The global rise in obesity and overweight, particularly among women of reproductive age, necessitates a deeper understanding of its impact on fetal health. Studies have highlighted the offspring's sensitivity to the nutritional environment during prenatal and postnatal periods, impacting the development of metabolic complications in adulthood. This intrauterine programming involves genetic regulation, with maternal high-fat diet (moHF) leading to a cyclical transgenerational transmission of metabolic dysfunction. While sex-dependent metabolic responses to moHF have been observed, the underlying mechanisms remain unclear. Adipose tissue (AT), a crucial organ for metabolic homeostasis, undergoes development during prenatal and postnatal periods, making it a potential target of moHF's influence. This study aimed to characterize the in vivo metabolic response to moHF in offspring at different time points and to explore the transcriptome and lipidome of visceral (VAT), subcutaneous (SAT), and brown (BAT) AT, focusing on sex-specific responses.

Several studies have demonstrated the detrimental effects of maternal obesity on offspring metabolism. These effects include altered insulin signaling, hepatic lipid modulation, and sex-dependent metabolic adaptations in adulthood. The intrauterine programming of obesity involves genetic regulation and cyclical transgenerational transmission. Adipose tissue development occurs early in life, making it susceptible to programming by maternal diet. Existing research has also shown sex-specific differences in metabolic adaptations to moHF, but the underlying mechanisms require further elucidation.

C57bl/6 mice dams were fed either a control diet (CD) or a high-fat diet (HFD) for 6 weeks before mating and throughout gestation and lactation. Offspring were weaned and then fed the HFD until sacrifice. In vivo metabolic response was characterized using nuclear magnetic resonance (NMR) at midterm and endterm. Visceral (VAT), subcutaneous (SAT), and brown (BAT) adipose tissues were collected for lipidomic analysis and RNA sequencing at endterm. The study used a variety of techniques including in vivo magnetic resonance imaging (MRI) to assess total adiposity and body composition, localized 1H-MRS to quantify the fatty acid composition of triglycerides, hematoxylin and eosin (H&E) staining to assess adipocyte morphology, biochemical assays for plasma glucose and insulin levels, LC-MS for triglyceride and fatty acid analysis, and RNA sequencing (RNA-seq) for transcriptomic analysis.

Maternal HFD altered adipocyte morphology and adipose transcriptional activity in a sex-dependent manner. Male offspring from moHF mothers exhibited VAT hyperplasia and reduced hypertrophy, while female offspring showed no significant changes in these parameters. Triglyceride profiles varied across adipose depots, sexes, and maternal diets. moHF resulted in sex-dependent triglyceride remodeling in WAT, particularly at midterm. In BAT, moHF affected triglyceride composition differently in males and females. In terms of gene expression, moHF modulated the offspring's transcriptome in a sex- and adipose depot-specific manner, affecting pathways related to insulin resistance, inflammation, and lipid metabolism. Male offspring exhibited increased insulin resistance and inflammation, while female offspring showed adaptations that may buffer against these negative metabolic consequences. In BAT, moHF differentially affected thermogenesis and inflammatory pathways in males and females, with female offspring exhibiting increased thermogenesis and males increased inflammation. Finally, sex chromosome-linked genes played a role in the sexual dimorphism observed in adipose tissue transcriptomes. The study showed differential expression of genes related to glucose metabolism, adipogenesis, and inflammation in VAT, SAT, and BAT, between males and females from moC and moHF groups.

This study's findings highlight the complex interplay between maternal diet, offspring sex, and adipose tissue development in programming metabolic health. The sex-specific adaptations observed in response to moHF suggest distinct metabolic vulnerabilities and protective mechanisms in male and female offspring. The protective adaptation seen in female offspring, potentially involving enhanced BAT thermogenesis and triglyceride remodeling, contrasts with the metabolic impairment observed in males characterized by increased VAT and inflammation. The differences in transcriptional regulation and lipid profiles across adipose depots suggest tissue-specific responses to moHF. The influence of sex chromosomes on gene expression further emphasizes the complexity of sex-dependent metabolic programming. These findings offer significant implications for understanding the developmental origins of metabolic syndrome and for developing targeted interventions to reduce the risk of obesity-related complications in offspring.

This research demonstrates that maternal HFD reprograms adipose tissue development and function in a sex- and tissue-dependent manner, influencing offspring's metabolic health. Female offspring show adaptations that may protect against metabolic dysfunction, while males exhibit increased risk. These sex-specific responses have implications for precision medicine and highlight the need for targeted interventions to mitigate the long-term consequences of maternal obesity on offspring. Future research should investigate the specific molecular mechanisms underlying these sex-dependent adaptations and explore the potential for therapeutic interventions to modulate these pathways.

The study used a mouse model, which may not perfectly replicate the complexities of human metabolic responses. The sample sizes, while determined based on prior experiments, could be considered for expansion to enhance statistical power. While the study focused on a specific high-fat diet, further research is needed to determine the generalizability of findings across different dietary compositions.