Thyroid hormone excess secondary to global type 3 deiodinase(DIO3)deficiency leads to increased locomotor activity and reduced adiposity,but also to concurrent alterations in parameters of the leptin-melanocortin syst...Thyroid hormone excess secondary to global type 3 deiodinase(DIO3)deficiency leads to increased locomotor activity and reduced adiposity,but also to concurrent alterations in parameters of the leptin-melanocortin system that would predict obesity.To distinguish the underlying contributions to the energy balance phenotype of Dlo3 deficiency,we generated mice with thyroid hormone excess targeted to pro-opiomelanocortin(POMC)-expressing cells via cell-specific DIO3 inactivation.These mice exhibit a male-specific phenotype of reduced hypothalamic Pomc expression,hyperphagia,and increased activity in brown adipose tissue,with adiposity and serum levels of leptin and thyroid hormones remained normal.These male mice also manifest a marked and widespread hypothalamic reduction in the expression of bone morphogenetic receptor 1a(BMPR1A),which has been shown to cause similar phenotypes when inactivated in PoMC-expressing cells.Our results indicate that developmental overexposure to thyroid hormone in PoMC-expressing cells programs energy balance mechanisms in a sexually dimorphic manner by suppressing adult hypothalamic BMPR1A expression.展开更多
Fragmented data suggest that bisphenol AF(BPAF),a chemical widely used in a variety of products,might have potential impacts on the hypothalamus.Here,we employed male neonatal mice following maternal exposure to explo...Fragmented data suggest that bisphenol AF(BPAF),a chemical widely used in a variety of products,might have potential impacts on the hypothalamus.Here,we employed male neonatal mice following maternal exposure to explore the effects of low-dose BPAF on hypothalamic development by RNA-sequencing.We found that maternal exposure to approximately 50μg/(kg·day)BPAF from postanal day(PND)0 to PND 15 altered the hypothalamic transcriptome,primarily involving the pathways and genes associated with extracellular matrix(ECM)and intercellular adhesion,neuroendocrine regulation,and neurological processes.Further RNA analysis confirmed the changes in the expression levels of concerned genes.Importantly,we further revealed that low-dose BPAF posed a stimulatory impact on pro-opiomelanocortin(POMC)neurons in the arcuate nucleus of the hypothalamus and induced the browning of inguinal white adipose tissue.All findings indicate that developmental exposure to low-dose BPAF could interfere with hypothalamic development and thereby lead to alterations in the metabolism.Interestingly,5000μg/(kg·day)BPAF caused slighter,non-significant or even inverse alterations than the low dose of 50μg/(kg·day),displaying a dose-independent effect.Further observations suggest that the the dose-independent effects of BPAF might be associated with oxidative stress and inflammatory responses caused by the high dose.Overall,our study highlights a risk of low-dose BPAF to human neuroendocrine regulation and metabolism.展开更多
基金We are grateful for the technical support of the Molecular Phenotyping,Histopathology and Histomorphometry,Confocal Microscopy,and Physiology Core facilities at MaineHealth Institute for Research.These core facilities are supported by grants P30GM106391,U54GM115516,and P20GM121301 from the National Institute of General Medical SciencesThis work was supported by grant DK095908(to A.H.)from the National Institute of Diabetes,Digestive and Kidney Diseases,National Institutes of Health,USA.
文摘Thyroid hormone excess secondary to global type 3 deiodinase(DIO3)deficiency leads to increased locomotor activity and reduced adiposity,but also to concurrent alterations in parameters of the leptin-melanocortin system that would predict obesity.To distinguish the underlying contributions to the energy balance phenotype of Dlo3 deficiency,we generated mice with thyroid hormone excess targeted to pro-opiomelanocortin(POMC)-expressing cells via cell-specific DIO3 inactivation.These mice exhibit a male-specific phenotype of reduced hypothalamic Pomc expression,hyperphagia,and increased activity in brown adipose tissue,with adiposity and serum levels of leptin and thyroid hormones remained normal.These male mice also manifest a marked and widespread hypothalamic reduction in the expression of bone morphogenetic receptor 1a(BMPR1A),which has been shown to cause similar phenotypes when inactivated in PoMC-expressing cells.Our results indicate that developmental overexposure to thyroid hormone in PoMC-expressing cells programs energy balance mechanisms in a sexually dimorphic manner by suppressing adult hypothalamic BMPR1A expression.
基金supported by the National Natural Science Foundation of China(No.21677166)the National Key Research and Development Program of China(No.2018YFA0901103)。
文摘Fragmented data suggest that bisphenol AF(BPAF),a chemical widely used in a variety of products,might have potential impacts on the hypothalamus.Here,we employed male neonatal mice following maternal exposure to explore the effects of low-dose BPAF on hypothalamic development by RNA-sequencing.We found that maternal exposure to approximately 50μg/(kg·day)BPAF from postanal day(PND)0 to PND 15 altered the hypothalamic transcriptome,primarily involving the pathways and genes associated with extracellular matrix(ECM)and intercellular adhesion,neuroendocrine regulation,and neurological processes.Further RNA analysis confirmed the changes in the expression levels of concerned genes.Importantly,we further revealed that low-dose BPAF posed a stimulatory impact on pro-opiomelanocortin(POMC)neurons in the arcuate nucleus of the hypothalamus and induced the browning of inguinal white adipose tissue.All findings indicate that developmental exposure to low-dose BPAF could interfere with hypothalamic development and thereby lead to alterations in the metabolism.Interestingly,5000μg/(kg·day)BPAF caused slighter,non-significant or even inverse alterations than the low dose of 50μg/(kg·day),displaying a dose-independent effect.Further observations suggest that the the dose-independent effects of BPAF might be associated with oxidative stress and inflammatory responses caused by the high dose.Overall,our study highlights a risk of low-dose BPAF to human neuroendocrine regulation and metabolism.
