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Introduction 10% calories from fat) or high fat diet (HFD; 60% from fat) ad lib to induce obesity. After 4 weeks, HFD-fed mice were separated, creating 4 groups: (1) continued LFD, (2) continued HFD, (3) HFD with SGLT2i canagliflozin (CANA, 25 mg/kg/day), or (4) HFD with 15-30% caloric restriction (CR) to achieve weight matched to HFD-CANA (n=16/group). HFD-CANA and HFD-CR had lower weight and glucose vs. HFD (P0.05). At 16 weeks, males were bred with chow-fed females. After pregnancy confirmation, day 3.5 blastocysts were isolated, and pools from each of the 4 groups were analyzed using mass spectrometry; metabolomic data were analyzed using Metaboanalyst. Results: Blastocysts derived from HFD males had reductions in acetyl-CoA, α-ketoglutarate (α-KG), and S-adenosyl-L-methionine (SAM) (P0.05), while decarboxylated-SAM (dc-SAM) (P0.05) was increased vs. LFD. This pattern was largely reversed in blastocysts derived from HFD-CANA males, with increased acetyl-CoA, α-KG and SAM and decreased dc-SAM (P0.05) vs. HFD. Changes in HFD-CR shared some features with HFD-CANA, including reduced dc-SAM (P0.05) and increased spermidine and spermine (P0.05). Conclusion: Paternal HFD and interventions to improve paternal metabolism can modulate the blastocyst metabolome. Top-ranking regulated metabolites are key constituents of one-carbon metabolism and cofactors for epigenetic regulation including DNA methylation and histone modification; thus, changes in the early-embryo metabolome could contribute to sustained differences in epigenetic control and offspring phenotypes. Disclosure R. Ferraz-Bannitz: None. B. Ozturk: None. V. Efthymiou: None. M. Patti: Research Support; Dexcom, Inc. Consultant; Hanmi Pharm. Co., Ltd., MBX Biosciences. Other Relationship; Fractyl Health, Inc. Consultant; AstraZeneca, Spruce Biosciences.
Ferraz‐Bannitz et al. (Fri,) studied this question.