Preventive cognitive protection based on AAV9 overexpression of IGF1 in hippocampal astrocytes.

Astrocytes play key roles in the brain. When astrocyte support fails, neurological disorders follow, resulting in disrupted synaptic communication, neuronal degeneration, and cell death. We posit that astrocytes overexpressing neurotrophic factors, such as Insulin Like Growth Factor 1 (IGF1), prevent the onset of neurodegeneration. We overexpressed IGF1 and the reporter TdTomato (TOM) in hippocampal astrocytes with bicistronic Adeno-Associated Virus (AAV) harboring the Glial Fibrillary Acidic Protein (GFAP) promoter and afterwards induced neurodegeneration by the intracerebroventricular (ICV) injection of streptozotocin (STZ), a rat model of behavioral impairment, neuroinflammation and shortening of hippocampal astrocytes. We achieved a thorough transgene expression along the hippocampus with a single viral injection. Although species typical behavior was impaired, memory deficit was prevented by IGF1. STZ prompted astrocyte shortening, albeit the length of these cells in animals injected with GFP and IGF1 vectors did not statistically differ from the other groups. In STZ control animals, hippocampal microglial reactive cells increased dramatically, but this was alleviated in IGF1 rats. We conclude that overexpression of IGF1 in astrocytes prevents neurodegeneration onset. Hence, individuals with early neurotrophic exhaustion would be vulnerable to age-related neurodegeneration.

Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency.

BACKGROUND: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. METHODS: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. RESULTS: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels. CONCLUSION: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. FUNDING: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.

Acromegaly Type 1: A Representative Patient.

A 46-year-old woman was troubled by a 3-year history of constant headaches and arthralgias. She was treated with paracetamol with no symptom resolution. An abnormal fasting glucose level prompted endocrine evaluation. On physical examination, she casually mentioned that her wedding ring no longer fit, and she also confirmed an increase in shoe size. There were no characteristic facial features for acromegaly and there was no evidence of acral enlargement. Biochemical evaluation, including insulin-like growth factor type 1 (IGF-1) measurement and oral glucose loading with growth hormone (GH) measurement confirmed excess GH production and a diagnosis of acromegaly. Pituitary magnetic resonance imaging showed a central pituitary microadenoma. After transsphenoidal surgical resection, tissue immunohistochemistry revealed a densely granulated somatotroph adenoma. Currently, the patient is asymptomatic with biochemical disease control, normal fasting glucose levels, and no pituitary hormone deficiencies. This patient is illustrative of a type 1 acromegaly with mild clinical manifestations. Clinicians should be aware of acromegaly subtypes to avoid delay in diagnosis and to individualize therapy.

NT157 exhibits antineoplastic effects by targeting IRS and STAT3/5 signaling in multiple myeloma.

Multiple myeloma (MM) is a prevalent hematological malignancy with high recurrence and no definitive cure. The current study revisits the role of the IGF1/IGF1R axis in MM, introducing a novel inhibitor, NT157. The IGF1/IGF1R pathway is pivotal in MM, influencing cell survival, proliferation, and migration and impacting patient survival outcomes. NT157 targets intracellular proteins such as IRS and STAT proteins and demonstrates antineoplastic potential in hematological malignancies and solid tumors. In the present study, we assessed IGF1R signaling-related gene expression in MM patients and healthy donors, unveiling significant distinctions. MM cell lines displayed varying expression patterns of IGF1R-related proteins. A gene dependence analysis indicated the importance of targeting receptor and intracellular elements over autocrine IGF1. NT157 exhibited inhibitory effects on MM cell viability, clonal growth, cell cycle progression, and survival. Moreover, NT157 reduced IRS2 expression and STAT3, STAT5, and RPS6 activation and modulated oncogenes and tumor suppressors, fostering a tumor-suppressive molecular profile. In summary, our study demonstrates that the IGF1/IGF1R/IRS signaling axis is differentially activated in MM cells and the NT157's capacity to modulate crucial molecular targets, promoting antiproliferative effects and apoptosis in MM cells. NT157 may offer a multifaceted approach to enhance MM therapy.

The Impact of Prenatal Alcohol Exposure on Longitudinal Growth, Nutritional Status, and Insulin-Like Growth Factor 1 in Early Childhood in Leyte, the Philippines.

