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

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 4

Adult male TSC2-KOPlacenta mice are protected from obesity-induced metabolic dysfunction.

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Adult male TSC2-KOPlacenta mice are protected from obesity-induced metab...
Weight progression of Ctrl versus TSC2-KOPlacenta male mice fed with HFD over 9 weeks starting at 17 weeks of age (n = 4, 5, respectively, A). Food intake measurements of HFD male mice (n = 4, 5, B). Random blood glucose of HFD male mice (n = 4, 5, C). IPGTT after 16 hours of fasting at 2 weeks HFD (n = 4, 5, D) and corresponding random and fasting blood glucose (n = 4, 5, E). IPGTT after 16 hours of fasting at 4 weeks of HFD (n = 4, 5, F) in addition to random and fasting blood glucose (n = 4, 5, G). ITT at 5 weeks of HFD after 6 hours of fasting (n = 4, 5, H). HOMA-IR of HFD males at 6 weeks (n = 4, 5, I). Random insulin serum levels at 1 and 4 weeks of HFD (n = 4, 4–5, J). In vivo GSIS on males at 6 weeks of HFD (n = 4, 5, K) and concurrent IPGTT (n = 4, 5, L). β Cell mass of males at 10 weeks of HFD (n = 4, 5, M). Statistical analysis was performed using 2-tailed Mann-Whitney (I and M) and 2-way ANOVA with Sidak’s multiple comparisons (A–H and J–L) with repeated measures when appropriate. Error bars represent mean ± SEM. *P < 0.05, **P < 0.01 Ctrl vs. TSC2-KOPlacenta. ##P < 0.01 vs. time point 0 (within genotype).