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GH and GHR Signaling in Disease and Health

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (10 July 2021) | Viewed by 65593

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Dr. Vera M. Chesnokova

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Guest Editor

Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Interests: GH; DNA damage; cellular senescence; aging; cancer

Special Issue Information

Dear Colleagues,

Research on the effects of growth hormone (GH) on physiologic processes is generating much debate and controversy. Accumulating evidence supports the direct effects of GH on multiple cell types and tissues, independent of its systemic actions via the GH/IGF1 axis. GH is involved in bone, muscle, and adipose tissue homeostasis, as well as glucose metabolism.

The remarkable longevity and increased healthspan in animal models with GH signaling deficiency, and its protective effects in human patients with GHR mutation against cancer, diabetes, and atherosclerosis have led some to hypothesize that somatopause, or age-related decline in secreted GH, is an evolutionary mechanism defending from age-associated diseases. Based on these observations, GH-related products are being widely marketed as anti-aging therapy and enhancers of athletic performance. However, GH excess alters DNA damage repair, and many animal models with GH overexpression develop neoplasia and have a shorter life span. In cancers, GH excess modifies the tumor microenvironment, promoting chemo- and radiotherapy resistance. These findings highlight potentially adverse risks for GH administration in pituitary-replete adults.

These contrary findings undoubtedly reflect the large variety of molecular and cellular processes affected by GH. A better understanding of the molecular mechanisms driving GH action, as well as elucidation of involved pathways, is critically needed.

This Special Issue is a forum that will bring together a collection of original research articles, reviews, and communications covering any topics related to GH actions, and/or its physiological/pathophysiological roles.

Dr. Vera M. Chesnokova
Guest Editor

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Keywords

GH
GHR
animal models
tumorigenesis
metabolic pathways
GH signaling mutations
age-related pathologies
anti-aging therapy
longevity
somatopause

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 179 KiB

Open AccessEditorial

The Multiple Faces of the GH/IGF Axis

by Vera Chesnokova

Cells 2022, 11(2), 217; https://doi.org/10.3390/cells11020217 - 10 Jan 2022

Cited by 3 | Viewed by 1827

Abstract

Over the past two decades, interest in the role of the somatotroph growth hormone/insulin-like growth factor (GH/IGF1) axis in multiple aspects of physiology and pathology has grown exponentially [...] Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

Research

Jump to: Editorial, Review

19 pages, 2065 KiB

Open AccessArticle

Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP)

by Julia Brenmoehl, Christina Walz, Caroline Caffier, Elli Brosig, Michael Walz, Daniela Ohde, Nares Trakooljul, Martina Langhammer, Siriluck Ponsuksili, Klaus Wimmers, Uwe K. Zettl and Andreas Hoeflich

