Biology subjects

Oelkrug, R.

Publications and source records attributed to Oelkrug, R..

2 recordsLinked to original sources

bioRxiv2024

Sex-specific role of epigenetic modification of a leptin upstream enhancer in the adipose tissue

ObjectiveMaternal 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. MethodsPregnant 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. ResultsHigh 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. ConclusionMaternal 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.

genetics↗

bioRxiv2017

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e. the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally-arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of a AKR/J mouse strain (B6-mtAKR) together with a C57BL/6J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to wild-type C57BL/6J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair metabolic health and lifespan in mice.\n\nHighlightsO_LIWe identify heteroplasmy of the adenine-repeat variation (9 to 13A) in nt5172 in the origin of light-strand DNA replication (OriL) in inbred mice.\nC_LIO_LIB6-mtAKR mice carry >20% 12A heteroplasmy in the OriL, while B6 mice carry only [~] 10% heteroplasmy.\nC_LIO_LIThe level of 12A heteroplasmy correlates to mtDNA copy number, glucose metabolism, and lifespan in mice.\nC_LIO_LIGiven the established role of mtDNA heteroplasmy in regards to endurance exercise performance in athletes, these findings may impact our understanding of metabolism and aging in humans.\nC_LI

genetics↗