Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

Abstract

In pregnancies complicated by maternal obesity and gestational diabetes mellitus, there is strong evidence to suggest that the insulin signaling pathway in the placenta may be impaired. This may have potential effects on the programming of the metabolic health in the offspring; however, a direct link between the placental insulin signaling pathway and the offspring health remains unknown. Here, we aimed to understand whether specific placental loss of the insulin receptor (InsR) has a lasting effect on the offspring health in mice. Obesity and glucose homeostasis were assessed in the adult mouse offspring on a normal chow diet (NCD) followed by a high-fat diet (HFD) challenge. Compared to their littermate controls, InsR KOplacenta offspring were born with normal body weight and pancreatic β-cell mass. Adult InsR KOplacenta mice exhibited normal glucose homeostasis on an NCD. Interestingly, under a HFD challenge, adult male InsR KOplacenta offspring demonstrated lower body weight and a mildly improved glucose homeostasis associated with parity. Together, our data show that placenta-specific insulin receptor deletion does not adversely affect offspring glucose homeostasis during adulthood. Rather, there may potentially be a mild and transient protective effect in the mouse offspring of multiparous dams under the condition of a diet-induced obesogenic challenge.

RISING STARS: Mechanistic insights into maternal–fetal cross talk and islet beta-cell development

“…Possible mechanisms that may explain these sex differences include X-inactivation escape of genes, imprinting, and fetal androgen production ( Howerton et al 2013 , Gong et al 2018 , Braun et al 2021 , Arevalo et al 2021 ). In line with this idea, manipulations of placental genes or maternal diet also lead to sex dimorphic responses in offspring glucose metabolism ( Yokomizo et al 2014 , Akhaphong et al 2018 , 2021 a , Chung et al 2022 ).…”

“…Additionally, multiparity positively associated with glucose intolerance in nonhuman primates at 3 years of age ( Elsakr et al 2019 ). The negative metabolic effect on offspring from multiparity appears to be correlated with placental insulin signaling, as deletion of placental insulin receptor improved glucose homeostasis in multiparous offspring ( Chung et al 2022 ). Further studies are needed to examine the alterations to islet and beta-cell physiology in the context of maternal aging and parity.…”

Diabetes: A Multifaceted Disorder

“…After, two experimental studies, the first examines the role of tyrosine isoforms ortho- and meta-tyrosine in the development of insulin resistance [ 7 ]. The second, conducted in a mouse model, focuses on the impairment of the insulin signaling pathway in the placenta during pregnancies complicated by maternal obesity and gestational diabetes mellitus [ 8 ]. Additionally, four studies conducted in human samples have been included.…”