK performed animal experiments, western blotting, RT-PCR, flow cytometry, and tissue staining. KS performed ELISA assay. SKP and AM developed formulations. AG and SV did metabolic experiments. SR did western blotting in the BAT. AS and SG performed RT-PCR analysis. ALV analyzed FACS data. All the authors participated in drafting and reviewing the manuscript. ANG is the guarantor of this manuscript.

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Authors and Affiliations

  1. Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Durgesh Kumar, Salil Varshney, Kripa Shankar, Sujith Rajan, Ankita Srivastava, Abhishek Gupta, Sanchita Gupta & Anil N. Gaikwad

  2. Academy of Scientific and Innovative Research, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Durgesh Kumar, Sanket Kumar Pandya, Salil Varshney, Sujith Rajan, Ankita Srivastava & Sanchita Gupta

  3. Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Sanket Kumar Pandya & Amit Misra

  4. Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Achchhe Lal Vishwakarma

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  1. Durgesh Kumar
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Correspondence to Anil N. Gaikwad.

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Kumar, D., Pandya, S.K., Varshney, S. et al. Temporal immmunometabolic profiling of adipose tissue in HFD-induced obesity: manifestations of mast cells in fibrosis and senescence. Int J Obes 43, 1281–1294 (2019). https://doi.org/10.1038/s41366-018-0228-5

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