Cells 2021, 10(12), 3418; https://doi.org/10.3390/cells10123418 - 4 Dec 2021

Cited by 3 | Viewed by 2778

Abstract

The somatotropic axis is required for a number of biological processes, including growth, metabolism, and aging. Due to its central effects on growth and metabolism and with respect to its positive effects on muscle mass, regulation of the GH/IGF-system during endurance exercise is of particular interest. In order to study the control of gene expression and adaptation related to physical performance, we used a non-inbred mouse model, phenotype-selected for high running performance (DUhTP). Gene expression of the GH/IGF-system and related signaling cascades were studied in the pituitary gland and muscle of sedentary males of marathon and unselected control mice. In addition, the effects of three weeks of endurance exercise were assessed in both genetic groups. In pituitary glands from DUhTP mice, reduced expression of Pou1f1 (p = 0.002) was accompanied by non-significant reductions of Gh mRNA (p = 0.066). In addition, mRNA expression of Ghsr and Sstr2 were significantly reduced in the pituitary glands from DUhTP mice (p ≤ 0.05). Central downregulation of Pou1f1 expression was accompanied by reduced serum concentrations of IGF1 and coordinated downregulation of multiple GH/IGF-signaling compounds in muscle (e.g., Ghr, Igf1, Igf1r, Igf2r, Irs1, Irs2, Akt3, Gskb, Pik3ca/b/a2, Pten, Rictor, Rptor, Tsc1, Mtor; p ≤ 0.05). In response to exercise, the expression of Igfbp3, Igfbp 4, and Igfbp 6 and Stc2 mRNA was increased in the muscle of DUhTP mice (p ≤ 0.05). Training-induced specific activation of AKT, S6K, and p38 MAPK was found in muscles from control mice but not in DUhTP mice (p ≤ 0.05), indicating a lack of mTORC1 and mTORC2 activation in marathon mice in response to physical exercise. While hormone-dependent mTORC1 and mTORC2 pathways in marathon mice were repressed, robust increases of Ragulator complex compounds (p ≤ 0.001) and elevated sirtuin 2 to 6 mRNA expression were observed in the DUhTP marathon mouse model (p ≤ 0.05). Activation of AMPK was not observed under the experimental conditions of the present study. Our results describe coordinated downregulation of the somatotropic pathway in long-term selected marathon mice (DUhTP), possibly via the pituitary gland and muscle interaction. Our results, for the first time, demonstrate that GH/IGF effects are repressed in a context of superior running performance in mice. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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21 pages, 4930 KiB

Open AccessArticle

Dynamic Regulation of GH–IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury

by Christina Vohlen, Jasmine Mohr, Alexey Fomenko, Celien Kuiper-Makris, Tiffany Grzembke, Rabia Aydogmus, Rebecca Wilke, Dharmesh Hirani, Jörg Dötsch and Miguel A. Alejandre Alcazar

Cells 2021, 10(11), 2947; https://doi.org/10.3390/cells10112947 - 29 Oct 2021

Cited by 9 | Viewed by 2725

Abstract

Prematurely born infants often require supplemental oxygen that impairs lung growth and results in arrest of alveolarization and bronchopulmonary dysplasia (BPD). The growth hormone (GH)- and insulin-like growth factor (IGF)1 systems regulate cell homeostasis and organ development. Since IGF1 is decreased in preterm infants, we investigated the GH- and IGF1 signaling (1) in newborn mice with acute and prolonged exposure to hyperoxia as well as after recovery in room air; and (2) in cultured murine lung epithelial cells (MLE-12) and primary neonatal lung fibroblasts (pLFs) after treatment with GH, IGF1, and IGF1-receptor (IGF1-R) inhibitor or silencing of GH-receptor (Ghr) and Igf1r using the siRNA technique. We found that (1) early postnatal hyperoxia caused an arrest of alveolarization that persisted until adulthood. Both short-term and prolonged hyperoxia reduced GH-receptor expression and STAT5 signaling, whereas Igf1 mRNA and pAKT signaling were increased. These findings were related to a loss of epithelial cell markers (SFTPC, AQP5) and proliferation of myofibroblasts (αSMA⁺ cells). After recovery, GH-R-expression and STAT5 signaling were activated, Igf1r mRNA reduced, and SFTPC protein significantly increased. Cell culture studies showed that IGF1 induced expression of mesenchymal (e.g., Col1a1, Col4a4) and alveolar epithelial cell type I (Hopx, Igfbp2) markers, whereas inhibition of IGF1 increased SFTPC and reduced AQP5 in MLE-12. GH increased Il6 mRNA and reduced proliferation of pLFs, whereas IGF1 exhibited the opposite effect. In summary, our data demonstrate an opposite regulation of GH- and IGF1- signaling during short-term/prolonged hyperoxia-induced lung injury and recovery, affecting alveolar epithelial cell differentiation, inflammatory activation of fibroblasts, and a possible uncoupling of the GH-IGF1 axis in lungs after hyperoxia. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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14 pages, 3192 KiB

Open AccessArticle

ARC^GHR Neurons Regulate Muscle Glucose Uptake

by Juliana Bezerra Medeiros de Lima, Lucas Kniess Debarba, Alan C. Rupp, Nathan Qi, Chidera Ubah, Manal Khan, Olesya Didyuk, Iven Ayyar, Madelynn Koch, Darleen A. Sandoval and Marianna Sadagurski

