Unveiling the Role of Insulin Resistance and Placental Hormones in Fetal Development and Maternal Metabolism

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Insulin resistance during pregnancy has long been recognized as a physiological adaptation that ensures the adequate supply of glucose to the developing fetus.

This mechanism aims to limit maternal glucose utilization by target tissues, allowing for optimal fetal growth. In humans, there is a direct correlation between maternal glucose tolerance during pregnancy and birth weight, emphasizing the importance of insulin resistance in fetal development.

While the precise mechanisms underlying insulin resistance in pregnancy are not fully understood, it is believed that placental hormones play a significant role in this process. In particular, the peptide insulin-like growth factor 2 (IGF2), structurally similar to insulin and produced in placental endocrine cells, has been identified as a key player in establishing the state of insulin resistance during pregnancy.

Insights from Mouse Studies:

To shed light on the complex interplay between placental hormones and maternal metabolism, researchers have conducted studies using mouse models. In a recent study, the loss of Igf2 from the endocrine layer of the placenta in mice resulted in altered secretion of critical signaling proteins into the maternal circulation.

This disruption subsequently led to impaired maternal endocrine and lipid profiles. Analysis of placental endocrine cell function revealed defects in mitochondrial energetics and ribosome/translation capacity, as evidenced by the downregulation of key genes identified through single-nucleus RNA sequencing (snRNA-seq) techniques.

Interestingly, the density of endocrine cells in the placenta did not show significant differences, suggesting that changes in signaling likely occurred through autocrine and paracrine routes via the insulin receptor (IR) and downstream pathway proteins, such as PI3K (phosphoinositide 3-kinase), which were altered in the study. Previous research has already highlighted the importance of PI3K signaling in hormone expression by the mouse placenta.

Consequences for Maternal and Fetal Health:

The altered placental events caused by the loss of Igf2 ultimately rendered maternal organs more insulin sensitive, leading to significant implications for fetal development. The study strongly suggests that the observed effects, including fetal hypoglycemia, growth restriction, and compromised fetal viability, are primarily attributed to insufficient glucose and lipid delivery to the fetus.

This imbalance arises from increased glucose tolerance and insulin sensitivity in maternal organs, resulting in heightened glucose utilization by these tissues. Remarkably, the study reveals that the impaired endocrine signaling from the placenta to the mother, rather than defects in the transport epithelium, plays a pivotal role in compromising fetal growth trajectories.

Impaired Pancreatic β Cell Expansion:

Another noteworthy finding from the study is the failure of pancreatic β cell mass expansion in mothers carrying mutant Igf2 UE (uniparental expression) placentas. β cell mass expansion typically occurs in response to increased insulin resistance in maternal tissues during pregnancy.

The researchers speculate that the observed results reflect the inability to acquire the insulin resistance state due to the placenta’s deficient secretion of hormones necessary for β cell expansion, such as prolactins. Indeed, prolactin levels were found to be decreased in the circulation of UE dams. These findings provide insights into the potential molecular mechanisms underlying the regulation of pancreatic β cell mass expansion during pregnancy.

Evolutionary Significance and Human Implications:

Imprinted Igf2 expression in placental endocrine cells may have evolved as a strategy to mobilize nutrients to the growing fetus, aligning with the concept of imprinted genes evolving due to conflict. Pregnancy complications like pre-eclampsia and gestational diabetes can be viewed as instances where these conflict-based manipulation systems go awry, leading to increased blood pressure and glucose levels that primarily serve fetal interests rather than those of the mother. Supporting this proposal, previous research on human imprinting disorders such as Beckwith-Wiedemann Syndrome (BWS) and Silver-Russell Syndrome (SRS) has revealed metabolic abnormalities and altered hormonal profiles.

Studies in mouse models have shown that Igf2 deficiency in placental endocrine cells reduces the expression of prolactin genes and disrupts the expression of genes involved in hormonal regulation, suggesting a potential role in metabolic dysregulation.

Furthermore, the study highlights the programming effects on offspring. Male and female offspring with Igf2 deficiency in placental endocrine cells exhibited insulin resistance and increased adiposity, with the effect being more pronounced under conditions favoring a mismatch of programmed adaptations in utero (e.g., intrauterine growth restriction with a postnatal obesogenic environment). These findings open avenues for exploring the long-term phenotypic consequences in later adulthood and potential transgenerational effects on offspring.

Conclusion:

The research presented here provides experimental evidence of an intricate fetal manipulation system operating within the placenta to modify maternal metabolism and nutrient partitioning, with profound implications for the metabolic health and disease risk of offspring in later life.

Insights gained from this study enhance our understanding of the complex interactions between placental hormones, maternal metabolism, and fetal development. The findings may pave the way for further investigations into the role of placental imprinting in fetal programming of metabolic diseases, potentially uncovering novel therapeutic strategies to improve both maternal and offspring health outcomes.


reference link : https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00217-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413123002176%3Fshowall%3Dtrue#secsectitle0070

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