proteins

2026-07-13 | Novel NPR2 heterozygous variant in a familial short stature and the therapeutic response to rhGH: a case report.

Natriuretic peptide receptor 2 (NPR2) expression in the hypertrophic zone of the growth plate is essential for endochondral ossification. Heterozygous variants in the NPR2 gene have been identified in 2-6 % of idiopathic short stature cases. Here, we present a large family with a novel heterozygous NPR2 variant, detailing endocrine features and long-term recombinant human growth hormone (rhGH) therapy outcomes. A total of 18 subjects among the family exhibited short stature. The proband was a 5.2-year-old boy presenting with proportionate short stature, delayed bone age, facial abnormalities, premature delivery, small for gestational age and hypospadias. Whole-exome sequencing revealed a novel heterozygous variant, c.553G>A variant, in the NPR2 gene, leading to the missense variant site in the extracellular ligand-binding domain of NPR2 protein. All the family members with NPR2 gene mutation demonstrated marked short stature, except for four subjects. Five other children who received rhGH therapy were also included in the results. The difference between bone age and chronological age in all six children ranged from -2.3 to 0 years. The average height SDS before rhGH treatment ranged from -4.01 to -1.20 (-2.59 ± 1.16). The treatment has lasted for 4.68 ± 2.68 years, and height SDS improved by 1.54 ± 0.78 after rhGH therapy. Our study confirms NPR2 variants as a cause of familial short stature (FSS), with variability in phenotypes, clinical features, and rhGH response, even within families. Early genetic testing might be crucial for offspring with FSS, as it allows for timely initiation of rhGH therapy.

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2026-03-25 | A cartilage-targeted IGF-1-antibody fusion protein as a new therapeutic approach for IGF-1 deficiency.

Growth hormone (GH) insensitivity syndrome (GHIS) is a childhood growth disorder characterized by an inability to generate insulin-like growth factor-1 (IGF-1) in response to GH. Consequently, GH therapy is ineffective in patients with GHIS. Patients are often treated with recombinant IGF-1 instead, which requires twice-daily injections and is associated with adverse effects including hypoglycemia. In the current study, we evaluated CV1623-1, a cartilage-targeted antibody-like IGF-1 fusion protein as a potential new treatment for GHIS and for other disorders of linear growth involving IGF-1 deficiency. Using Ghrhrlit mice as a model for IGF-1 deficiency, we found that CV1623-1 stimulated the growth plate at a lower dose and decreased dose frequency compared with IGF-1. Alternate-day injections of CV1623-1 significantly increased body weight, tail length, and tibial bone length. In addition, CV1623-1, unlike IGF-1, did not induce hypoglycemia. Taken together, our findings indicate that CV1623-1 represents a promising new drug candidate for GHIS with improved efficacy, longer duration of action, and reduced hypoglycemia compared with the current treatment, recombinant IGF-1. Preclinical studies and clinical trials would be required to further validate the safety and efficacy of CV1623-1, paving the way for its potential clinical application as a new treatment for GHIS.

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2026-03-09 | The role of GH/IGF-1 axis dysfunction and inflammatory cytokines in pediatric short stature.

Short stature in children is a common clinical condition frequently associated with abnormalities in the GH/IGF-1 axis. Emerging evidence points to the involvement of inflammatory cytokines and serum markers in modulating this dysfunction. This study aims to investigate the molecular pathways underlying GH/IGF-1 axis impairment and assess the levels of inflammatory cytokines and other related biomarkers in children with short stature. A total of 150 children diagnosed with short stature were recruited from the endocrinology department of a tertiary care hospital. An ageand sex-matched group of 150 healthy children served as controls for comparison. Serum concentrations of growth hormone (GH), insulin-like growth factor-1 (IGF-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and other relevant biomarkers were measured using enzyme-linked immunosorbent assay (ELISA). Genetic testing was performed to detect mutations in genes involved in the GH/IGF-1 signalling pathway. Data analysis was conducted using SPSS software, with statistical significance set at p< 0.05. Children with short stature showed significantly reduced GH and IGF-1 levels (p< 0.001) and elevated IL-6 and IL-8 levels (p< 0.01). A moderate negative correlation was found between IL-6 and IGF-1 levels (r=-0.45, p< 0.001), suggesting that inflammation may impair growth signalling. GHR gene mutations were significantly more common in the short stature group (14.7% vs. 2.7%, p< 0.001) and were associated with lower IGF-1 levels. This findings of the study suggest that impaired GH/IGF-1 signalling, increased inflammatory cytokines, and a higher prevalence of GHR gene mutations collectively contribute to the pathophysiology of pediatric short stature. These results highlight the need for integrative diagnostic approaches and future therapeutic strategies that target both endocrine and inflammatory pathways.