Cells 2021, 10(5), 1093; https://doi.org/10.3390/cells10051093 - 3 May 2021

Cited by 15 | Viewed by 3836

Abstract

The growth hormone receptor (GHR) is expressed in brain regions that are known to participate in the regulation of energy homeostasis and glucose metabolism. We generated a novel transgenic mouse line (GHR^cre) to characterize GHR-expressing neurons specifically in the arcuate nucleus of the hypothalamus (ARC). Here, we demonstrate that ARC^GHR+ neurons are co-localized with agouti-related peptide (AgRP), growth hormone releasing hormone (GHRH), and somatostatin neurons, which are activated by GH stimulation. Using the designer receptors exclusively activated by designer drugs (DREADD) technique to control the ARC^GHR+ neuronal activity, we demonstrate that the activation of ARC^GHR+ neurons elevates a respiratory exchange ratio (RER) under both fed and fasted conditions. However, while the activation of ARC^GHR+ promotes feeding, under fasting conditions, the activation of ARC^GHR+ neurons promotes glucose over fat utilization in the body. This effect was accompanied by significant improvements in glucose tolerance, and was specific to GHR⁺ versus GHRH⁺ neurons. The activation of ARC^GHR+ neurons increased glucose turnover and whole-body glycolysis, as revealed by hyperinsulinemic-euglycemic clamp studies. Remarkably, the increased insulin sensitivity upon the activation of ARC^GHR+ neurons was tissue-specific, as the insulin-stimulated glucose uptake was specifically elevated in the skeletal muscle, in parallel with the increased expression of muscle glycolytic genes. Overall, our results identify the GHR-expressing neuronal population in the ARC as a major regulator of glycolysis and muscle insulin sensitivity in vivo. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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11 pages, 3699 KiB

Open AccessCommunication

Hypothalamic GHR—SIRT1 Axis in Fasting

by Juliana Bezerra Medeiros de Lima, Chidera Ubah, Lucas Kniess Debarba, Iven Ayyar, Olesya Didyuk and Marianna Sadagurski

Cells 2021, 10(4), 891; https://doi.org/10.3390/cells10040891 - 14 Apr 2021

Cited by 10 | Viewed by 3316

Abstract

Many aspects of physiological functions are controlled by the hypothalamus, a brain region that connects the neuroendocrine system to whole-body metabolism. Growth hormone (GH) and the GH receptor (GHR) are expressed in hypothalamic regions known to participate in the regulation of feeding and whole-body energy homeostasis. Sirtuin 1 (SIRT1) is the most conserved mamma-lian nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacetylase that plays a key role in controlling life span and sensing nutrient availability in the hypothalamus in response to caloric restriction. However, the interaction between GHR signaling and SIRT1 in the hypothal-amus is not established. In the arcuate nucleus (ARC) of the hypothalamus, the anorexigenic proopiomelanocortin (POMC)-expressing neurons and the orexigenic agouti-related protein (AgRP)-expressing neurons are the major regulators of feeding and energy expenditure. We show that in the ARC, the majority of GHR-expressing neurons also express SIRT1 and respond to fasting by upregulating SIRT1 expression. Accordingly, hypothalamic upregulation of SIRT1 in response to fasting is blunted in animals with GHR deletion in the AgRP neurons (AgRP^EYFPΔGHR). Our data thus reveal a novel interaction between GH and SIRT1 in responses to fasting. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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Review

Jump to: Editorial, Research

23 pages, 875 KiB

Open AccessFeature PaperReview

Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism

by Mari C. Vázquez-Borrego, Mercedes del Rio-Moreno and Rhonda D. Kineman

Cells 2021, 10(10), 2532; https://doi.org/10.3390/cells10102532 - 24 Sep 2021

Cited by 23 | Viewed by 6284

Abstract

Growth hormone (GH) is critical for achieving normal structural growth. In addition, GH plays an important role in regulating metabolic function. GH acts through its GH receptor (GHR) to modulate the production and function of insulin-like growth factor 1 (IGF1) and insulin. GH, IGF1, and insulin act on multiple tissues to coordinate metabolic control in a context-specific manner. This review will specifically focus on our current understanding of the direct and indirect actions of GH to control liver (hepatocyte) carbohydrate and lipid metabolism in the context of normal fasting (sleep) and feeding (wake) cycles and in response to prolonged nutrient deprivation and excess. Caveats and challenges related to the model systems used and areas that require further investigation towards a clearer understanding of the role GH plays in metabolic health and disease are discussed. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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39 pages, 4179 KiB

