Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue

Abstract

Brown adipose tissue (BAT) is an exclusive tissue of nonshivering thermogenesis. It is fueled by lipids and glucose and involved in energy and metabolic homeostasis. Intrauterine exposure to hyperglycemia during gestational diabetes mellitus may result in abnormal fetal development and metabolic phenotypes in adulthood. However, whether intrauterine hyperglycemia influences the development of BAT is unknown. In this study, mouse embryos were exposed to the intrauterine hyperglycemia environment by injecting streptozocin into pregnant mice at 1 d post coitum (dpc). The structure of BAT was examined by hematoxylin and eosin staining and immunohistochemical analysis. The glucose uptake in BAT was measured in vivo by [18F]‐fluoro‐2‐deoxyglucose–micro–positron emission tomography. The gene expression in BAT was determined by real‐time PCR, and the 5′‐C‐phosphate‐G‐3′ site‐specific methylation was quantitatively analyzed. Intrauterine hyperglycemia exposure resulted in the impaired structure of BAT and decreased glucose uptake function in BAT in adulthood. The expressions of the genes involved in thermogenesis and mitochondrial respiratory chain in BAT, such as Ucp1, Cox5b, and Elovl3, were down‐regulated by intrauterine hyperglycemia exposure at 18.5 dpc and at 16 wk of age. Furthermore, higher methylation levels of Ucp1, Cox5b, and Elovl3 were found in offspring of mothers with streptozotocin‐induced diabetes. Our results provide the evidence for enduring inhibitory effects of intrauterine hyperglycemia on BAT development in offspring. Intrauterine hyperglycemia is associated with increased DNA methylation of the BAT specific genes in offspring, which support an epigenetic involvement.—Yu, D.‐Q., Lv, P.‐P., Yan, Y.‐S., Xu, G.‐X., Sadhukhan, A., Dong, S., Shen, Y., Ren, J., Zhang, X.‐Y., Feng, C., Huang, Y.‐T., Tian, S., Zhou, Y., Cai, Y.‐T., Ming, Z.‐H., Ding, G.‐L., Zhu, H., Sheng, J.‐Z., Jin, M., Huang, H.‐F. Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue. FASEB J. 33, 5425–5439 (2019). http://www.fasebj.org

Relationship of prenatal maternal obesity and diabetes to offspring neurodevelopmental and psychiatric disorders: a narrative review

“…The effects of hyperglycemia are in rodent models partly mediated by epigenetic changes, being modifications of histones, DNA and noncoding RNAs ultimately influencing gene expression [102]. Indeed, maternal hyperglycemia is associated with increased DNA methylation in specific genes in offspring, inducing chronic effects for offspring development [103]. Furthermore, methylation-mediated epigenetic mechanisms for intergenerational susceptibility to metabolic disorders were found in a mouse model for GDM [104].…”

“…Furthermore, methylation-mediated epigenetic mechanisms for intergenerational susceptibility to metabolic disorders were found in a mouse model for GDM [104]. Epigenetic effects of obesity and diabetes on the offspring have in models been shown to occur not only at the fetus level, but also already in the oocyte and sperm [103][104][105][106] implying an influence of both maternal and paternal metabolic disorder [103][104][105][106][107]. Reported DNA methylation changes of maternal metabolic state with putative effects in the brain include, but are not limited to, those on offspring leptin signaling [93,108].…”

Gestational Diabetes Mellitus and Developmental Programming

“…A study of streptozotocin-induced maternal diabetes in mice showed an inhibitory effect of intrauterine hyperglycaemia exposure on the development of brown adipose tissue (BAT) in offspring, thereby impairing the glucose uptake function of BAT in adulthood [40]. The authors found a downregulation of BAT-associated genes, Ucp1 , Cox5b , and Elovl3 , which is accompanied by disorganized ultra-structure of mitochondria in BAT, probably contributing to intracellular lipid accumulation and fat-induced insulin resistance [40]. Another GDM mouse model showed altered DNA methylation patterns in pancreatic tissues, manifested as dyslipidaemia, impaired glucose tolerance, and insulin resistance with advancing age [41].…”

Maternal Roux-en-Y gastric bypass surgery reduces lipid deposition and increases UCP1 expression in the brown adipose tissue of male offspring

“…In agreement with this hypothesis, in the present study, for the first time, we showed that maternal obesity, induced by the CAF diet, can program the ETC of BAT in offspring, resulting in reductions in the expressions of CI and CIII. Similarly, Yu et al 38 have demonstrated that offspring born from diabetic dams present smaller expression of ETC and UCP1 in the BAT due to epigenetic DNA methylation. These findings indicate that the offspring of obese dams have a reduced flow of energetic substrates for oxidative phosphorylation, including lipids, and consequently a lower magnitude of the proton gradient, which is associated with histological characteristics, such as greater lipid deposition, suggesting hypoactivity of thermogenesis.…”