List, E. O. | bioRxiv Science

bioRxiv2026

Reproductive experience promotes permanent body growth independently of growth hormone

Pregnancy leads to many adaptations in the maternal body, some of which are reversible. However, reproductive experience can also result in permanent effects. Here, we investigated how pregnancy influences the somatotrophic system and the lasting effects of reproductive experience on the maternal organism. Reproductive experience induced a pronounced increase in lean body mass and longitudinal growth in both wild-type and growth hormone (GH)-deficient mice compared with age-matched virgins. Body growth was primarily observed during the first pregnancy, whereas a second gestation was mostly associated with increased adiposity. Increased GH secretion was observed in pregnant wild-type mice but not in pregnant GHRHR-deficient mice. Pregnancy-induced body growth is preserved despite disruption of GH-, ghrelin-, and estrogen-related signaling pathways. Data from a cohort of women with isolated GH deficiency (IGHD) caused by a loss-of-function mutation in the GHRHR gene revealed that nulliparous women were 7 cm shorter than those with one or more pregnancies. In conclusion, reproductive experience induces permanent changes in the maternal organism, promoting body growth in models that allow this response. Pregnancy-induced body growth appears to be independent of GH action. These findings underscore the need for further studies to investigate the long-lasting consequences of reproductive experience in females.

physiology↗

bioRxiv2025

Hepatic fructose metabolism is antagonized by growth hormone/insulin-like growth factor signaling via regulation of ketohexokinase expression

Overconsumption of added sugars such as fructose has been associated with a remarkable decline in metabolic health. Fructose is primarily metabolized by the small intestines and the liver, via phosphorylation mediated by ketohexokinase (KHK). KHK activity is traditionally viewed as lacking negative feedback mechanisms, such as those present to limit glucose metabolism, leading to excessive fat accumulation characteristic of metabolic dysfunction-associated liver disease (MASLD). In this study, we observe KHK downregulation in hepatocytes of diet-induced and genetic models of MASLD. Reduced KHK coincides with decreased flux of fructose-derived carbons into glycolytic and amino acid metabolic pathways, suggesting the presence of mechanisms that limit KHK-mediated fructolysis in the liver. We subsequently focused on the growth hormone (GH)/insulin-like growth factor (IGF) signaling pathway as a potential mechanism antagonizing KHK expression. In transgenic mice with enhanced GH signaling, KHK levels are reduced, whereas reduced GH activity leads to increased KHK expression. Additionally, administration of GH and IGF-1 in liver cell cultures induces time-dependent degradation of KHK, facilitated by direct interactions between KHK and the IGF-1 receptor (IGF-1R). Single-nuclei RNA sequencing revealed elevated IGF-1R expression in hepatocytes from diet-induced MASLD mice, supported by human MASLD patient samples, which also show reduced KHK expression. Taken together, these findings describe a novel pathway by which GH/IGF-1 signaling regulates KHK, offering new insights into how the liver adapts to metabolic stress to limit fructose-driven liver dysfunction.

molecular biology↗