The impact of preconception parental obesogenic diets on offspring metabolic health in a rat model

Parental diet has emerged as a critical factor in programming offspring's metabolic health, yet the independent and combined effects of maternal and paternal obesogenic exposures remain largely underexplored (1, 2) . In Aotearoa New Zealand, obesity affects around one in three adults and one in eight children, disproportionately burdening Māori and Pacific communities (3) . Understanding how both parents contribute to offspring metabolic health is key for preventive strategies. Growing evidence suggests that increasing omega-3 intake can improve metabolic programming, offering a potential means to mitigate early obesogenic effects. Building on earlier findings of altered birth weight, this study examined adult offspring metabolism. The objective was to assess maternal, paternal, and combined obesogenic (OB) diet exposures on offspring energy metabolism and skeletal muscle citrate synthase (CS) activity, and to evaluate whether early-life omega-3 treatment could act as a rescue intervention. Male (pat) and female (mat) Sprague Dawley rats received either a control diet (CON) or OB diet for five weeks pre-mating. Females remained on their diets throughout pregnancy and lactation. Four parental diet groups were established: 1-matCON-patCON, 2-matCON-patOB, 3-matOB-patCON, and 4-matOB-patOB. Offspring from each group received either omega-3 or placebo from postnatal day (PN) 21-63. Indirect calorimetry at PN145 measured 24-h energy expenditure (EE) and respiratory exchange ratio (RER), and dark/light phase ratios were calculated to assess patterns of metabolic variation. CS activity was assessed in skeletal muscle at PN180. Statistical analysis was performed using one-way and two-way ANOVA with sex and treatment as factors. In females, offspring from 4-matOB-patOB parents showed reduced EE dark/light ratios compared with 1-matCON-patCON (p = 0.003) and 3-matOB-patCON (p = 0.04), indicating impaired metabolic flexibility. Early-life omega-3 intervention restored this EE variation in 4-matOB-patOB females, suggesting a protective effect. In males, EE ratios were reduced in 4-matOB-patOB compared with 2-matCON-patOB (p = 0.02) and 3-matOB-patCON (p = 0.04), and RER phase shifts were absent, reflecting disrupted substrate switching. Omega-3 rescued this RER rhythmicity in males but increased RER ratios in 3-matOB-patCON offspring (p = 0.04), highlighting context-dependent responses. CS activity was reduced in omega-3 treated males from 1-matCON-patCON parents (p = 0.04), pointing to potential adverse effects in low-risk backgrounds. Together, these outcomes demonstrate sex-specific programming, with males being more vulnerable to disrupted substrate switching, whereas females showed greater responsiveness to omega-3 rescue. These findings demonstrate that parental OB diets impair offspring EE and RER in a sex- and context-dependent manner, reflecting disrupted dark/light metabolic regulation. This disruption may represent an early pathway by which parental diet programs later metabolic disease risk. Early-life omega-3 provided targeted rescue but carried risks in low-risk settings, underscoring the need for tailored interventions and highlighting the importance of including both parents in strategies to break the cycle of obesity.