OBJECTIVE: To assess the impact and potential mechanistic pathways of prenatal alcohol exposure (PAE) on longitudinal growth and nutritional status in early childhood. STUDY DESIGN: A cohort of 296 mother-infant dyads (32% with PAE vs 68% unexposed) were recruited in Leyte, the Philippines, and followed from early gestation through 24 months of age. PAE was assessed using serum phosphatidylethanol (PEth) captured twice prenatally and in cord blood and supplemented with self-reported alcohol consumption. Linear mixed models were used to examine longitudinal effects of PAE on growth from birth through 2 years including key potential mediating factors (placental histopathology, and infant serum leptin and Insulin-like Growth Factor 1 [IGF-1]). RESULTS: After adjusting for potential confounders, we found that PAE was significantly associated with a delayed blunting of linear growth trajectories (height-for-age z-score, body length) and weight (weight-for-age z-score, body weight) that manifested between 4 and 6 months and continued through 12-24 months. PAE was also associated with a decreased rate of mid-upper-arm circumference growth from birth to 12 months, and a lower mean IGF-1 levels at birth and 6 months. CONCLUSION: This study demonstrates a delayed impact of PAE on growth that manifested around 6 months of age, underscoring the importance of routine clinical monitoring in early childhood. Furthermore, the findings supported prior animal model findings that suggest a mechanistic role for IGF-1 in PAE-induced growth delay.

Impact of Growth Hormone on Microglial and Astrocytic Function.

The role of growth hormone (GH) in the central nervous system (CNS) involves neuroprotection, neuroregeneration, formation of axonal projections, control of cognition, and regulation of metabolism. As GH induces insulin-like growth factor-1 (IGF-1) expression in many tissues, differentiating the specific functions of GH and IGF-1 in the organism is a significant challenge. The actions of GH and IGF-1 in neurons have been more extensively studied than their functions in nonneuronal cells (e.g., microglial cells). Glial cells are fundamentally important to CNS function. Microglia, astrocytes, oligodendrocytes, and tanycytes are essential to the survival, differentiation, and proliferation of neurons. As the interaction of the GH/IGF-1 axis with glial cells merits further exploration, our objective for this review was to summarize and discuss the available literature regarding the genuine effects of GH on glial cells, seeking to differentiate them from the role played by IGF-1 action whenever possible.

Higher levels of insulin-like growth factor-1 in cord blood associate with risk of asthma at age 3.

RATIONALE: Experimental studies and epidemiological data in adults suggest that somatomedin-C (insulin-like growth factor-1, IGF-1) may play a role in asthma by modulating airway inflammation, bronchial hyperreactivity, and airway smooth muscle hyperplasia. However, its role in children with asthma is not well understood. METHODS: We established a birth cohort with 339 Chilean pregnant mothers enrolled at the time of delivery from December 2014 to January 2016. We obtained cord blood at birth and followed the offspring every 6 months until 30 months of age, recording data on atopy, wheezing, and other respiratory illnesses. We measured IGF-1 in cord blood and determined the Asthma Predictive Index (API) at 30 months. The cohort was divided according to the API. RESULTS: Complete data were available for 307/339 (91%) dyads, including 44 preschoolers with API+ and 263 with API-. Demographic characteristics were similar between groups, but mothers of API+ children had a higher prevalence of obesity, previous use of oral contraceptives, and higher education than those of API- children. API+ children had higher birth weight and significantly higher IGF-1 in cord blood (37.4 ± 13.2 in API+ vs. 30.5 ± 13.0 ng/ml in API-, p = .01). In the multivariable analysis, IGF-1 in cord blood remained independently associated with a higher risk of asthma (adjusted OR for API+ per ng/ml higher IGF-1 = 1.03 [1.0-1.06], p = .015). CONCLUSIONS: Higher insulin-like growth factor-1 in cord blood is associated with asthma risk in the preschool years.

Evaluation of miRNAs regulation of BDNF and IGF1 genes in T2DM insulin resistance in experimental models: bioinformatics based approach / Avaliação da regulação por miRNAs dos genes BDNF e IGF1 na resistência a insulina no diabetes do tipo 2 em modelos experimentais: in silico

microRNAs (miRNAs) are recognized as diabetes mellitus type 2 (T2DM) biomarkers useful for disease metabolism comprehension and have great potential as therapeutics targets. BDNF and IGF1 increased expression are highly involved in the benefits of insulin and glucose paths, however, they are down-regulated in insulin resistance conditions, while their expression increase is correlated to the improvement of glucose and insulin metabolism. Studies suggest the microRNA regulation of these genes in several different contexts, providing a novel investigation approach for comprehending T2DM metabolism and revealing potential therapeutic targets. In the present study, we investigate in different animal models (human, rat, and mouse) miRNAs that target BDNF and IGF1 in skeletal muscle tissue with T2DM physiological conditions. Bioinformatics tools and databases were used to miRNA prediction, molecular homology, experimental validation of interactions, expression in the studied physiological condition, and network interaction. The findings showed three miRNAs candidates for IGF1(miR-29a, miR-29b, and miR-29c) and one for BDNF (miR-206). The experimental evaluations and the search for the expression in skeletal muscle from T2DM subjects confirmed the predicted interaction between miRNA-mRNA for miR-29b and miR-206 through human, rat, and mouse models. This interaction was reaffirmed in multiple network analyses. In conclusion, our results show the regulation relationship between miR-29b and miR-206 with the investigated genes, in several tissues, suggesting an inhibition pattern. Nevertheless, these data show a large number of possible interaction physiological processes, for future biotechnological prospects.

