Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice
Brian Akhaphong1, Daniel C Baumann1, Megan Beetch1
1Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Insights
Placental mechanistic target of rapamycin (mTOR) signaling impacts fetal growth and offspring metabolic health. Disrupting placental mTOR function leads to low birth weight and adult obesity, while enhancing it offers protection.
Area of Science:
- Reproductive biology
- Metabolic disease research
- Developmental programming
Background:
- Fetal growth restriction (low birth weight) is linked to adult obesity and type 2 diabetes.
- Placental mechanistic target of rapamycin (mTOR) signaling is implicated in regulating fetal weight and offspring metabolic health.
Purpose of the Study:
- To investigate the direct role of placental mTOR signaling in determining fetal birth weight and the metabolic health of adult offspring.
- To elucidate the mechanistic link between placental function and the developmental programming of metabolic disorders.
Main Methods:
- Utilized a genetic mouse model with loss of placental mTOR function (mTOR-KOPlacenta).
- Assessed placental and fetal growth parameters at embryonic day 17.5.
- Evaluated birth weight, serum insulin, and pancreatic beta cell mass in newborns.
- Challenged adult offspring with a high-fat diet to assess metabolic dysfunction.
- Employed genetic ablation of TSC2 to enhance placental mTOR complex 1 (mTORC1) signaling in utero.
Main Results:
- mTOR-KOPlacenta animals exhibited reduced placental size, fetal body weight, and birth weight.
- Newborn mTOR-KOPlacenta offspring had lower serum insulin but normal beta cell mass.
- Adult mTOR-KOPlacenta offspring showed exacerbated obesity and metabolic dysfunction upon high-fat diet challenge.
- Enhanced placental mTORC1 signaling via TSC2 ablation protected offspring from diet-induced obesity.
Conclusions:
- Placental mTORC1 signaling is a critical regulator of fetal growth and the programming of metabolic health in adult offspring.
- Dysregulation of placental mTORC1 contributes to low birth weight and increased susceptibility to obesity and insulin resistance.
- Targeting placental mTORC1 may offer therapeutic strategies for preventing metabolic diseases programmed during development.
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.
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