Abstract
It is understood that intrauterine hyperglycemia increases the risk of obesity and diabetes in offspring of consecutive generations but its mechanisms remain obscure. This study is aimed at establishing an intrauterine hyperglycemia rat model to investigate the growth and glycolipid metabolic characteristics in transgenerational offspring and discuss the effects of Rho guanine nucleotide exchange factor 11 (ARHGEF11) and the PI3K/AKT signaling pathway in offspring development. The severe intrauterine hyperglycemia rat model was caused by STZ injection before mating, while offspring development and glycolipid metabolism were observed for the following two generations. The expression of ARHGEF11, ROCK1, PI3K, and AKT was tested in the liver and muscle tissue of F2 offspring. The results showed severe growth restriction in F1 offspring and obesity, fatty liver, and insulin resistance in female F2 offspring, especially the offspring of female intrauterine hyperglycemia-exposed parents (F2G♀C♂) and both (F2G♀G♂). The expression of ARHGEF11 and ROCK1 was significantly elevated; PI3K and phosphorylation of AKT were significantly decreased in liver tissues of F2G♀C♂ and F2G♀G♂. Our study revealed that intrauterine hyperglycemia could cause obesity and abnormal glycolipid metabolism in female transgenerational offspring; the programming effect of the intrauterine environment could cause a more obvious phenotype in the maternal line. Further exploration suggested that increased expression of ARHGEF11 and ROCK1 and the decreased expression of PI3K and phosphorylation of AKT in the liver could be responsible for the abnormal development in F2 offspring.
Highlights
Growing evidence has proved that the incidence of multiple diseases in adulthood is closely related to nutritional conditions and environmental exposure early in life, which developed into a new branch of scientific knowledge known as the developmental origins of health and disease (DOHaD) [1]
The mechanisms of intrauterine hyperglycemia affecting the glucolipid metabolism of offspring are still under discussion [5, 6]; this study is aimed at providing a basis for future research to explore the impact of intrauterine hyperglycemia on two generations of offspring and its corresponding mechanisms
Compared to F1C, F1G rats possessed significantly abnormal glucose tolerance, while the area under the curve (AUC) of OGTT was significantly lower in F1G than F1C rats when measured at 4, 12, 16, and 20 weeks and the serum insulin was significantly higher in F1G rats when measured at 8, 12, and 16 weeks
Summary
Growing evidence has proved that the incidence of multiple diseases in adulthood is closely related to nutritional conditions and environmental exposure early in life, which developed into a new branch of scientific knowledge known as the developmental origins of health and disease (DOHaD) [1]. Rho guanine nucleotide exchange factor 11 (ARHGEF11) is an activator of Rho GTPases that plays a fundamental role in the regulation of G protein signaling and a number of cellular processes, including insulin secretion, insulin signaling, and lipid metabolism. Rho protein kinase (ROCK), a serine/threonine (Ser/Thr) kinase, is the predominant and most direct effector molecule downstream of Rho GTPases [12, 13], and it can directly affect the Ser/Thr phosphorylation of the insulin receptor substrate (IRS) and regulate insulin resistance through the PI3K/AKT signaling pathway [14, 15]. Several studies have confirmed that ARHGEF11 affects the metabolism of glucose and fatty acids through the insulin signaling pathway and acts as a key determinant of metabolism- and obesity-associated pathologies [16,17,18].
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