Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver

Luo, Qianqian; Hu, Jianan; Yang, Guang; Yuan, Xiaoyu; Chen, Zhongping; Wang, Dan; Lu, Yapeng; Zhu, Li; Wang, Guohua

doi:10.1007/s12011-020-02114-x

“…Ghsr expression was not detectable in either controls or Kiss1-GHSR KO females (data not shown), these findings are corroborated in multiple publications [ 57 , 58 ]. More recent publications have found that liver Ghsr expression does increase to detectable values after a 24 h fast, which we did not do [ 59 , 60 ]. These findings indicate that the differences in glucose levels after a 5 h fast are due, in part, to the central deletion of GHSR from Kiss1 neurons and not a peripheral deletion.…”

Section: Resultscontrasting

confidence: 86%

Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity

Conde

¹

,

Kulyk

²

,

Vanschaik

³

et al. 2022

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The gut peptide, ghrelin, mediates energy homeostasis and reproduction by acting through its receptor, growth hormone secretagogue receptor (GHSR), expressed in hypothalamic neurons in the arcuate (ARC). We have shown 17β-estradiol (E2) increases Ghsr expression in Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons, enhancing sensitivity to ghrelin. We hypothesized that E2-induced Ghsr expression augments KNDy sensitivity in a fasting state by elevating ghrelin to disrupt energy expenditure in females. We produced a Kiss1-GHSR knockout to determine the role of GHSR in ARC KNDy neurons. We found that changes in ARC gene expression with estradiol benzoate (EB) treatment were abrogated by the deletion of GHSR and ghrelin abolished these differences. We also observed changes in metabolism and fasting glucose levels. Additionally, knockouts were resistant to body weight gain on a high fat diet (HFD). Behaviorally, we found that knockouts on HFD exhibited reduced anxiety-like behavior. Furthermore, knockouts did not refeed to the same extent as controls after a 24 h fast. Finally, in response to cold stress, knockout females had elevated metabolic parameters compared to controls. These data indicate GHSR in Kiss1 neurons modulate ARC gene expression, metabolism, glucose homeostasis, behavior, and thermoregulation, illustrating a novel mechanism for E2 and ghrelin to control Kiss1 neurons.

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“…Total RNA extraction and RT‒PCR analysis were performed essentially as described previously ( Luo et al, 2021 ). Primer sequences were as follows:…”

Section: Methodsmentioning

confidence: 99%

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

Yang

¹

,

Li

²

,

Ding

³

et al. 2024

eLife

1

0

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High-altitude polycythemia (HAPC) occurs in high-altitude (HA) environments and involves an imbalance between erythropoiesis and eryptosis. Spleen/splenic macrophages are an important primary tissue/cell of eryptosis and iron recycling. However, the role of the spleen in the pathogenesis of HAPC and the effect of hypobaric hypoxia (HH) on the biology of the spleen and splenic macrophages are still unclear. We used a mouse hypobaric hypoxia (HH) exposure model to simulate an in vivo study of 6000 m HA exposure. For in vitro studies, we used a primary splenic macrophage model treated with 1% hypoxia. We found that the HH-treated mouse model promoted erythropoiesis and led to erythrocytosis. In addition, HH exposure resulted in marked splenic contraction followed by splenomegaly for up to 14 days. HH exposure impaired the red blood cell (RBC) handling capacity of the spleen, which was caused by a decrease in splenic macrophages in the red pulp. Moreover, HH treatment for 7 and 14 days promoted iron mobilization and ferroptosis in the spleen, as reflected by the expression of metabolism-related proteins and ferroptosis-related proteins. All of the protein expression levels were similar to the gene expression levels in human peripheral blood mononuclear cells. Single-cell sequencing of the spleen further demonstrated a significant decrease in macrophages in the spleen 7 days after HH exposure. In in vitro studies, we confirmed that primary splenic macrophages decreased and induced ferroptosis following hypoxic treatment, which was reversed by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Taken together, HH exposure induces splenic ferroptosis, especially in red pulp macrophages, which further inhibits the clearance of RBCs from the spleen. As such, it promotes the retention of RBCs in the spleen and causes splenomegaly, which may further lead to the persistent production of RBCs and ultimately to the development of HAPC.

show abstract

“…Total RNA extraction and RT‒PCR analysis were performed essentially as described previously [21]. Primer sequences were as follows:…”

Section: Methodsmentioning

confidence: 99%

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

Yang

¹

,

Li

²

,

Ding

³

et al. 2023

Preprint

0

View full text Add to dashboard Cite

High-altitude polycythemia (HAPC) occurs in high-altitude (HA) environments and involves an imbalance between erythropoiesis and eryptosis. Spleen/splenic macrophages are an important primary tissue/cell of eryptosis and iron recycling. However, the role of the spleen in the pathogenesis of HAPC and the effect of hypobaric hypoxia (HH) on the biology of the spleen and splenic macrophages are still unclear. We used a mouse hypobaric hypoxia (HH) exposure model to simulate an in vivo study of 6000 m HA exposure. For in vitro studies, we used a primary splenic macrophage model treated with 1% hypoxia. We found that the HH-treated mouse model promoted erythropoiesis and led to erythrocytosis. In addition, HH exposure resulted in marked splenic contraction followed by splenomegaly for up to 14 days. HH exposure impaired the red blood cell (RBC) handling capacity of the spleen, which was caused by a decrease in splenic macrophages in the red pulp. Moreover, HH treatment for 7 and 14 days promoted iron mobilization and ferroptosis in the spleen, as reflected by the expression of metabolism-related proteins and ferroptosis-related proteins. All of the protein expression levels were similar to the gene expression levels in human peripheral blood mononuclear cells. Single-cell sequencing of the spleen further demonstrated a significant decrease in macrophages in the spleen 7 days after HH exposure. In in vitro studies, we confirmed that primary splenic macrophages decreased and induced ferroptosis following hypoxic treatment, which was reversed by pre-treatment with the ferroptosis inhibitor ferrostatin-1. Taken together, HH exposure induces splenic ferroptosis, especially in red pulp macrophages, which further inhibits the clearance of RBCs from the spleen. As such, it promotes the retention of RBCs in the spleen and causes splenomegaly, which may further lead to the persistent production of RBCs and ultimately to the development of HAPC.

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Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver

Cited by 9 publications

References 45 publications

Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity

Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

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