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2025-10-16 | Phosphoglucomutase 1 deficiency misdiagnosed as Laron syndrome.

Protein glycosylation is a crucial process involving the addition of oligosaccharides to proteins, which plays a significant role in stabilizing proteins and mediating protein-protein interactions. Mutations in genes associated with glycosylation can lead to congenital disorders of glycosylation (CDG), resulting in multisystem disorders. One such example is phosphoglucomutase 1 (PGM1) -CDG, caused by a deficiency of the PGM1 enzyme. In this report, we describe a patient with PGM1-CDG who was initially misdiagnosed with growth hormone insensitivity and benefited from recombinant human insulin-like growth factor-1 (rhIGF-1) therapy. A 2-year-11-month-old female patient, born to first-degree cousin parents, presented with hypoglycemia and short stature. Her physical examination revealed frontal bossing, infantile facial appearance, and short stature. Laboratory investigations revealed that basal and stimulated growth hormone levels were very high, IGF-1 was low, and the inadequate response to the IGF generation test was consistent with growth hormone insensitivity (GHI). The patient was started on rhIGF-1 therapy, resulting in significant height gain. Subsequently, the patient showed improvement in height with rhIGF-1 therapy. The patient, who had additional findings such as elevated creatine kinase (CK) and transaminase levels and cardiomyopathy, was diagnosed with PGM1-CDG. This case highlights that PGM1-CDG can mimic clinical and laboratory findings of GHI. CDG diagnosis should be considered in cases with clinical and laboratory findings of GHI accompanied by multisystem disorders such as hepatopathy, elevated CK, and cardiomyopathy. This patient's successful response to rhIGF-1 therapy highlights the potential benefits of targeted therapies in treating growth hormone-related disorders in patients.

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2025-10-01 | SAT-217 Severe Short Stature and Growth Hormone (GH) Insensitivity in an Adolescent Male Associated with a Novel Homozygous Variant in the GH Receptor Gene: A Unique Case of Laron Syndrome

