A well choreographed ballet among the hypothalamus, the pituitary and thyroid gland maintains an equilibrium that allows the fetus to develop normally and use energy efficiently. When any of the steps in this delicate dance are botched, the risk of developmental and metabolic dysfunction rises.
"We found that at the beginning of the third week of gestation, the offspring of pregnant primates fed a high fat diet have lower levels of thyroid hormone than the offspring of primates fed a normal diet," said Dr. Melissa Suter, a postdoctoral associate in the laboratory of Dr. Kjersti Aagaard, associate professor of obstetrics and gynecology at Baylor College of Medicine. "The finding has really attracted the interest of people who study thyroid metabolism."
A report on their work appears on line in the journal Molecular Endocrinology.
Importance of thyroid
Building on that, Suter, Aagaard, the report’s senior author, and their colleagues sought to discover if the high fat diet affected regulation of the whole thyroid-producing system from the hypothalamus in the brain to the thyroid gland to the peripheral tissues that respond to thyroid hormone. Thyroid hormone is important because it is critical in regulating energy and thus has implications for weight maintenance. Thyroid is also important for fetal development. State health departments test the levels of thyroid hormone in the blood of newborns to prevent cognitive delay associated with very low levels.
"There is a fundamental question of what programs the thyroid hormone axis during development," said Aagaard. "Does obesity drive thyroid resistance or does hypothyroidism (low thyroid) drive obesity? We found that you can disrupt that complex network of the thyroid hormone axis with a high fat maternal diet."
"Thyroid hormone regulation is like a teeter totter," said Aagaard. "When you are low on thyroid hormone, your body increases production of thyroid stimulating hormone, which stimulates greater production of the thyroid hormone itself. Ideally, you are in perfect balance and the two are normal. Thyroid hormone is low in the fetuses exposed to a high fat diet but all the different components of the system that should drive that up are dysregulated. The system is no longer well balanced."
The problem extends from the brain to the liver, she said. Not only are the different forms of thyroid hormone low, but the genes that convert them to a form the cell can use are also out of kilter. Even the things that the thyroid hormones regulate fats and glucose are out of balance. Because Aagaard’s laboratory has not been previously involved in thyroid hormone research, they turned to other experts in the field who recommended they take an exhaustive approach to characterizing the fetal thyroid axis in their studies.
"We looked at the expression and production of nearly all known key proteins, hormones, and receptors important in regulating thyroid hormone. We looked from the brain to the thyroid gland and all the way down to the liver. We looked deeply into the regulation of the thyroid hormone receptor as well as the effector molecules. It is a deeply perturbed axis," she said.
Identifying changes in the womb
Aagaard’s laboratory is involved in identifying and studying changes that happen in the womb that can affect the risk of disease 40 years or more later.
“Changes in the thyroid axis in utero may make an individual more susceptible to the metabolic changes seen with obesity, diabetes or cardiovascular disease,” she said. “What is particularly interesting is that it appears that it is largely the maternal diet (and not maternal obesity per se) that most influences the fetal thyroid axis. We were particularly intrigued by the ability of the maternal diet to epigenetically program the thyroid hormone receptor beta histone code in the developing fetus.” (Histones are proteins in the cell nucleus that help package the DNA into nucleosomes and act as spools around which DNA winds.)
Others who took part in this work include Haleh Sangi-Haghpeykar, Lori Showalter, Cynthia Shope, Min Hu, Kathleen Brown, R. Alan Harris of BCM, Sarah Williams and Kevin L. Grove of the Oregon National Primate Center and Robert H. Lane of the University of Utah in Salt Lake City.
Funding for this work came from National Institutes of Health Director New Innovator Award, the National Institute of Child Health and Human Development/National Institute of Diabetes and Digestive and Kidney Diseases and the NIH Research Education and Career Horizon Institutional Research and Academic Career Development Award (REACH IRACDA).