Background <p>Maternal consumption of monosaccharides during pregnancy and lactation can program long-term metabolic and neurobehavioral outcomes in offspring. The melanocortin-4 receptor (MC4R) is a key regulator of metabolism and behavior. However, the impact of maternal monosaccharide diets on MC4R signaling within mesocorticolimbic regions remains unclear. In this study, we investigated the effects of maternal glucose (GLU) and fructose (FRU) diets on metabolic, molecular, and neurochemical outcomes in offspring.</p> Methods <p>Adolescent and young adult male and female Wistar rat offspring, following maternal GLU and FRU exposure during pregnancy and lactation, underwent sucrose preference testing, intraperitoneal glucose tolerance tests, and serum lipid profiling. In addition, the gene expression of <i>Mc4r</i>, proopiomelanocortin (<i>Pomc</i>), agouti-related peptide (<i>Agrp</i>), and melanocortin-2 receptor accessory protein 2 (<i>Mrap2</i>) was quantified in the nucleus accumbens, prelimbic cortex, dorsal striatum, and basolateral amygdala, while the levels of MC4R protein were assessed in synaptosomal fractions from these brain regions.</p> Results <p>The maternal GLU diet reduced total calorie intake during lactation, while the FRU diet increased the dams’ caloric intake from sugar during both pregnancy and lactation. In the offspring, a maternal FRU diet increased sucrose consumption in young adult males and dysregulated glucose homeostasis in both adolescent and young adult males. Maternal monosaccharide diets also influenced serum lipid profiles and increased the body weights of their offspring. At the molecular level, region-, sex-, and age-specific changes in gene expression were observed, particularly the upregulation of <i>Mc4r</i>. Neurochemical analyses showed that maternal FRU diet increased synaptosomal MC4R levels in the mesocorticolimbic regions of young adult offspring. Principal component analysis revealed distinct clustering of metabolic and MC4R-related variables based on diet and sex, while regression analyses indicated significant diet-dependent correlations between MC4R levels and lipid parameters.</p> Conclusions <p>These findings suggest that maternal monosaccharide diets induce persistent alterations in the metabolic profiles of offspring and MC4R signaling, potentially contributing to the development of programmed metabolic and behavioral outcomes.</p> Clinical trial number <p>Not applicable.</p>