Abstract Disclosure: V.X. Yu: None. M.E. Geffner: Diurnal, Novo Nordisk, Neurocrine Biosciences: Research support, Advisory board/Consultant, Spruce Biosciences: Research support, Advisory board/Consultant, Ascendis: Advisory board/Consultant, Eton Pharmaceuticals: Advisory board/Consultant, Theratechnologies, Inc: Advisory board/Consultant, McGraw-Hill: Royalties, Up To Date. L.M. Randolph: BioMarin Pharmaceuticals- Advisory board/consultant. Z. Laron: None. A. Ryabets-Lienhard: Ultragenyx, Principal investigator receiving grant support for research, Takeda, Principal investigator receiving grant support for research, Alexion Pharmaceuticals, Inc., Advisory board/consultant, BioMarin Pharmaceuticals- Advisory board/consultant. Introduction: Laron syndrome (LS) is a rare autosomal recessive disorder with an estimated 500 global cases, characterized by GH resistance due to pathogenic variants in the GH receptor (GHR) gene, resulting in primary IGF-1 deficiency. Affected patients exhibit severe short stature, distinctive facial features, and extremely low levels of IGF-1 despite normal or elevated GH levels. The broad spectrum of pathogenic GHR variants in LS includes missense, nonsense, splice-site, and deletion variants that often involve the extracellular (EC) GH binding domain of the GHR (exons 1-7) and result in low GH-binding protein (GHBP) levels. We present a unique case of an adolescent male with severe LS associated with a novel missense variant in GHR exon 7, but normal GHBP levels. Case: An almost 16-yr-old male of Mexican ancestry with no known significant family history or consanguinity presented with severe relatively proportional short stature (height -7.06 SD, BMI 0.37 SD). He had an infantile face with round cheeks, depressed nasal bridge, high-pitched voice, slightly blue sclerae, Tanner Stage (TS) 2 puberty with testosterone 77 ng/dL (8-66), and bone age 11.6 yr. He was found to have undetectable IGF-1 (&lt;10 ng/mL, 201-609) and low IGFBP-3 (0.8 mg/L, 3.5-10.0) with normal GH stimulation (peak GH 10.9 ng/mL) and GHBP (1446 pmol/L, 290-3140). TSH was elevated (6.43 mlU/mL, 0.50-5.00) with normal FT4 (1.09 ng/dL, 0.70-1.65). Genetic testing using the Discover Dysplasias gene panel (Invitae) identified a novel homozygous c.650T&gt;G (p.Val217Gly) variant in GHR exon 7, classified as a variant of uncertain significance, in the last codon of the EC binding domain. There was no response in IGF-1 generation testing to GH 33 mg/kg/day x 7 days (IGF-1 averaged 11 ng/dL, 201-609; -5.5 SD), further supporting a diagnosis of LS. After 3 mo, height remained -7.08 SD while puberty progressed to TS3 with increased testosterone (526 ng/dL, 26-800). TSH increased further to 9.74 mlU/mL with normal FT4 1.13 ng/dL. Patient started recombinant human IGF-1 therapy at 0.1 mg/kg once daily x 1 wk, then increased to 0.18 mg/kg once daily x 1 wk and subsequently to 0.12 mg/kg twice daily (with no hypoglycemia or other side effects). Letrozole (2.5 mg daily) was also started to delay epiphyseal fusion. Conclusion: This unique case of severe Laron syndrome involves a novel homozygous missense variant of uncertain significance in the EC GH binding domain of GHR with unexpectedly normal GHBP levels, potentially expanding the scope of known GHR pathogenic variants. Its position in the last codon of the EC domain adjacent to the transmembrane domain may explain normal GHBP levels with disruption of GH action downstream. Functional studies are planned to further analyze this novel variant and confirm its pathogenicity. The co-occurrence of subclinical hypothyroidism also warrants further study regarding its contribution to the LS phenotype. Presentation: Saturday, July 12, 2025

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small molecules

2026-05-01 | Growth hormone receptor blockade in cancer treatment.

Cancer remains as the most feared human disease and embodies deep psychological and physical suffering (1). It is one of the unsolved medical problems nowadays and constitutes a heavy burden not only for the individual and his family but also for health systems worldwide (2). In this context, cancer prevention and early diagnosis and treatment is of cardinal importance; hence, identification of cancer risk factors in the genesis of human cancer is an urgent necessity. Among these deleterious influences, obesity and aberrantly increased growth hormone receptor (GHR) signaling have been identified as two of the most relevant factors in the etiology of malignancy (3, 4). Considering the above premises, attempts at effectively and safely treating patients with cancer are within the noblest aims in medicine and science. At present, radical surgery, radio and chemotherapy, targeted therapy, and immunotherapy are the basis for dealing with this widespread issue (5). Nevertheless, and especially in several types of cancer, all efforts are ineffective (6). In consequence, strategies to discover new medicines aimed at safely and effectively treating individuals affected by cancer are needed. Similarly, adjuvant methods aimed at making more effective use of standard therapies are required. Contextually, a new experimental approach to dealing with melanoma, liver cancer, pancreatic cancer, and cholangiocarcinoma, some of the most lethal malignancies in humans, has been developed based on the previous discovery of a GHR antagonist used for acromegaly and its mode of action (7, 8). Development of new drugs for cancer treatment is partially based on observations in humans who have a distinct phenotype that combines obesity -the most epidemiologic risk factor in cancer etiology- along with absent growth hormone receptor (GHR) signaling (4, 9).

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2026-03-30 | The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation.

