Effects of maternal thermogenesis on fetal programming of growth and metabolism
Final Report Abstract
Recent studies demonstrate that the intrauterine environment exerts a significant influence on the long-term metabolic health of the offspring. The identification of prenatal risk factors thus offers new perspectives for the development of targeted prevention strategies against metabolic disorders such as obesity and type 2 diabetes. Within the framework of the present project, the effects of maternal thermogenesis during pregnancy on the fetal programming of growth and metabolism were investigated. The focus was on the role of brown adipose tissue (BAT) as a central thermogenic organ. In the first experimental approach, pregnant wild-type mice were exposed to different ambient temperatures to physiologically modulate maternal BAT activity. Increased thermogenesis at 18 °C resulted in male offspring exhibiting reduced lean body mass and impaired glucose tolerance in adulthood (Oelkrug et al. 2020). In contrast, female offspring showed no comparable changes, indicating sex-specific effects in maternal programming. Molecular analyses of the liver in male offspring revealed persistent alterations in gene expression associated with impaired glucose homeostasis. Conversely, male offspring from dams with suppressed thermogenesis—induced either by genetic inactivation of uncoupling protein 1 (UCP1) or by thermoneutral housing—displayed increased skeletal muscle mass and improved glucose tolerance. These findings highlight the pivotal role of maternal thermogenesis in the metabolic programming of the offspring. In a second approach, pregnant mice were treated with the active thyroid hormone triiodothyronine (T3) to modulate maternal thermogenesis and metabolism. This intervention resulted in a sustained activation of BAT in male offspring, persisting into adulthood, and was associated with improved glucose tolerance . Again, female offspring remained unaffected. Complementary metabolomic analyses of the dams revealed significantly elevated serum concentrations of choline, an essential metabolite and key methyl group donor in epigenetic regulation via S-adenosylmethionine (SAM). In addition, elevated levels of fibroblast growth factor 21 (FGF21) were detected, which may represent a potential central regulator of maternal thermogenesis and energy homeostasis during pregnancy. In summary, the results demonstrate that increased maternal thermogenesis—induced by cold exposure or T3 administration—mediates a sex-specific, long-lasting metabolic programming of the offspring. These findings underscore the critical importance of maternal energy metabolism during pregnancy for the metabolic health of the next generation and suggest novel approaches for preventive and therapeutic interventions in metabolic diseases.
Publications
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Maternal Brown Fat Thermogenesis Programs Glucose Tolerance in the Male Offspring. Cell Reports, 33(5), 108351.
Oelkrug, Rebecca; Krause, Christin; Herrmann, Beate; Resch, Julia; Gachkar, Sogol; El Gammal, Alexander T.; Wolter, Stefan; Mann, Oliver; Oster, Henrik; Kirchner, Henriette & Mittag, Jens
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An improved method for the precise unravelment of non-shivering brown fat thermokinetics. Scientific Reports, 11(1).
Oelkrug, Rebecca & Mittag, Jens
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Maternal Thyroid Hormone Programs Cardiovascular Functions in the Offspring. Thyroid®, 31(9), 1424-1435.
Pedaran, Mehdi; Oelkrug, Rebecca; Sun, Qian; Resch, Julia; Schomburg, Lutz & Mittag, Jens
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Thyroid hormones in the regulation of brown adipose tissue thermogenesis. Endocrine Connections, 10(2), R106-R115.
Sentis, Sarah Christine; Oelkrug, Rebecca & Mittag, Jens
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Too Much Too Soon—Tissue-specific Inactivation of Deiodinase Type 3 Prematurely Exposes Brown Fat to Thyroid Hormone. Endocrinology, 163(5).
Oelkrug, Rebecca & Mittag, Jens
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Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring. Nature Communications, 14(1).
Oelkrug, Rebecca; Harder, Lisbeth; Pedaran, Mehdi; Hoffmann, Anne; Kolms, Beke; Inderhees, Julica; Gachkar, Sogol; Resch, Julia; Johann, Kornelia; Jöhren, Olaf; Krause, Kerstin & Mittag, Jens
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Sex-specific role of epigenetic modification of a leptin upstream enhancer in adipose tissue. Clinical Epigenetics, 17(1).
Müller, Luise; Oelkrug, Rebecca; Mittag, Jens; Hoffmann, Anne; Ghosh, Adhideb; Noé, Falko; Wolfrum, Christian; Guiu Jurado, Esther; Klöting, Nora; Dietrich, Arne; Blüher, Matthias; Kovacs, Peter; Krause, Kerstin & Keller, Maria
