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Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin

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Abstract

A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the regulation of RBP4/STRA6 expression in 3T3-L1 adipocytes exposed to glucolipotoxicity (GLT) and in visceral adipose tissue (VAT) from high fat diet (HFD) fed insulin-resistant rats. 3T3-L1 adipocytes were subjected to GLT and other experimental maneuvers with and without vildagliptin or metformin. Real-time PCR and western-blot experiments were performed to analyze RBP4, STRA6, PPARγ gene and protein expression. Adipored staining and glucose uptake assay were performed to evaluate lipid and glucose metabolism. Oral glucose tolerance test (OGTT) and Insulin Tolerance Test (ITT) were performed to determine the extent of insulin resistance in HFD fed male Wistar rats. Total serum RBP4 was measured by quantitative sandwich enzyme-linked immunosorbent assay kit. Adipocytes under GLT exhibited significantly increased RBP4/STRA6 expressions and decreased insulin sensitivity/glucose uptake. Vildagliptin and metformin not only restored the above but also decreased the expression of IL-6, NFκB, SOCS-3 along with lipid accumulation. Furthermore, HFD fed rats exhibited significantly increased serum levels of RBP4 along with VAT expression of RBP4, STRA6, PPARγ, IL-6. These molecules were significantly altered by the vildagliptin/ metformin treatment. We conclude that RBP4/STRA6 pathway is primarily involved in mediating inflammation and insulin resistance in adipocytes and visceral adipose tissues under glucolipotoxicity and in insulin resistant rats.

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Abbreviations

RBP4:

Retinol Binding Protein-4

STRA6:

Stimulated by retinoic Acid 6

GLT:

Glucolipotoxicity

VAT:

Visceral Adipose Tissue

NPD:

Normal Pellet Diet

HFD:

High Fat Diet

JAK:

Janus Kinase

STAT:

Signal Transducer and activator of Transcription

PPARα/γ:

Peroxisome proliferator-activated receptor alpha/gamma

IBMX:

Isobutyl methylxanthine

cAMP:

Cyclic adenosine 3ʹ,5ʹ-cyclic monophosphate

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Acknowledgements

Authors acknowledge research grant supports received from the Department of Biotechnology (DBT), Govt. of India (Grant No. BT/PR4082/MED/30/684/2011) and the Madras Diabetes Research Foundation—Intramural Research Funding (MIRF). Gautam Kumar Pandey acknowledges the Council of Scientific & Industrial Research (CSIR), India for his financial assistance (Senior Research Fellowship). Dr. Kuppan Gokulakrishnan acknowledges the DBT/Wellcome Trust India Alliance for their support.

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Author notes

  1. Kuppan Gokulakrishnan and Gautam Kumar Pandey have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bengaluru, 560029, India

    Kuppan Gokulakrishnan

  2. Department of Research Biochemistry, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600086, India

    Kuppan Gokulakrishnan, Gautam Kumar Pandey & Viswanathan Mohan

  3. Department of Cell and Molecular Biology, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600086, India

    Chandrakumar Sathishkumar, Prabhu Durairaj & Muthuswamy Balasubramanyam

  4. Department of Vascular Biology, Madras Diabetes Research Foundation, Gopalapuram, Chennai, 600086, India

    Saravanakumar Sundararajan & Nagaraj Manickam

  5. Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, 27514, USA

    Gautam Kumar Pandey

  6. Department of Medical and Health Sciences (MHS), SRM Medical College Hospital & Research Centre, SRM Institute of Science and Technology (SRMIST), Kattankulathur, Chennai, 603203, India

    Prabhu Durairaj & Muthuswamy Balasubramanyam

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  1. Kuppan Gokulakrishnan
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Contributions

KG conceptualized the work; KG and GKP designed & executed the study methods, analyzed data, interpreted the results and drafted the manuscript. GKP performed experiments and cell-culture related work. SC helped in confocal microscopy. SS and PD helped in performing animal study. KG, NM, MB, and VM edited the manuscript, critically reviewed and helped in drafting the final version.

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Correspondence to Kuppan Gokulakrishnan.

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Gokulakrishnan, K., Pandey, G.K., Sathishkumar, C. et al. Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin. Mol Biol Rep 48, 4093–4106 (2021). https://doi.org/10.1007/s11033-021-06420-y

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