Open AccessReview

Regulation of GH and GH Signaling by Nutrients

by Marina Caputo, Stella Pigni, Emanuela Agosti, Tommaso Daffara, Alice Ferrero, Nicoletta Filigheddu and Flavia Prodam

Cells 2021, 10(6), 1376; https://doi.org/10.3390/cells10061376 - 2 Jun 2021

Cited by 56 | Viewed by 17624

Abstract

Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF-I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, and treatment of GH/IGF-I deficiency or excess during life. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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29 pages, 4959 KiB

Open AccessReview

The Role of GH/IGF Axis in Dento-Alveolar Complex from Development to Aging and Therapeutics: A Narrative Review

by Kouassi Armel Koffi, Sophie Doublier, Jean-Marc Ricort, Sylvie Babajko, Ali Nassif and Juliane Isaac

Cells 2021, 10(5), 1181; https://doi.org/10.3390/cells10051181 - 12 May 2021

Cited by 12 | Viewed by 5823

Abstract

The GH/IGF axis is a major regulator of bone formation and resorption and is essential to the achievement of normal skeleton growth and homeostasis. Beyond its key role in bone physiology, the GH/IGF axis has also major pleiotropic endocrine and autocrine/paracrine effects on mineralized tissues throughout life. This article aims to review the literature on GH, IGFs, IGF binding proteins, and their respective receptors in dental tissues, both epithelium (enamel) and mesenchyme (dentin, pulp, and tooth-supporting periodontium). The present review re-examines and refines the expression of the elements of the GH/IGF axis in oral tissues and their in vivo and in vitro mechanisms of action in different mineralizing cell types of the dento-alveolar complex including ameloblasts, odontoblasts, pulp cells, cementoblasts, periodontal ligament cells, and jaw osteoblasts focusing on cell-specific activities. Together, these data emphasize the determinant role of the GH/IGF axis in physiological and pathological development, morphometry, and aging of the teeth, the periodontium, and oral bones in humans, rodents, and other vertebrates. These advancements in oral biology have elicited an enormous interest among investigators to translate the fundamental discoveries on the GH/IGF axis into innovative strategies for targeted oral tissue therapies with local treatments, associated or not with materials, for orthodontics and the repair and regeneration of the dento-alveolar complex and oral bones. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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14 pages, 2752 KiB

Open AccessReview

Central Regulation of Metabolism by Growth Hormone

by Jose Donato, Jr., Frederick Wasinski, Isadora C. Furigo, Martin Metzger and Renata Frazão

Cells 2021, 10(1), 129; https://doi.org/10.3390/cells10010129 - 11 Jan 2021

Cited by 45 | Viewed by 8136

Abstract

Growth hormone (GH) is secreted by the pituitary gland, and in addition to its classical functions of regulating height, protein synthesis, tissue growth, and cell proliferation, GH exerts profound effects on metabolism. In this regard, GH stimulates lipolysis in white adipose tissue and antagonizes insulin’s effects on glycemic control. During the last decade, a wide distribution of GH-responsive neurons were identified in numerous brain areas, especially in hypothalamic nuclei, that control metabolism. The specific role of GH action in different neuronal populations is now starting to be uncovered, and so far, it indicates that the brain is an important target of GH for the regulation of food intake, energy expenditure, and glycemia and neuroendocrine changes, particularly in response to different forms of metabolic stress such as glucoprivation, food restriction, and physical exercise. The objective of the present review is to summarize the current knowledge about the potential role of GH action in the brain for the regulation of different metabolic aspects. The findings gathered here allow us to suggest that GH represents a hormonal factor that conveys homeostatic information to the brain to produce metabolic adjustments in order to promote energy homeostasis. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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18 pages, 2054 KiB

