Sex‐Specific Effects of Myo‐Inositol Ingested During Lactation in the Improvement of Metabolic Health in Adult Rats

Abstract

Scope To examine the effects of myo‐inositol supplementation during lactation in male and female rats on metabolic parameters and its potential to reverse metabolic alterations associated with a moderate gestational calorie restriction. Methods and results The offspring of control and 25% gestational calorie‐restricted rats are supplemented with myo‐inositol or vehicle throughout lactation and exposed to a Western diet (WD) from 5 to 7 months of age. Blood parameters are measured and gene expression and protein levels in retroperitoneal white adipose tissue (rWAT) and liver are analyzed. In male offspring, but not in females, myo‐inositol supplementation resulted in lower fasting triglyceride and insulin levels and HOMA‐IR at 7 months, and reversed the alterations in these parameters due to gestational calorie restriction. The expression pattern of key genes in metabolism in rWAT and liver support the beneficial effect of myo‐inositol supplementation in reversing metabolic alterations programmed by gestational calorie restriction in male rats. Conclusions Myo‐inositol supplementation at physiological doses during lactation improves metabolic health and prevents the programmed trend to develop insulin resistance and hypertriglyceridemia in male rats acquired by inadequate fetal nutrition and exacerbated by a diabetogenic diet in adulthood. The absence of clear effects in females deserves further investigation.

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

“…In fact, a positive correlation between circulating levels of insulin and Insr mRNA levels has been found, particularly in male rats. These data on the early effects of myo-inositol on insulin signaling are in accordance with our previous finding showing that male animals treated with myo-inositol during lactation are more protected against the development of insulin resistance and hypertriglyceridemia after a diabetogenic diet in adulthood [ 31 ]. Contrarily, circulating myo-inositol levels were negatively correlated with hypothalamic Insr expression in males.…”

“…There is compelling evidence from intervention studies in animal models on the essential role of leptin ingested during lactation in the prevention of obesity and other related pathologies in adulthood since it ensures a correct programming and development of hypothalamic structures involved in energy metabolism [ 16 ]. Recent studies also point to myo-inositol as a milk component of potential interest since its supplementation at physiological doses during the suckling period has shown beneficial effects on the prevention of insulin resistance and hypertriglyceridemia in male offspring of calorie-restricted rats when exposed to an obesogenic diet in adulthood [ 31 ]. However, short-term programming effects of myo-inositol during lactation and whether it may also affect hypothalamic circuitry involved in energy homeostasis are still unknown.…”

“…After delivery, litters were equated to 10 pups per dam on day 1 of lactation (5 males and 5 females, when possible). Pups from all CR-dams were divided into 4 groups: CR-L, supplemented with an oral solution of recombinant murine leptin (PeproTech, London, UK), equivalent to five times the average amount ingested normally from maternal milk, as previously described [ 18 ]; CR-M, supplemented with an oral solution of myo-inositol (Sigma-Aldrich, St. Louis, MO, USA), equivalent to two times the average amount ingested normally from maternal milk, as previously detailed [ 31 ]; CR-LM, supplemented with an oral combination of both compounds that provided animals the same amount of leptin and myo-inositol as CR-L and CR-M groups, respectively; and CR-V, treated with the vehicle (water). Pups from all CON-dams were treated with water (CON-V).…”

“…For hypothalamus, 0.25 µg of RNA (in a final volume of 12.5 µL) were denatured at 65 °C for 10 min and reverse transcribed using MuLV reverse transcriptase (Applied Biosystems, Madrid, Spain) at 25 °C for 10 min, 37 °C for 50 min, and 70 °C for 15 min. In the case of RNA from PBMC, cDNA was obtained using the iScript cDNA Synthesis Kit (Bio-Rad Laboratories, SA, Madrid, Spain), as previously described [ 31 ]. RT-qPCR reactions were carried out from diluted cDNA template (1/10 for hypothalamus and 1/5 for PBMC), forward and reverse primers (10 μM), and Power SYBER Green PCR Master Mix (Applied Biosystems, CA, USA), using the Applied Biosystems StepOne Plus Real-time PCR Systems (Applied Biosystem).…”

“…On the other hand, this compound has been found at increased levels in the milk of rat dams subjected to mild/moderate calorie restriction during lactation [ 27 ], a condition associated with a healthier metabolic profile of offspring both at a juvenile age [ 27 , 28 ] and in adulthood [ 28 , 29 , 30 ], contrary to the model of CR during gestation. Interestingly, myo-inositol supplementation at physiological doses during the suckling period has been shown to improve metabolic health in male rats, ameliorating the insulin resistance and hypertriglyceridemia programmed by moderate gestational calorie restriction (CR), particularly evident when animals were exposed to a diabetogenic diet in adulthood [ 31 ]. It is noteworthy that the lasting effects of myo-inositol supplementation at physiological doses during the suckling period in adult male rats are comparable, to some extent, to those described for leptin [ 21 ] since both compounds have been shown to be capable of reversing, at least in part, the postnatal sequelae in the phenotype associated with fetal malnutrition, particularly in terms of insulin resistance.…”