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Metformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes in sex-dependent and sex-independent manners

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Abstract

Metformin has attracted increasing interest for its potential benefits in extending healthspan and longevity. This study examined the effects of early-life metformin treatment on the development and metabolism of C57BL/6 J (B6) mice, with metformin administered to juvenile mice from 15 to 56 days of age. Metformin treatment led to decreased body weight in both sexes (P < 0.05, t-test). At 9 weeks of age, mice were euthanized and organ weights were recorded. The relative weight of retroperitoneal fat was decreased in females, while relative weights of perigonadal and retroperitoneal fat were decreased, and relative liver weight was increased in males (P < 0.05, t-test). Glucose and insulin tolerance tests (GTT and ITT) were conducted at the age of 7 weeks. ANOVA revealed a significant impairment in insulin sensitivity by the treatment, and a significantly interactive effect on glucose tolerance between sex and treatment, underscoring a disparity in GTT between sexes in response to the treatment. Metformin treatment reduced circulating insulin levels in fasting and non-fasting conditions for male mice, with no significant alterations observed in female mice. qRT-PCR analysis of glucose metabolism-related genes (Akt2, Glut2, Glut4, Irs1, Nrip1, Pi3k, Pi3kca, Pkca) in the liver and skeletal muscle reveals metformin-induced sex- and organ-specific effects on gene expression. Comparison with previous studies in heterogeneous UM-HET3 mice receiving the same treatment suggests that genetic differences may contribute to variability in the effects of metformin treatment on development and metabolism. These findings indicate that early-life metformin treatment affects development and metabolism in both sex- and genetics-dependent manners.

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Funding

This study was supported by grants from the William E. McElroy Charitable Foundation, the National Institute of Aging (R21AG062985), the American Diabetes Association (1–19-IBS-126) to A.B., the School of Medicine at Southern Illinois University Research Seed Grant to R.Y., the Southern Illinois University System Collaborative Grant to R.Y. and B.E., and 2022 AOA Student Research Fellowship to M.E.

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Authors and Affiliations

  1. Department of Internal Medicine, Southern Illinois University School of Medicine, 801 N. Rutledge, P.O. Box 19628, Springfield, IL, 62702, USA

    Yun Zhu, Morgan Engmann, David Medina, Xiuqi Han, Andrzej Bartke & Rong Yuan

  2. Department of Physiology, Southern Illinois University SIU School of Medicine, 1135 Lincoln Drive, Life Science III, Room 2062, Carbondale, IL, 62901, USA

    Pratyusa Das & Buffy S. Ellsworth

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  1. Yun Zhu
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  2. Morgan Engmann
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  3. David Medina
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  4. Xiuqi Han
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  5. Pratyusa Das
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  6. Andrzej Bartke
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  8. Rong Yuan
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Y.Z., M.E., D.M., X.H., P.D., and R.Y. The first draft of the manuscript was written by Y.Z., M.E., and R.Y., all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Rong Yuan.

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Zhu, Y., Engmann, M., Medina, D. et al. Metformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes in sex-dependent and sex-independent manners. GeroScience 46, 3197–3218 (2024). https://doi.org/10.1007/s11357-024-01067-6

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