High-fat (HF) diets, particularly those rich in saturated fatty acids, have been linked to impaired glucose metabolism and increased predisposition to glucose intolerance and type 2 diabetes by modifying the primary metabolic pathways, including insulin signaling [1]. Within the developmental programming field, maternal diet composition (e.g. HFD), nutritional status, and pre-existing metabolic complications prior to and/or during pregnancy and/or lactation strongly impact offspring's health and metabolism in a sex-specific manner [1], [2], [3], [4].

The quality of the maternal diet is also a crucial factor, as different types of fatty acids can trigger specific responses in the offspring's metabolic-related tissues [4], [5], [6], [7]. Our previous investigations revealed that maternal consumption of distinct types of fatty acids during pregnancy and lactation - whether saturated, trans, or n-3 polyunsaturated fatty acids - differently influences offspring's visceral fat mass, body weight gain, glucose response curve, and pro-inflammatory hepatic responses in males at 21 days of age. Early exposure to normolipidic diets rich in saturated and trans fatty acids was associated with health impairments in offspring, while maternal consumption of n-3 polyunsaturated fatty acids-based diets was suggested to be beneficial for offspring's health [6,7].

Early programmed responses (i.e. developmental programming) and epigenome regulation are considered interconnected processes that contribute to determine the offspring's phenotype. Developmental programming refers to adaptative responses of the fetus and/or neonate to adverse maternal environmental conditions, which can alter gene expression and permanently affect the structure and function of organs and tissues in the offspring. Consequently, negative responses to maternal unhealthy diet (e.g. HF diet) and/or nutritional status may modify the offspring's long-term phenotype and increase their susceptibility to developing metabolic diseases throughout life [5,[8], [9], [10]]. Epigenetics has been employed to partially explain the link between maternal environment and offspring phenotype. Moreover, evidence indicates that the earlier the developmental phase, the more critical the environmental influence on the offspring's phenotype [11]. Epigenetic markers have a transgenerational inheritance and are represented by DNA methylation, histone modifications, and micro RNAs (miRNAs) expression profiles [11]. In particular, miRNAs are a class of small non-coding RNA molecules that play a vital role in post-transcriptional gene regulation by binding to target messenger RNAs (mRNAs), leading to translational repression and degradation [12]. Dysregulation of miRNA expression in different tissues and experimental models has been associated with impaired metabolism, contributing to the development of pathological conditions such as obesity and type 2 diabetes [13], [14], [15].

Given the pivotal role of both lipid quantity and quality of the maternal diet, this study aimed to investigate whether modifying the pre-gestational lipid content of the diet could mitigate the metabolic damage observed in the offspring born to dams continuously exposed to an HF diet prior to conception and during pregnancy and lactation, with a particular emphasis on assessing sex-specific outcomes. We also explored the specific effects of maternal intake of normolipidic diets, containing different types of fatty acids (saturated and polyunsaturated n-3) on serum metabolites, adiposity, liver phenotype, and miRNA expression in male and female offspring.