Os microRNAs (miRNAs) são reconhecidos como biomarcadores do diabetes mellitus tipo 2 (DM2), úteis para a compreensão do metabolismo da doença, e possuem grande potencial como alvos terapêuticos. O aumento da expressão de BDNF e IGF1 está altamente envolvido nos benefícios as vias de insulina e glicose, porém, são regulados negativamente em condições de resistência à insulina, enquanto seu aumento de expressão está correlacionado com a melhora do metabolismo da glicose e da insulina. Estudos sugerem a regulação desses genes por microRNA em vários contextos diferentes, proporcionando uma nova abordagem de investigação para compreender o metabolismo do DM2 e revelar potenciais alvos terapêuticos. No presente estudo, investigamos em diferentes modelos animais (humanos, ratos e camundongos) miRNAs que têm como alvo BDNF e IGF1 em tecido muscular esquelético com condições fisiológicas de DM2. As análises foram realizadas utilizando ferramentas de bioinformática e bancos de dados para predição de miRNA, homologia molecular, validação experimental de interações, expressão na condição fisiológica estudada e interação em rede. Os resultados mostraram três candidatos a miRNAs para IGF1 (miR-29a, miR-29b e miR-29c) e um para BDNF (miR-206). As avaliações experimentais e a busca pela expressão no músculo esquelético de indivíduos com DM2 confirmaram a interação prevista entre miRNA-mRNA para miR-29b e miR-206 através de modelos humanos, ratos e camundongos. Essa interação foi reafirmada em múltiplas análises de rede. Em conclusão, nossos resultados mostram a relação de regulação entre miR-29b e miR-206 com os genes investigados, em diversos tecidos, sugerindo um padrão de inibição. Contudo, esses dados mostram um grande número de possíveis processos fisiológicos de interação para perspectivas biotecnológicas.

Atypical Course of a Patient With AIP-Positive Acromegaly: From GH Excess to GH Deficiency and Back to GH Excess.

Acromegaly/giantism results from the chronic excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), in more than 96% of cases, due to a GH-secreting pituitary adenoma. Primary treatment of choice is transsphenoidal resection of the adenoma. More than 30% to 40% of operated cases require adjunctive forms of treatment, be it pharmacological or radiotherapeutical. The multimodal treatment of acromegaly has resulted in substantial improvements in the quality of life and life expectancy of these patients. We herein present the complex case of a patient with acromegaly due to a mammosomatotrope adenoma, with a germ-line AIP (aryl hydrocarbon receptor-interacting protein) mutation, who had a chronic and protracted course of more than 15 years during which he was treated with surgery, somatostatin receptor ligands, dopamine agonist, and the GH receptor antagonist pegvisomant. At one point, he was able to come off medications and was even found to be transiently GH-deficient, only to develop acromegaly again after a couple of years.

Dietary Supplementation with R-(+)-Limonene Improves Growth, Metabolism, Stress, and Antioxidant Responses of Silver Catfish Uninfected and Infected with Aeromonas hydrophila.

R-(+)-limonene is a monoterpene from plants of the genus Citrus with diverse biological properties. This research evaluated the effects of dietary supplementation with R-(+)-limonene on growth, metabolic parameters in plasma and liver, and the antioxidant and stress responses in silver catfish, Rhamdia quelen, challenged or not with Aeromonas hydrophila. Fish were fed for 67 days with different doses of R-(+)-limonene in the diet (control 0.0, L0.5, L1.0, and L2.0 mL/kg of diet). On the 60th day, a challenge with A. hydrophila was performed. R-(+)-limonene in the diet potentiated the productive performance of the fish. The metabolic and antioxidant responses indicate that R-(+)-limonene did not harm the health of the animals and made them more resistant to the bacterial challenge. Histological findings showed the hepatoprotective effect of dietary R-(+)-limonene against A. hydrophila. Igf1 mRNA levels were upregulated in the liver of fish fed with an L2.0 diet but downregulated with bacterial challenge. The expression levels of crh mRNA were higher in the brains of fish fed with the L2.0 diet. However, the L2.0 diet downregulated crh and hspa12a mRNA expression in the brains of infected fish. In conclusion, the results indicated that R-(+)-limonene can be considered a good dietary supplement for silver catfish.

Molecular Characterization of Patients with Cryptorchidism: Preliminary Search for an Expression Profile Related to That of Testicular Germ-Cell Tumors.

