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Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice
Brian Akhaphong, … , Maria Ruth B. Pineda-Cortel, Emilyn U. Alejandro
Brian Akhaphong, … , Maria Ruth B. Pineda-Cortel, Emilyn U. Alejandro
Published May 25, 2021
Citation Information: JCI Insight. 2021;6(13):e149271. https://doi.org/10.1172/jci.insight.149271.
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Research Article Endocrinology Metabolism

Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

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Abstract

Fetal growth restriction, or low birth weight, is a strong determinant for eventual obesity and type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulates fetal birth weight and the metabolic health trajectory of the offspring. In the current study, we used a genetic model with loss of placental mTOR function (mTOR-KOPlacenta) to test the direct role of mTOR signaling on birth weight and metabolic health in the adult offspring. mTOR-KOPlacenta animals displayed reduced placental area and total weight, as well as fetal body weight at embryonic day (E) 17.5. Birth weight and serum insulin levels were reduced; however, β cell mass was normal in mTOR-KOPlacenta newborns. Adult mTOR-KOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared with littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.

Authors

Brian Akhaphong, Daniel C. Baumann, Megan Beetch, Amber D. Lockridge, Seokwon Jo, Alicia Wong, Tate Zemanovic, Ramkumar Mohan, Danica L. Fondevilla, Michelle Sia, Maria Ruth B. Pineda-Cortel, Emilyn U. Alejandro

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Figure 3

TSC2-KOPlacenta newborn offspring have normal placental weight and β cell mass.

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TSC2-KOPlacenta newborn offspring have normal placental weight and β cel...
Schematic diagram and timeline of the TSC2-KO study (A). H&E staining of E17.5 Ctrl and TSC2-KOPlacenta (B). Placental weights of male Ctrl versus TSC2-KOPlacenta (n = 7, 6) and female Ctrl versus TSC2-KOPlacenta (n = 7, 8) mice at E17.5 (C). Fetal weights of male (nE17.5 = 8, 5; nP0 = 10, 6) and female (nE17.5 = 7, 8; nP0 = 6, 9) Ctrl vs. TSC2-KOPlacenta mice at E17.5 and P0 (D). Pancreas weights of male (nE17.5 = 8, 5; nP0 = 8, 6) and female (nE17.5 = 7, 8; nP0 = 6, 9) mice measured at E17.5 and P0 (E). Random blood glucose of males (n = 8, 6) and females (n = 6, 9) at P0 (F). Random serum insulin of males (n = 4, 6) and females (n = 4, 6) at P0 (G). β Cell mass of males (n = 4 Ctrl, 2 TSC2-HETPlacenta, 3 TSC2-KOPlacenta) and females at P0 (n = 7 Ctrl, 4 TSC2-HETPlacenta, 5 TSC2-KOPlacenta, H). Whole pancreatic insulin content of males (n = 4 Ctrl, 6 TSC2-KOPlacenta) and females (n = 5 Ctrl, 6 TSC2-KOPlacenta) at P0 (I). Statistical analysis was performed using 2-way ANOVA with Sidak’s multiple comparisons (C–I). Error bars represent mean ± SEM. Scale bars in images are 500 μm. *P < 0.05 Ctrl vs. TSC2-KOPlacenta.

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