Insulin-like growth factor-1 (IGF-1) signaling plays a paradoxical role in aging, acting as both a mediator of tissue repair and a driver of chronic inflammation through the senescence-associated secretory phenotype (SASP). In this review, we propose a biphasic senescence switch model in which the temporal pattern of IGF-1 exposure, acute versus chronic, determines cellular fate. Transient IGF-1 signaling supports homeostasis and repair, whereas sustained activation promotes stable senescence via reactive oxygen species (ROS)-mediated DNA damage, p53/p21 pathway activation, and a potent pro-inflammatory SASP. Central to this process is IGF-binding protein-5 (IGFBP-5), which amplifies senescence in vascular and stromal cells by linking coagulation and inflammatory signals to p53-dependent arrest. The contrasting human conditions of IGF-1 deficiency (Laron syndrome) and excess (acromegaly) illustrate the lifespan and disease risks associated with dysregulated IGF-1 signaling. Emerging evidence highlights the role of extracellular vesicles in bypassing soluble IGFBP regulation, enabling paracrine propagation of senescence even under systemic IGF-1 modulation. Ultimately, we position the IGF-1/IGFBP axis as a prime target for precision senomodulation, advocating for combined strategies that temporally tune endocrine signaling with senolytic and senomorphic therapies to mitigate chronic inflammation, delay age-related dysfunction, and extend healthspan.

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2026-03-05 | JAK-STAT signaling: molecular mechanism and targeted treatment in dento-maxillofacial abnormalities.

Dento-maxillofacial abnormalities are highly prevalent and arise as a result of a variety of etiological factors, presenting substantial challenges to treatment. The JAK-STAT signaling plays a pivotal role in dentofacial development, regulating endochondral ossification, intramembranous ossification, dental follicle formation, and enamel development. Mutations in the JAK-STAT signaling lead to syndromes associated with severe dento-maxillofacial abnormalities, including Growth Hormone Insensitivity Syndrome and Autosomal Dominant Hyper-IgE Syndrome. Corresponding mouse disease models have been developed to simulate the phenotypes observed in clinical patients and investigate their underlying mechanism. Meanwhile, several medications targeting JAK-STAT signaling, including baricitinib and imatinib, have been developed for clinical application, demonstrating significant effects in skeletal disorders such as osteoporosis and osteoarthritis, indicating promising effects in development and abnormalities of dento-maxillofacial. In this review, we aim to summarize the role of JAK-STAT signaling in the development and abnormalities of dento-maxillofacial bone, and the relevant molecules that may be utilized for clinical treatment, to shed new light on the precise treatment of dento-maxillofacial abnormalities.

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2024-10-26 | In Vivo Effects of a GHR Synthesis Inhibitor During Prolonged Treatment in Dogs.

Background: The activation of the growth hormone receptor (GHR) is a major determinant of body growth. Defective GHR signaling, as seen in human Laron dwarfism, resulted in low plasma IGF-1 concentrations and limited growth, but also marked absence in the development of breast cancer and type 2 diabetes. In vitro, we identified a small molecule (C#1) that inhibits the translation of GHR mRNA to receptor protein. Methods: Before its application in humans as a potential anticancer drug, C#1 was tested in animals to evaluate whether it could be administered to achieve a plasma concentration in vivo that inhibits cell proliferation in vitro without causing unwanted toxicity. To evaluate the efficacy and toxicity of C#1, a group of six intact female Beagle dogs was treated daily each morning for 90 days with an oral solution of C#1 in Soiae oleum emulgatum at a dose of 0.1 mg/kg body weight. During treatment, dogs were closely monitored clinically, and blood samples were taken to measure plasma C#1 concentrations, complete blood counts (CBC), clinical chemistry, and endocrinology. At the end of the treatment, dogs were euthanized for gross and histopathological analysis. An additional group of six female Beagle dogs was included for statistical reasons and only evaluated for efficacy during treatment for 30 days. Results: Daily administration of C#1 resulted in a constant mean plasma concentration of approximately 50 nmol/L. In both groups, two out of six dogs developed decreased appetite and food refusal after 4-5 weeks, and occasionally diarrhea. No significant effects in CBC or routine clinical chemistry were seen. Plasma IGF-1 concentrations, used as biomarkers for defective GHR signaling, significantly decreased by 31% over time. As plasma growth hormone (GH) concentrations decreased by 51% as well, no proof of GHR dysfunction could be established. The measured 43% decrease in plasma acylated/non-acylated ghrelin ratios will also lower plasma GH concentrations by reducing activation of the GH secretagogue receptor (GHSR). C#1 did not directly inhibit the GHSR in vivo, as shown in vitro. There were no significant effects on glucose, lipid, or folate/homocysteine metabolism. Conclusions: It is concluded that with daily dosing of 0.1 mg C#1/kg body weight, the induction of toxic effects prevented further increases in dosage. Due to the concomitant decrease in both IGF-1 and GH, in vivo inhibition of GHR could not be confirmed. Since the concept of specific inhibition of GHR synthesis by small molecules remains a promising strategy, searching for compounds similar to C#1 with lower toxicity should be worthwhile.

