Effects of maternal thermogenesis on fetal programming of growth and metabolism

• Applicant: Rebecca Ölkrug, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434396546

In recent years, epigenetic regulation of metabolic health became the focus of attention in metabolic medicine, as it represents a powerful tool to discover the origin of metabolic diseases where no major genetic cause can be identified. Maternal and environmental factors have been shown to control in utero epigenetic programming (= fetal programming) of the embryo and thereby to define the susceptibility for metabolic or endocrine disorders. While in recent years some steps have been taken in understanding the role of maternal metabolism on fetal programming, still little is known about the physiological role of environmental temperature on maternal-fetal interaction. Recently, we demonstrated that pharmacological interventions to treat gestational disorders such as hypertension can affect fetal programming by affecting the GH/IGF-1 axis, leading to dwarfism and insulin resistance in adulthood. Interestingly, dams displayed increased thermogenesis as a side-effect of the treatment. I hypothesized that this increase in maternal thermogenesis contributed to the observed changes in the epigenetic programming of the GH/IGF-1 axis. To test my hypothesis, I conducted a preliminary study where I exposed dams to different ambient temperatures (30°C-10°C) during pregnancy to stimulate maternal thermogenesis and analyzed the metabolic phenotype of their offspring. These preliminary unpublished data clearly demonstrated that maternal thermogenesis indeed modulates the offspring’s endocrine and metabolic status by changing the fetal epigenome. Interestingly, changes in GH/IGF-1 signaling levels might constitute one target of these fetal programming processes through mechanisms that are incompletely understood and the focus of this proposal.With this new conceptual framework using environmental temperature as an external stimulus, I aim to unravel the role of maternal thermogenesis in fetal metabolic programming and to identify the fetal epigenetic changes that contribute to metabolic disease susceptibility in adulthood. Tracing back metabolic and endocrine effects in the offspring to the underlying molecular pathway, I aim to determine novel targets of maternal fetal programming and to correlate the epigenetic changes to markers reacting sensitive to maternal thermogenesis (in particular brown adipose tissue thermogenesis).Connecting a maternal factor to changes in metabolic disease susceptibility in the offspring is of high clinical relevance concerning the increased prevalence of obesity and type II diabetes in young children. Thus, the proposed objective is not only the first step in understanding the influence of maternal thermogenesis on fetal programming of metabolic disease susceptibility, but will also provide novel targets and epigenetic mechanisms for future clinical studies.

• DFG Programme: Research Grants