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Insulin resistance corresponds with a progressive increase in NOD1 in high fat diet-fed mice

Abstract

Purpose

Innate immune components participate in obesity-induced inflammation, which can contribute to endocrine dysfunction during metabolic diseases. However, the chronological activation of specific immune proteins such as Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and relevance to cellular crosstalk during the progression of obesity-associated insulin resistance (IR) is not known.

Methods

The NOD1 signaling in various insulin-sensitive metabolic tissues during the progression of diet-insulin resistance was assessed in C57BL/6J mice fed with 60% high-fat diet (HFD) for 4, 8, 12, and 16 weeks. Intestinal permeability was measured using FITC-dextran. NOD1 activating potential was analyzed using HEK-Blue mNOD1 cells.

Results

HFD-fed mice showed progressive induction of glucose intolerance and impairment of insulin signaling in key metabolic tissues. We found a time-dependent increase in intestinal permeability coupled with transport and accumulation of NOD1 activating ligand in the serum of HFD-fed mice. We also observed a progressive accumulation of γ-D-glutamyl-meso-diaminopimelic acid (DAP), a microbial peptidoglycan ligand known to activate NOD1, in serum samples of the HFD-fed mice. There was also a progressive increase in transcripts levels of NOD1 in bone marrow-derived macrophages during HFD-feeding. In addition, skeletal muscle, adipose and liver, the key insulin sensitive metabolic tissues also had a time-dependent increase in transcripts of NOD1 and Rip2 and a corresponding activation of pro-inflammatory responses in these tissues.

Conclusion

These data highlight the correlation of inflammation and insulin resistance to NOD1 activation in the bone marrow derived macrophages and insulin responsive metabolic tissues during high fat diet feeding in mice.

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Availability of data and materials

Data supporting the reported results will be available with the corresponding author (AK Tamrakar).

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Funding

This work was supported by grant from the Department of Biotechnology, New Delhi, India [No. BT/PR15667/BRB/10/1465/2015]. AS, SS, SA and FG are supported by Research Fellowship from the Council of Scientific and Industrial Research (CSIR) New Delhi. JDS holds a grant from the Canadian Institutes of Health Research (CIHR; FDN -154295) and a Canada Research Chair in Metabolic Inflammation.

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Contributions

AS, SS, AM, and AKR conducted the experiments, analyzed the data and drafted the manuscript. IA, SA and FG contributed to acquisition and analysis of data. JDS and AS interpreted the data and reviewed and edited the manuscript. AKT contributed to the design and analysis of the study, interpreted the data, wrote and reviewed the manuscript. All listed authors approved the final version of the manuscript. This manuscript bears the CDRI communication No. 10351.

Corresponding author

Correspondence to Akhilesh K. Tamrakar.

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The authors declare no competing interests.

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Animal study reported in the manuscript was approved by Institutional Animal Ethics Committee (IAEC) of the CSIR-Central Drug Research Institute, Lucknow.

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Sharma, A., Singh, S., Mishra, A. et al. Insulin resistance corresponds with a progressive increase in NOD1 in high fat diet-fed mice. Endocrine 76, 282–293 (2022). https://doi.org/10.1007/s12020-022-02995-z

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  • DOI: https://doi.org/10.1007/s12020-022-02995-z

Keywords

  • NOD
  • Glucose metabolism
  • Inflammation
  • Innate immunity
  • Insulin resistance