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2023-10-01 | SAT033 Disruption Of GHR In “Middle Aged” Mice Enhances Insulin Sensitivity And Extends Male Lifespan

Abstract Disclosure: S. Duran-Ortiz: None. E.O. List: None. J.A. Young: None. S.C. Mathes: None. R. Basu: None. Y.B. Slama: None. D.E. Berryman: None. Reduced growth hormone (GH) action has been shown to extend healthspan and lifespan in several organisms. In fact, mice and humans with a congenital disruption in the GH receptor (R) gene (GHRKO mice and patients with Laron Syndrome, respectively) have improved insulin sensitivity and are resistant to diabetes, cancer and age-associated cognitive decline. Importantly, the GHRKO mice hold the record for the longest-lived laboratory mice, with a lifespan one week shy of five years of age. GHRKO mice also show reduced markers of aging such as adipose tissue senescence and mTORC1 signaling in liver, kidney, heart and muscle. However, as GH action is required for normal growth and development, we and others have hypothesized that targeted inhibition of GH action at an adult age could be a potent method to extend healthy lifespan. To test this hypothesis and to elucidate how far in development would disruption of GHR extend healthy lifespan, our laboratory recently reported on two mouse lines with post-natal ablation of the GHR at a pubertal age (1.5 months - 1.5mGHRKO mice) and at mature-adult age (6 months - 6mGHRKO mice). We found that ablation of the GHR gene at both 1.5- and 6-months of age extends maximal and mean lifespan preferentially in females. Furthermore, 6mGHRKO mice showed improved oxidative stress resistance while males had improved insulin sensitivity and reduced cancer incidence. With these promising results, we believe that interventions to extend aging should be effective when administered later in life. In the current study, we disrupted the GHR in middle aged mice (12 months - 12mGHRKO mice) using the Cre-Lox system. We found that 12mGHRKO mice exhibit GH insensitivity (high serum GH and low IGF-1 levels), increased adipose tissue mass, reduced lean mass, minimal impact on body weight and length, improved insulin sensitivity and reduced glucose levels in males as well as decreased adipose tissue fibrosis in females compared to males. Moreover, despite the increased fat mass, motor coordination and strength as measured by rotarod and grip strength tests show no deficit in 12mGHRKO mice compared to the controls. Importantly, the male 12mGHRKO mice showed a preferential and significant lifespan extension compared to control mice. Collectively, our results indicate that not only does post-natal GHR disruption does not affect growth and development, but it also confers several crucial healthspan and lifespan advantages. Acknowledgements: This work is supported by the State of Ohio's Eminent Scholar Program, by NIH grant AG059779, by the American Federation for Aging Research (AFAR) and by the Diabetes Institute and by the AMVETS. Presentation: Saturday, June 17, 2023

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gene therapies

2026-06-15 | GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes.

Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40-45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.

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2022-06-20 | First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model.

The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.

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2021-09-17 | Growth hormone receptor knockout: Relevance to xenotransplantation.

Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications, effective immunosuppressive therapy, and anti-inflammatory therapy to protect pig tissues from the primate immune and inflammatory responses and correct molecular incompatibilities. Further study is required regarding identification and investigation of physiological incompatibilities. Although the exact cause remains uncertain, we and others have observed relatively rapid growth of kidney xenografts after transplantation into nonhuman primates (NHPs). There has also been some evidence of growth, or at least ventricular hypertrophy, of the pig heart after orthotopic transplantation into NHPs. Rapid growth could be problematic, particularly with regard to the heart within the relatively restricted confines of the chest. It has been suggested that the problem of rapid growth of the pig organ after transplantation could be resolved by growth hormone receptor (GHR) gene knockout in the pig. The GHR, although most well-known for regulating growth, has many other biological functions, including regulating metabolism and controlling physiological processes. Genetically modified GHRKO pigs have recently become available. We provide data on their growth compared to comparable pigs that do not include GHRKO, and we have reviewed the literature regarding the effect of GHRKO, and its relevance to xenotransplantation.

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2020-02-01 | p.R209H GH1 variant challenges short stature assessment

to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive.We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group.Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI.We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).

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2017-12-04 | Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling

Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism.