Open AccessReview

Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

by Haim Werner, Rive Sarfstein, Karthik Nagaraj and Zvi Laron

Cells 2020, 9(11), 2446; https://doi.org/10.3390/cells9112446 - 9 Nov 2020

Cited by 22 | Viewed by 6441

Abstract

Laron syndrome (LS) is a rare genetic endocrinopathy that results from mutation of the growth hormone receptor (GH-R) gene and is typically associated with dwarfism and obesity. LS is the best characterized entity under the spectrum of the congenital insulin-like growth factor-1 (IGF1) deficiencies. Epidemiological analyses have shown that LS patients do not develop cancer, whereas heterozygous family members have a cancer prevalence similar to the general population. To identify genes and signaling pathways differentially represented in LS that may help delineate a biochemical and molecular basis for cancer protection, we have recently conducted a genome-wide profiling of LS patients. Studies were based on our collection of Epstein–Barr virus (EBV)-immortalized lymphoblastoid cell lines derived from LS patients, relatives and healthy controls. Bioinformatic analyses identified differences in gene expression in several pathways, including apoptosis, metabolic control, cytokine biology, Jak-STAT and PI3K-AKT signaling, etc. Genes involved in the control of cell cycle, motility, growth and oncogenic transformation are, in general, down-regulated in LS. These genetic events seem to have a major impact on the biological properties of LS cells, including proliferation, apoptosis, response to oxidative stress, etc. Furthermore, genomic analyses allowed us to identify novel IGF1 downstream target genes that have not been previously linked to the IGF1 signaling pathway. In summary, by ‘mining’ genomic data from LS patients, we were able to generate clinically-relevant information in oncology and, potentially, related disciplines. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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14 pages, 1511 KiB

Open AccessReview

Growth Hormone-Releasing Hormone in Lung Physiology and Pulmonary Disease

by Chongxu Zhang, Tengjiao Cui, Renzhi Cai, Medhi Wangpaichitr, Mehdi Mirsaeidi, Andrew V. Schally and Robert M. Jackson

Cells 2020, 9(10), 2331; https://doi.org/10.3390/cells9102331 - 21 Oct 2020

Cited by 20 | Viewed by 4830

Abstract

Growth hormone-releasing hormone (GHRH) is secreted primarily from the hypothalamus, but other tissues, including the lungs, produce it locally. GHRH stimulates the release and secretion of growth hormone (GH) by the pituitary and regulates the production of GH and hepatic insulin-like growth factor-1 (IGF-1). Pituitary-type GHRH-receptors (GHRH-R) are expressed in human lungs, indicating that GHRH or GH could participate in lung development, growth, and repair. GHRH-R antagonists (i.e., synthetic peptides), which we have tested in various models, exert growth-inhibitory effects in lung cancer cells in vitro and in vivo in addition to having anti-inflammatory, anti-oxidative, and pro-apoptotic effects. One antagonist of the GHRH-R used in recent studies reviewed here, MIA-602, lessens both inflammation and fibrosis in a mouse model of bleomycin lung injury. GHRH and its peptide agonists regulate the proliferation of fibroblasts through the modulation of extracellular signal-regulated kinase (ERK) and Akt pathways. In addition to downregulating GH and IGF-1, GHRH-R antagonist MIA-602 inhibits signaling pathways relevant to inflammation, including p21-activated kinase 1-signal transducer and activator of transcription 3/nuclear factor-kappa B (PAK1-STAT3/NF-κB and ERK). MIA-602 induces fibroblast apoptosis in a dose-dependent manner, which is an effect that is likely important in antifibrotic actions. Taken together, the novel data reviewed here show that GHRH is an important peptide that participates in lung homeostasis, inflammation, wound healing, and cancer; and GHRH-R antagonists may have therapeutic potential in lung diseases. Full article

(This article belongs to the Special Issue GH and GHR Signaling in Disease and Health)

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