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Metformin Disrupts Signaling and Metabolism in Fetal Hepatocytes

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posted on 2023-06-22, 17:19 authored by Karli S. Swenson, Dong Wang, Amanda K. Jones, Michael J. Nash, Rebecca O’Rourke, Diana L. Takahashi, Paul Kievit, Jon D. Hennebold, Kjersti M. Aagaard, Jacob E. Friedman, Kenneth L. Jones, Paul J. Rozance, Laura D. Brown, Stephanie R. Wesolowski

Metformin is used by women during pregnancy to manage diabetes and crosses the placenta, yet its effects on the fetus are unclear. We show that the liver is a site of metformin action in fetal sheep and macaques, given relatively abundant OCT1 transporter expression and hepatic uptake following metformin infusion into fetal sheep. To determine the effects of metformin action, we performed studies in primary hepatocytes from fetal sheep, fetal macaques, and juvenile macaques. Metformin increases AMP-activated protein kinase (AMPK) signaling, decreases mammalian target of rapamycin (mTOR) signaling, and decreases glucose production in fetal and juvenile hepatocytes. Metformin also decreases oxygen consumption in fetal hepatocytes. Unique to fetal hepatocytes, metformin activates stress pathways (e.g., increased PGC1A gene expression, NRF-2 protein abundance, and phosphorylation of eIF2a and CREB proteins) alongside perturbations in hepatokine expression (e.g., increased growth/differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) expression and decreased insulin-like growth factor 2 (IGF2) expression). Similarly, in liver tissue from sheep fetuses infused with metformin in vivo, AMPK phosphorylation, NRF-2 protein, and PGC1A expression are increased. These results demonstrate disruption of signaling and metabolism, induction of stress, and alterations in hepatokine expression in association with metformin exposure in fetal hepatocytes.

Funding

This work was supported by the National Institutes of Health grant R01-DK108910 (to SRW). We would like to thank the primary investigators on NCTRI grant P50-HD071836 (Jon D. Hennebold) for the provision of fetal tissue samples and liver tissue for hepatocytes and the primary investigators on R24-DK090964 grant (Jacob E. Friedman, Kjersti M. Aagaard, Paul Kievit) for the provision of postnatal tissue samples and liver tissue for hepatocytes. Additional support was provided by P51-OD011092 for operation of the ONPRC, CA04693 for the University of Colorado Genomic Core, DK048520 for the Nutrition Obesity Research Center (NORC), R01-HD093701 (to PJR), R01-HD079404 (to LDB), R01-DK128187 (to KMA), R01-DK089201 (to KMA), T32-HD007186 (to AKJ), F32- DK120070 (to AKJ), and F30- DK122672 (to MJN).

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