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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 5

Adult female TSC2-KOPlacenta offspring are protected from obesity-induced metabolic dysfunction.

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Adult female TSC2-KOPlacenta offspring are protected from obesity-induce...
Weight progression of female mice fed with HFD over the course of 12 weeks starting at 8 weeks old (n = 6 Ctrl, 4 TSC2-KOPlacenta, A). Random blood glucose of HFD females over the duration of treatment (n = 6, 4, B). Female IPGTT after 16-hour fast at 6 weeks of HFD (n = 6, 4, C). Female ITT after 6-hour fast at 8 weeks of HFD (n = 6, 4, D). Blood glucose and insulin serum measurements at random and fasting times of 8-week HFD females (n = 6, 4, E; n = 5, 3, F). HOMA-IR of HFD females at 8 weeks (n = 5, 3, G). Pancreas weight (n = 6, 4, H) and β cell mass (n = 6, 4, I) of females at 12 weeks of HFD. In vivo GSIS of aged Ctrl versus TSC2-KOPlacenta females under normal diet (n = 3, 5, J). In vitro GSIS of 12-week-old female islets under low glucose, high glucose, high glucose plus palmitate, and KCl stimulation (n = 7, 6, K). Insulin content normalized to DNA (n = 7, 6, L). β Cell mass of female Ctrl versus TSC2-KOPlacenta under normal chow (n = 3, 4, M). Statistical analysis was performed using 2-tailed Mann-Whitney (G–I, L, and M) and 2-way ANOVA with Sidak’s multiple comparisons in (A–F, J, and K) with repeated measures when appropriate. Error bars represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 Ctrl vs. TSC2-KOPlacenta. #P < 0.05 vs. time point 0 or LG (within genotype).

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