Myo-Inositol Supplementation in Suckling Rats Protects against Adverse Programming Outcomes on Hypothalamic Structure Caused by Mild Gestational Calorie Restriction, Partially Comparable to Leptin Effects

Abstract

We studied whether myo-inositol supplementation throughout lactation, alone and combined with leptin, may reverse detrimental effects on hypothalamic structure and function caused by gestational calorie gestation (CR) in rats. Candidate early transcript-based biomarkers of metabolic health in peripheral blood mononuclear cells (PBMC) were also studied. Offspring of dams exposed to 25% gestational CR and supplemented during lactation with physiological doses of leptin (CR-L), myo-inositol (CR-M), the combination (CR-LM), or the vehicle (CR-V) as well as control rats (CON-V) were followed and sacrificed at postnatal day 25. Myo-inositol and the combination increased the number of neurons in arcuate nucleus (ARC) (only in females) and paraventricular nucleus, and myo-inositol (alone) restored the number of αMSH+ neurons in ARC. Hypothalamic mRNA levels of Lepr in CR-M and Insr in CR-M and CR-LM males were higher than in CR-V and CON-V, respectively. In PBMC, increased expression levels of Lrp11 and Gls in CR-V were partially normalized in all supplemented groups (but only in males for Gls). Therefore, myo-inositol supplementation throughout lactation, alone and combined with leptin, reverts programmed alterations by fetal undernutrition on hypothalamic structure and gene expression of potential early biomarkers of metabolic health in PBMC, which might be attributed, in part, to increased leptin sensitivity.

Early Life Programming of Adipose Tissue Remodeling and Browning Capacity by Micronutrients and Bioactive Compounds as a Potential Anti-Obesity Strategy

“…The effects were more apparent in males, who were also more sensitive than females to exposure to the obesogenic diet. Moreover, MI supplementation also partially reversed the postnatal phenotypic consequences linked to fetal malnutrition in terms of hypothalamic development, leading to an increased number of neurons in the ARC and PVN nuclei, albeit in a sex-dependent manner [226]. Interestingly, some of the effects of MI supplementation observed in these preclinical studies were comparable, to some extent, to those observed for leptin, both facilitating the reversal of adverse outcomes resulting from gestational undernutrition.…”

“…In animal models, it has been shown that treatment with exogenous leptin during the lactation period, but not in adulthood, promotes neuronal development and allows the recovery of neuronal projections of the arcuate nucleus interrupted in genetically leptin-deficient mice [222]. Likewise, oral supplementation with physiological doses of leptin during lactation reverses much of the alterations in the CNS caused by moderate gestational calorie restriction [225,226]. This was translated into a healthier phenotype in adulthood [227].…”

“…However, studies addressing the effects of MI present in milk are scarce. We recently investigated the impact of MI supplementation at physiological doses during the suckling period both in control rats and the offspring of rats exposed to gestational calorie restriction [198,226,262]. The effects were more evident in the offspring of dams undergoing gestational calorie restriction.…”

Leptin and Metabolic Programming

“…Interestingly, one of the articles of this Special Issue shows that some of the neurotrophic effects observed with leptin supplementation during the suckling period in the offspring of dams exposed to a mild/moderate calorie restriction during gestation are mimicked, to some extent, by myo-inositol supplementation [ 14 ]. Myo-inositol is a component of breast milk with a potential interest during development.…”

“…Such effects were comparable, to a certain extent, to those of leptin, and may account for the beneficial effects on the adult phenotype [ 15 ]. How myo-inositol exerts these effects is not yet established but considering that myoinositol supplemented animals displayed higher expression levels of the leptin receptor ( Lepr ) in the hypothalamus, it was hypothesized that myo-inositol may increase the sensitivity to leptin naturally ingested with milk [ 14 ]. It would be of interest to further explore this possibility as well as if other compounds may also empower leptin action during this critical period of development.…”