Maternal high-fat diet programs white and brown adipose tissue lipidome and transcriptome in offspring in a sex- and tissue-dependent manner in mice

Objective: Childhood overweight and obesity are rising, and maternal obesity is a key contributor. Nutrition-driven transgenerational regulation of metabolic genes underlies developmental origins of metabolic syndrome, potentially differing by offspring sex. Methods: Female mice (dams) received control diet or high-fat diet (HFD) for 6 weeks before mating and throughout gestation and lactation. Offspring of both sexes were fed HFD post-weaning. White (visceral, subcutaneous) and brown adipose tissues (WAT, BAT) were assessed in vivo by MRI/MRS at midterm and endterm; tissues were collected at endterm for lipidomics and RNA sequencing to examine sex- and depot-specific programming. Results: Triglyceride (TG) profiles varied by depot, sex, and maternal diet. In females, maternal HFD remodeled TG in subcutaneous WAT and BAT and increased BAT thermogenesis and cell differentiation, potentially protecting against later metabolic complications. In males, maternal HFD promoted BAT whitening and VAT hyperplasia with impaired metabolic profile. Maternal HFD differentially programmed gene expression in WAT and BAT of female and male offspring. Conclusion: Maternal HFD modulates offspring metabolic profiles in a sex-dependent manner, with sex- and depot-specific gene programming in VAT, SAT, and BAT that may drive sexual dimorphism in metabolic adaptation.