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oligonucleotides

2025-12-21 | Oligosaccharides ameliorate insulin resistance and hepatic metabolism by promoting the leptin/POMC axis to accelerate short stature growth and development.

Leptin and pro-opiomelanocortin (POMC) signaling critically regulates metabolism and growth. The potential of oligosaccharides to modulate this axis and its physiological impacts remains unclear. Male wild-type (WT) and leptin-deficient (ob/ob) mice received daily oral oligosaccharides for 8 weeks. Lentiviral POMC overexpression (LV-POMC) or control (LV-NC) was administered to ob/ob mice. Metabolic function was assessed via glucose/insulin tolerance tests (GTT/ITT). Serum/tissue levels of leptin, POMC, metabolic markers, growth hormones, and bone regulators were quantified by enzyme-linked immunosorbent assay and Western blot. Femur length was recorded, and trabecular architecture was evaluated by hematoxylin-eosin staining. Oligosaccharides increased leptin and POMC levels in WT but not ob/ob mice. Oligosaccharides improved insulin sensitivity, hepatic metabolism (reduced triglycerides, aspartate aminotransferase, alanine aminotransferase, and free fatty acids), and bone growth (increased femur length, osteoprotegerin; decreased receptor activator of nuclear factor kappa-B ligand/cathepsin K) in WT mice. These benefits were absent in ob/ob mice. Crucially, POMC overexpression in ob/ob mice rescued metabolic dysfunction (improved GTT/ITT and normalized hepatic markers), restored growth hormone balance (reduced adrenocorticotropic hormone/cortisol and increased insulin-like growth factor 1), and reversed bone defects. Oligosaccharides exert insulin-sensitizing, hepatoprotective, and growth-promoting effects via leptin-dependent POMC activation. POMC restoration rescues deficits in leptin deficiency, establishing the leptin/POMC axis as the essential mechanistic pathway.

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2023-08-02 | Congenital IGF-1 deficiency protects from cancer: lessons from Laron syndrome.

Many clinical and experimental studies have implicated the growth hormone (GH)-insulin-like growth factor (IGF-1) axis with the progression of cancer. The epidemiological finding that patients with Laron syndrome (LS), the best-characterized disease under the spectrum of congenital IGF-1 deficiencies, do not develop cancer is of major scientific and translational relevance. The evasion of LS patients from cancer emphasizes the central role of the GH-IGF-1 system in cancer biology. To identify genes that are differentially expressed in LS and that might provide a biological foundation for cancer protection, we have recently conducted genome-wide profiling of LS patients and normal controls. Analyses were performed on immortalized lymphoblastoid cell lines derived from individual patients. Bioinformatic analyses identified a series of genes that are either over- or under-represented in LS. Differential expression was demonstrated in a number of gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT and PI3K-AKT signaling, etc. Major differences between LS and controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. The identification of novel downstream targets of the GH-IGF-1 network highlights the biological complexity of this hormonal system and sheds light on previously unrecognized mechanistic aspects associated with GH-IGF-1 action in the cancer cell.

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2021-06-01 | Investigation of the role of β-TrCP in growth hormone transduction defect (GHTD).

Background Growth hormone(GH) and epidermal growth factor (EGF) stimulate cell growth and differentiation, and crosstalking between their signaling pathways is important for normal cellular development. Growth hormone transduction defect (GHTD) is characterized by excessive GH receptor (GHR) degradation, due to over-expression of the E3 ubiquitin ligase, cytokine inducible SH2-containing protein (CIS). GH induction of GHTD fibroblasts after silencing of messenger RNA (mRNA) CIS (siCIS) or with higher doses of GH restores normal GH signaling. β-Transducing-repeat-containing protein (β-TrCP), another E3 ubiquitin ligase, also plays a role in GHR endocytosis. We studied the role of β-TrCP in the regulation of the GH/GHR and EGF/EGF receptor (EGFR) pathways in normal and GHTD fibroblasts. Materials and methods Fibroblast cultures were developed from gingival biopsies of a GHTD (P) and a control child (C). Protein expression and cellular localization of β-TrCP were studied by Western immunoblotting and immunofluorescence, respectively, after: (1) GH 200 μg/L human GH (hGH) induction, either with or without silence CIS (siCIS), and (2) inductions with 200 μg/L GH or 1000 μg/L GH or 50 ng/mL EGF. Results After induction with: (1) GH200/siCIS, the protein expression and cytoplasmic-membrane localization of β-TrCP were increased in the patient, (2) GH200 in the control and GH1000 in the patient, the protein and cytoplasmic-membrane localization of β-TrCP were increased and (3) EGF, the protein expression and cytoplasmic-membrane localization of β-TrCP were increased in both the control and the patient. Conclusions (1) β-TrCP appears to be part of the negative regulatory mechanism of the GH/GHR and EGF/EGFR pathways. (2) There appears to be a negative correlation between β-TrCP and CIS. (3) In the control and GHTD patient, β-TrCP increases when CIS is suppressed, possibly as a compensatory inhibitor of the GH/GHR pathway.

