Abstract
Objective Maternal hormonal status can have long-term effects on offspring metabolic health, likely regulated via epigenetic mechanisms. We elucidated the effect of maternal thyroid hormones on epigenetic regulation of Leptin (Lep) transcription in adipose tissue (AT) and investigated the role of DNA methylation at a Lep upstream enhancer (UE) in adipocyte biology.
Methods Pregnant mice were treated with Triiodothyronine (T3). Offspring body composition and adipose tissue were analysed at 6 months (treatment: N = 8, control: N = 12). DNA methylation at the Lep UE and Lep mRNA levels in gonadal white adipose tissue (gWAT) and leptin serum levels were measured. The Lep UE was hypomethylated in murine preadipocytes using a dCas9-SunTag-TET1 system, followed by differentiation. In human visceral AT samples (N = 52) from the Leipzig Obesity BioBank (LOBB) LEP UE methylation and LEP mRNA levels were assessed alongside leptin serum levels and correlated with body fat percentage. Causal relationships were explored using mediation analysis.
Results High maternal T3 levels reduced offspring body weight, total fat, and gWAT mass. Female offspring of T3-treated mothers showed lower Lep mRNA levels and higher Lep UE methylation compared to controls. CRISPR/dCas9 editing reduced Lep UE methylation by ∼20% in preadipocytes without altering Lep expression or lipid accumulation after differentiation. In humans, a mediation of sex-specific difference in body fat percentage via Lep UE methylation was found.
Conclusion Maternal thyroid hormones might affect offspring gWAT Lep expression in a sex-specific manner, potentially driven by DNA methylation at the Lep UE, influencing body fat percentage.
Competing Interest Statement
MB received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. All other authors declare that there are no conflicts of interests.