Dad’s Genes “Remote Control” Mom’s Metabolism to Benefit Fetus

The unborn baby “remote controls” its mother’s metabolism, resulting in a nutritional tug-of-war between the two. The mother’s body requires the baby to survive, but she also needs enough glucose and fats in her system to be able to deliver the baby, breastfeed, and reproduce again.

Recent research by the University of Cambridge looks at how the placenta communicates with the mother by releasing hormones so she can accommodate her baby’s growth. In pregnant women and other female mammals, the placenta develops alongside the fetus to assist the developing fetus.

Researchers selectively modified the signaling cells in the placenta that tell mothers to allot nutrients to their developing fetuses in pregnant mice.

It’s the first direct evidence that a gene inherited from the father is signaling to the mother to divert nutrients to the fetus.

Amanda Sferruzzi-Perri, Professor, Fetal and Placental Physiology, University of Cambridge

Amanda Sferruzzi-Perri is also a Fellow of St John’s College and co-senior author of the paper.

Dr. Miguel Constancia, MRC Investigator based at the Wellcome-MRC Institute of Metabolic Science and co-senior author of the paper, noted: “The baby’s remote control system is operated by genes that can be switched on or off depending on whether they are a ‘dad’s’ or ‘mum’s’ gene’, the so-called imprinted genes.”

Genes controlled by the father are ‘greedy’ and ‘selfish’ and will tend to manipulate maternal resources for the benefit of the fetuses, so to grow them big and fittest. Although pregnancy is largely cooperative, there is a big arena for potential conflict between the mother and the baby, with imprinted genes and the placenta thought to play key roles.

Dr. Miguel Constancia, MRC Investigator, Wellcome-MRC Institute of Metabolic Science

The results were published in Cell Metabolism by investigators from Cambridge’s Department of Physiology, Development, and Neuroscience and the Medical Research Council Metabolic Diseases Unit, part of the Wellcome-MRC Institute of Metabolic Science.

The genes governed by the father of the baby tend to promote fetal growth, while those governed by the mother tend to limit fetal growth.

Those genes from the mother that limit fetal growth are thought to be a mother’s way of ensuring her survival, so she doesn’t have a baby that takes all the nutrients and is too big and challenging to birth. The mother also has a chance of having subsequent pregnancies potentially with different males in the future to pass on her genes more widely.

Amanda Sferruzzi-Perri, Professor, Fetal and Placental Physiology, University of Cambridge

Investigators suppressed the expression of an essential imprinted gene called Igf2, which encodes a protein called “Insulin Like Growth Factor 2.” The gene encourages fetal growth and plays an important role in the development of fetal tissues such as the liver, placenta, and brain, similar to the hormone insulin, which is responsible for producing and adjusting glucose levels in circulation.

“If the function of Igf2 from the father is switched off in signaling cells, the mother doesn’t make enough amounts of glucose and lipids—fats—available in her circulation. These nutrients therefore reach the fetus in insufficient amounts and the fetus doesn’t grow properly,” states Dr. Jorge Lopez-Tello, a lead author of the study based at the University’s Department of Physiology, Development and Neuroscience.

The researchers discovered that removing Igf2 from the placenta’s signaling cells impacts the production of other hormones that influence how the mother’s pancreas produces insulin, as well as how her liver and other metabolic organs respond.

“We found Igf2 controls the hormones responsible for reducing insulin sensitivity in the mother during pregnancy. It means the mother’s tissues don’t absorb glucose so nutrients are more available in the circulation to be transferred to the fetus,” said Professor Sferruzzi-Perri.

Babies with Igf2 gene defects may be overgrown or have stunted growth. “Until now, we didn’t know that part of the Igf2 gene’s role is to regulate signaling to the mother to allocate nutrients to the fetus,” adds Professor Sferruzzi-Perri.

The mice experimented were smaller at birth, and their offspring developed diabetes and obesity early in life.

Professor Sferruzzi-Perri notes, “Our research highlights how important the controlled allocation of nutrients to the fetus is for the lifelong health of the offspring, and the direct role the placenta plays. The placenta is an amazing organ. At the end of pregnancy, the placenta is delivered by the mother, but the memories of how the placenta was functioning leaves a lasting legacy on the way those fetal organs have developed and then how they’re going to function through life.”

The next step is to comprehend how Igf2 regulates placental hormones and what those hormones do. Future research could assist scientists in developing new strategies to target the placenta to improve health outcomes for mothers and babies.

Mice are used in studies because their DNA organization and gene expression are similar to humans, with 98% of human genes having a mouse counterpart. They have reproductive and nervous systems similar to humans, and they suffer from many of the same diseases, like cancer, obesity, and diabetes.