Common and Uncommon Mouse Models of Growth Hormone Deficiency.

Mouse models of growth hormone deficiency (GHD) have provided important tools for uncovering the various actions of GH. Nearly 100 years of research using these mouse lines has greatly enhanced our knowledge of the GH/IGF-1 axis. Some of the shared phenotypes of the 5 "common" mouse models of GHD include reduced body size, delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, and enhanced insulin sensitivity.

Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy.

Excessive growth hormone (GH) has been shown to promote joint degeneration in both preclinical and clinical studies. Little is known about the effect of disrupted GH or GH receptor (GHR) on joint health. The goal of this study is to investigate joint pathology in mice with either germline (GHR) or adult inducible (iGHR) GHR deficiency.

Growth hormone receptor gene disruption.

Much of our understanding of growth hormone's (GH)'s numerous activities stems from studies utilizing GH receptor (GHR) knockout mice. More recently, the role of GH action has been examined by creating mice with tissue-specific or temporal GHR disruption. To date, 37 distinct GHR knockout mouse lines have been created.

GHR disruption in mature adult mice alters xenobiotic metabolism gene expression in the liver.

Background: Lifelong reduction of growth hormone (GH) action extends lifespan and improves healthspan in mice. Moreover, congenital inactivating mutations of GH receptor (GHR) in mice and humans impart resistance to age-associated cancer, diabetes, and cognitive decline. To investigate the consequences of GHR disruption at an adult age, we recently ablated the GHR at 6-months of age in mature adult (6mGHRKO) mice.

Increased Fibrosis in White Adipose Tissue of Male and Female bGH Transgenic Mice Appears Independent of TGF-β Action.

Fibrosis is a pathological state caused by excess deposition of extracellular matrix proteins in a tissue. Male bovine growth hormone (bGH) transgenic mice experience metabolic dysfunction with a marked decrease in lifespan and with increased fibrosis in several tissues including white adipose tissue (WAT), which is more pronounced in the subcutaneous (Sc) depot. The current study expanded on these initial findings to evaluate WAT fibrosis in female bGH mice and the role of transforming growth factor (TGF)-β in the development of WAT fibrosis.

Growth Hormone Alters Circulating Levels of Glycine and Hydroxyproline in Mice.

Growth hormone (GH) has established effects on protein metabolism, such as increasing protein synthesis and decreasing amino acid degradation, but its effects on circulating amino acid levels are less studied. To investigate this relationship, metabolomic analyses were used to measure amino acid concentrations in plasma and feces of mice with alterations to the GH axis, namely bovine GH transgenic (bGH; increased GH action) and GH receptor knockout (GHRKO; GH resistant) mice. To determine the effects of acute GH treatment, GH-injected GH knockout (GHKO) mice were used to measure serum glycine.

Promotion of Joint Degeneration and Chondrocyte Metabolic Dysfunction by Excessive Growth Hormone in Mice.

Objective: Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH) production, report pain in joints. We undertook this study to characterize the joint pathology of mice with overexpression of bovine GH (bGH) or a GH receptor antagonist (GHa) and to investigate the effect of GH on regulation of chondrocyte cellular metabolism.

Methods: Knee joints from mice overexpressing bGH or GHa and wild-type (WT) control mice were examined using histology and micro-computed tomography for osteoarthritic (OA) pathologies.

Long Term Weight Cycling Affects Fecal Microbiota of Mice.

Scope: Fighting obesity and associated comorbidities through dieting is not always sustained and results in a subsequent weight gain, a phenomenon referred to as weight cycling. Diet is among the most important factors in modifying the composition of gut microbiota. The objective of this work is to determine whether weight cycling affects the composition and the predicted function of mouse fecal bacteria on a long-term basis.

Disruption of Growth Hormone Receptor in Adipocytes Improves Insulin Sensitivity and Lifespan in Mice.

Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the effect that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity.

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma .

Knockdown of GH receptor (GHR) in melanoma cells downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters . We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling.

Covert actions of growth hormone: fibrosis, cardiovascular diseases and cancer.

Since its discovery nearly a century ago, over 100,000 studies of growth hormone (GH) have investigated its structure, how it interacts with the GH receptor and its multiple actions. These include effects on growth, substrate metabolism, body composition, bone mineral density, the cardiovascular system and brain function, among many others. Recombinant human GH is approved for use to promote growth in children with GH deficiency (GHD), along with several additional clinical indications.

Musculoskeletal Effects of Altered GH Action.