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2011-11-25 | Growth hormone insensitivity syndrome caused by a heterozygous GHR mutation: phenotypic variability owing to moderation by nonsense‐mediated decay

Growth hormone insensitivity syndrome (GHIS) is characterized by extreme short stature and resistance to the actions of growth hormone (GH). The heterogeneity ranges from the most severe form, known as Laron syndrome, to less severe phenotypes like idiopathic short stature and partial GH insensitivity. Here, we aimed to identify and characterize the molecular cause of severe short stature in a patient with resistance to GH treatment.We describe a male patient born small for gestational age [38 weeks gestation, length 38·5 cm; -7·8 standard deviation score (SDS), weight 1350 g; -4·84 SDS]. At the age of 7 years (109·7 cm; -2·89 SD), he received GH treatment (1 mg/m(2)/day) for 1 year without any increase in height SDS, IGF-I or IGFBP-3 levels. Double-GH-dose treatment for another year did not result in any improvement in growth factor level either. The patient does not have the typical Laron craniofacial and somatic features.Analysis of GHR showed a heterozygous nonsense mutation (c.703C>T; p.Arg217X). Extensive mutation screening as well as copy number variation analysis of other candidate genes in the GH-IGF-I axis excluded any additional genetic defects. Analysis of the patient's fibroblasts showed that growth hormone receptor (GHR) messenger ribonucleic acid (mRNA) expressed from the mutant allele was degraded by a mechanism called nonsense-mediated mRNA decay (NMD).GHIS in this patient is because of a heterozygous nonsense mutation in GHR. Our study is the first to demonstrate that NMD is involved in the phenotypic variability of GHIS caused by GHR mutations.

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2010-07-26 | Repair of aberrant splicing in growth hormone receptor by antisense oligonucleotides targeting the splice sites of a pseudoexon.

The GH receptor (GHR) pseudoexon 6Psi defect is a frequent cause of GH insensitivity (GHI) resulting from a non-functioning GH receptor (GHR). It results in a broad range of phenotypes and may also be present in patients diagnosed as idiopathic short stature. Our objective was to correct aberrant GHR splicing and inclusion of 6Psi using exon-skipping antisense oligonucleotides (ASOs). Three ASOs binding the 5' (ASO-5), 3' (ASO-3), and branch site (ASO-Br) of 6Psi were tested in an in vitro splicing assay and a cell transfection system. The wild-type (wt) and mutant (mt) DNA minigenes (wt- and mtL1-GHR6Psi-L2, respectively) were created by inserting the GHR 6Psi in a well-characterized splice reporter (Adml-par). For the in vitro splicing assay, the wt- and mtL1-GHR6Psi-L2 were transcribed into pre-mRNA in the presence of [alpha(32)P]GTP and incubated with ASOs in HeLa nuclear extracts. For the cell transfection studies, wt- and mtL1-GHR6Psi-L2 cloned into pcDNA 3.1 were transfected with ASOs into HEK293 cells. After 48 h, RNA was extracted and radiolabeled RT-PCR products quantified. ASO-3 induced an almost complete pseudoexon skipping in vitro and in HEK293 cells. This effect was dose dependent and maximal at 125-250 nm. ASO-5 produced modest pseudoexon skipping, whereas ASO-Br had no effect. Targeting of two splice elements simultaneously was less effective than targeting one. ASO-Br was tested on the wtL1-GHR6Psi-L2 and did not act as an enhancer of 6Psi inclusion. The exon-skipping ASO approach was effective in correcting aberrant GHR splicing and may be a promising therapeutic tool.

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