Central Control of Cardiovascular Function and Energy Expenditure by Thyroid Hormone

• Applicant: Professor Dr. Jens Mittag
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258199564

Thyroid hormone is important for brain development and function, modulating behavior as well as the central control of cardiovascular properties and energy homeostasis. However, the underlying cellular and molecular mechanisms are not completely understood. The project of the first funding period aimed to exploit the importance of thyroid hormone and its receptor TRa1 in the central nervous system to obtain a better understanding of the autonomic control of cardiovascular and metabolic functions. Our studies revealed that maternal TRa1 signaling is required for correct fetal programming of cannabinoid receptor 1 expression in the ventromedial hypothalamus of the male wildtype offspring, which regulates their metabolic and locomotor activity. In the second funding period we now aim to study the role of maternal TRb signaling and hyperthyroidism for wildtype offspring. Our preliminary data indicate severe alterations in the cardiovascular and thermoregulatory regulation without alterations in thyroid hormone economy. By dissecting the peripheral and central alterations in these offspring of hyperthyroid mothers using state-of-the-art radiotelemetry and metabolic profiling, we aim to understand more about the central control of cardiovascular functions and energy expenditure.In the second part of the project, we analyzed the role of thyroid hormone for a population of hypothalamic parvalbumin neurons that control heart rate and blood pressure. Using a combination of TRa1 and TRb mutant mice as well as mothers with high thyroid hormone levels during pregnancy, we revealed that both TR isoforms are crucial for the development of these neurons: unliganded TRb seems required for maintaining the proliferation of the precursors cells until E12, whereas liganded TRa1 is necessary for the differentiation after E12 until birth. In the second funding period we now want to build on these findings and treat pregnant females from conception to E12 as well as from E12 to birth with thyroid hormone and analyze the consequences for hypothalamic parvalbumin neuron development as well as cardiovascular function in the offspring. Moreover, using stereotaxic injection of adeno-associated virus vectors, we aim to express dominant-negative and constitutively active thyroid hormone receptors specifically in these neurons to elucidate the role of thyroid hormone signaling for these cells in the adult animal. Our results will contribute to a better understanding of the role of thyroid hormone in the mother as well as the adult offspring for the central control of autonomic functions such as heart rate, blood pressure and exergy expenditure. Moreover, they can reveal previously unknown epigenetic risk factors for cardiovascular disease and obesity.

• DFG Programme: Research Grants