Growth hormone (GH) is a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1 (IGF-1) stimulation. GH draws its name from its anabolic effects on muscle and bone but also has distinct metabolic effects in multiple tissues. In addition to its metabolic and musculoskeletal effects, GH is closely associated with aging, with levels declining as individuals age but GH action negatively correlating with lifespan.

Excess Growth Hormone Alters the Male Mouse Gut Microbiome in an Age-dependent Manner.

The gut microbiome has an important role in host development, metabolism, growth, and aging. Recent research points toward potential crosstalk between the gut microbiota and the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Our laboratory previously showed that GH excess and deficiency are associated with an altered gut microbial composition in adult mice.

Regulation of 11β-HSD1 by GH/IGF-1 in key metabolic tissues may contribute to metabolic disease in GH deficient patients.

Patients with growth hormone deficiency (GHD) have many clinical features in common with Cushing's syndrome (glucocorticoid excess) - notably visceral obesity, insulin resistance, muscle myopathy and increased vascular mortality. Within key metabolic tissues, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to the active glucocorticoid, cortisol (11-dehydrocorticosterone and corticosterone in rodents respectively), and thus amplifies local glucocorticoid action. We hypothesize that 11β-HSD1 expression is negatively regulated by growth hormone (GH), and that GHD patients have elevated 11β-HSD1 within key metabolic tissues (leading to increased intracellular cortisol generation) which contributes to the clinical features of this disease.

Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan.

Studies in multiple species indicate that reducing growth hormone (GH) action enhances healthy lifespan. In fact, GH receptor knockout (GHRKO) mice hold the Methuselah prize for the world's longest-lived laboratory mouse. We previously demonstrated that GHR ablation starting at puberty (1.

Mice with gene alterations in the GH and IGF family.

Much of our understanding of GH's action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor.

Growth hormone alters gross anatomy and morphology of the small and large intestines in age- and sex-dependent manners.

Purpose: Growth hormone (GH) has an important role in intestinal barrier function, and abnormalities in GH action have been associated with intestinal complications. Yet, the impact of altered GH on intestinal gross anatomy and morphology remains unclear.

Methods: This study investigated the influence of GH signaling on gross anatomy, morphology, and fibrosis by characterizing the small and large intestines in male and female bovine growth hormone transgenic (bGH) mice and GH receptor gene-disrupted (GHR-/-) mice at multiple timepoints.

Transcriptome profiling of insulin sensitive tissues from GH deficient mice following GH treatment.

Purpose: Most studies that have examined the transcriptional response to GH have been performed with a single tissue. Thus, the current study performed RNASeq across three insulin-sensitive tissues of GH-treated GH deficient (GHKO) mice.

Methods: GHKO mice were injected with recombinant human GH (hGH) or vehicle daily for 5 days and adipose, liver, and muscle tissues were collected 4 h after the final injection.

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro.

Differential gene signature in adipose tissue depots of growth hormone transgenic mice.

Bovine growth hormone (bGH) transgenic mice mimic the clinical condition of acromegaly, having high circulating growth hormone (GH) levels. These mice are giant, have decreased adipose tissue (AT) mass, impaired glucose metabolism and a shortened lifespan. The detrimental effects of excess GH have been suggested, in part, to be a result of its depot-specific actions on AT.

Mouse models of growth hormone insensitivity.

Growth hormone (GH) induces pleiotropic effects on growth and metabolism via binding and subsequent activation of the growth hormone receptor (GHR) and its downstream signaling pathways. Growth hormone insensitivity (GHI) describes a group of disorders in which there is resistance to the action of GH and resultant insulin-like growth factor I (IGF-I) deficiency. GHI is commonly due to genetic disorders of the GH receptor causing GH receptor deficiency (e.

Crosstalk between the growth hormone/insulin-like growth factor-1 axis and the gut microbiome: A new frontier for microbial endocrinology.

Both the GH/IGF-1 axis and the gut microbiota independently play an important role in host growth, metabolism, and intestinal homeostasis. Inversely, abnormalities in GH action and microbial dysbiosis (or a lack of diversity) in the gut have been implicated in restricted growth, metabolic disorders (such as chronic undernutrition, anorexia nervosa, obesity, and diabetes), and intestinal dysfunction (such as pediatric Crohn's disease, colonic polyps, and colon cancer). Over the last decade, studies have demonstrated that the microbial impact on growth may be mediated through the GH/IGF-1 axis, pointing toward a potential relationship between GH and the gut microbiota.