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Placental mesenchymal stem cells restore glucose and energy homeostasis in obesogenic adipocytes

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Abstract

Obesity (Ob) depicts a state of energy imbalance(s) being characterized by the accumulation of excessive fat and which predisposes to several metabolic diseases. Mesenchymal stem cells (MSCs) represent a promising option for addressing obesity and its associated metabolic co-morbidities. The present study aims at assessing the beneficial effects of human placental MSCs (P-MSCs) in mitigating Ob-associated insulin resistance (IR) and mitochondrial dysfunction both in vivo and in vitro. Under obesogenic milieu, adipocytes showed a significant reduction in glucose uptake, and impaired insulin signaling with decreased expression of UCP1 and PGC1α, suggestive of dysregulated non-shivering thermogenesis vis-a-vis mitochondrial biogenesis respectively. Furthermore, obesogenic adipocytes demonstrated impaired mitochondrial respiration and energy homeostasis evidenced by reduced oxygen consumption rate (OCR) and blunted ATP/NAD+/NADP+ production respectively. Interestingly, co-culturing adipocytes with P-MSCs activated PI3K-Akt signaling, improved glucose uptake, diminished ROS production, enhanced mitochondrial OCR, improved ATP/NAD+/NADP+ production, and promoted beiging of adipocytes evidenced by upregulated expression of PRDM16, UCP1, and PGC1α expression. In vivo, P-MSCs administration increased the peripheral blood glucose uptake and clearance, and improved insulin sensitivity and lipid profile with a coordinated increase in the ratio of ATP/ADP and NAD+ and NADP+ in the white adipose tissue (WAT), exemplified in WNIN/GR-Ob obese mutant rats. In line with in vitro findings, there was a significant reduction in adipocyte hypertrophy, increased mitochondrial staining, and thermogenesis. Our findings advocate for a therapeutic application of P-MSCs for improving glucose and energy homeostasis, i.e., probably restoring non-shivering thermogenesis towards obesity management.

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Acknowledgements

The authors would like to acknowledge Dr. R. Hemalatha, Director, ICMR-NIN, for providing the necessary infrastructure to conduct the current research. We also would like to acknowledge the members of the ICMR-NIN animal facility for their cooperation and support for animal experiments.

Funding

KN received a Senior Research Fellowship (5/3/8/31/ITR-F/2018-ITR) from ICMR. The present research is supported by ICMR-NIN intramural funding (Code: 15-BS03, 18-BS10) to Dr. VV, which is greatly acknowledged.

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Authors and Affiliations

  1. Division of Cell and Molecular Biology, ICMR-National Institute of Nutrition, Jamai-Osmania P.O, Tarnaka, Hyderabad, 500007, India

    Nagasuryaprasad Kotikalapudi, Samuel Joshua Pragasam Sampath & Vijayalakshmi Venkatesan

  2. Division of Food Safety, ICMR-National Institute of Nutrition, Jamai-Osmania P.O, Tarnaka, Hyderabad, 500007, India

    Sukesh Narayan Sinha & Sathish Kumar Mungamuri

  3. Department of Regenerative Medicine, Manipal Institute of Regenerative Medicine, GKVK Post, Bellary Road, Allalasandra, Yelahanka, Bangalore, 560065, India

    Bhonde R

  4. Present Address: Dr. D. Y. Patil Vidyapeeth, Pune, 411018, India

    Bhonde R

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  1. Nagasuryaprasad Kotikalapudi
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  2. Samuel Joshua Pragasam Sampath
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  3. Sukesh Narayan Sinha
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  4. Bhonde R
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  5. Sathish Kumar Mungamuri
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  6. Vijayalakshmi Venkatesan
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Contributions

KN carried out the majority of experiments, characterized, and injected P-MSCs, including animal maintenance. SJPS also contributed towards animal experiments and towards manuscript. SNS helped in metabolite analysis using LC–MS/MS. RRB is involved in human placenta collection and human ethical approval as well as isolation of P-MSCs. SKM is engaged in designing the experiments, data analysis, the configuration of figures, and preparation and final correction of the manuscript. VV coordinated the overall team, including the project design and manuscript preparation.

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Correspondence to Vijayalakshmi Venkatesan.

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Institutional Animal Ethics Committees (IAECs): P35F/IAEC/NIN/11/2012/VV/WNIN. Institutional Human Ethics Committees: MHB/SCR/021.

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Kotikalapudi, N., Sampath, S.J.P., Sinha, S.N. et al. Placental mesenchymal stem cells restore glucose and energy homeostasis in obesogenic adipocytes. Cell Tissue Res 391, 127–144 (2023). https://doi.org/10.1007/s00441-022-03693-y

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