Cryptorchidism (CO) is a risk factor for the development of testicular germ-cell tumors (TGCT). This is supported by reports showing the persistence of gonocytes in CO patients. These cells are proposed to be related to the development of germ-cell neoplasia in situ (GCNIS), which is considered the precursor stage/lesion of TGCT. Therefore, it is proposed that some patients with CO could express some molecular markers related to TGCT. In this study, we analyzed testicular tissue samples from CO, TGCT, and controls. We determined the expression of POU5F1, PLAP, and KIT by immunohistochemistry and that of the hsa-miR-371-373 cluster, hsa-miR-367, and LATS2, PTEN, and IGFR1 genes by RT-qPCR. We then carried out a bioinformatic analysis to identify other possible candidate genes as tumor biomarkers. We found that 16.7% (2/12) of the CO patients presented increased expression of POU5F1, KIT, PLAP, hsa-miR-371-373, and hsa-miR-367 and decreased expression of LATS2 and IGF1R. Finally, the genes ARID4B, GALNT3, and KPNA6 were identified as other possible candidate tumor biomarkers. This is the first report describing the expression of the hsa-miR-371-373 cluster, hsa-miR-367, LATS2, and IGF1R in the testicular tissues of two CO patients with cells immune-positive to POU5F1, PLAP, and KIT, which is similar to what is observed in TGCT.

Factor de crecimiento análogo a insulina-1 y cardiotrofina-1 inducido por ejercicio y su relación con hipertrofia miocárdica en maratonistas / Cardiotrophin-1 and Insulin like growth factor induced by exercise are associated to cardiac hypertrophy in marathon runners

Antecedentes: El ejercicio de alta intensidad induce hipertrofia miocárdica necesaria para adaptar al corazón a la mayor demanda de trabajo. Se desconoce si correr una maratón induce de forma aguda factores humorales asociados al desarrollo de hipertrofia miocárdica en atletas. Objetivo: Evaluar cardiotrofina-1 (CT1) y el factor de crecimiento análogo a insulina-1 (IGF-1), conocidos inductores de hipertrofia, en maratonistas previo y justo después de correr una maratón y su relación con hipertrofia cardíaca. Métodos: Estudio prospectivo ciego simple de atletas hombres que corrieron la maratón de Santiago. Se incluyó un grupo control sedentario. En todos los sujetos se realizó un ecocardiograma transtorácico estándar. Los niveles de CT1 e IGF-1 se determinaron en plasma obtenidos antes (basal) y justo después de haber terminado (antes de 15 minutos) la maratón, usando test de ELISA. Resultados: Los atletas tenían frecuencias cardíacas menores que los controles, asociado con una mayor hipertrofia miocárdica, determinado por el grosor del septo y pared posterior del corazón, y volúmenes del ventrículo y aurícula izquierda. Los niveles basales de CT1 e IGF-1 fueron similares entre atletas y controles sedentarios. El correr la maratón aumentó los niveles de estas dos hormonas en un subgrupo de atletas. Solo los atletas que incrementaron los niveles de IGF-1, pero no de CT1, tenían volúmenes de ventrículo izquierdo y derecho más grandes que los otros atletas. Conclusiones: IGF-1 que se incrementa de forma aguda por el ejercicio, pero no CT1, estaría asociado con el aumento de los volúmenes ventriculares observado en los atletas.

Background: High intensity exercise induces the development of myocardial hypertrophy necessary to adapt the heart to the increased work demand. Whether running a marathon is associated with acutely induced humoral factors responsible for the development of myocardial hypertrophy observed in athletes is not known. Objective: To evaluate the levels of cardiotrophin-1 (CT1) and insulin-like growth factor-1 (IGF-1), known hypertrophy inducers, in marathon runners before and just after running a marathon and their relationship with cardiac hypertrophy. Methodology: Single-blind prospective study of male athletes who ran the Santiago's marathon. A sedentary control group was included. All subjects underwent a standard transthoracic echocardiogram. CT1 and IGF-1 levels were determined in plasma obtained before (basal) and just after finishing (within 15 min) the marathon using ELISA assays. Results: Athletes had lower heart rates than controls, associated with greater myocardial hypertrophy, as determined by thickness of the heart's septum and posterior wall, and left atrial and ventricular volumes. Basal CT1 and IGF-1 levels were similar between athletes and sedentary controls. Marathon running increased the levels of these two hormones in a subgroup of athletes. Only the athletes who increased IGF-1 levels, but not CT1, had larger left and right ventricular volumes. Conclusion: IGF-1 acutely increased by exercise, but not CT1, was associated with the augmented ventricular volumes observed in athletes.

Cancer in growth hormone excess and growth hormone deficit.

The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulin-like growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypo-insulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events.

Real World Data on the Epidemiology, Diagnosis, and Treatment of Acromegaly: A Registries-based Approach.

INTRODUCTION: Despite the inherent heterogeneity of the information derived from national registries, they are a useful tool to investigate the epidemiological, clinical, biochemical and treatment outcome characteristics of low prevalence conditions such as acromegaly. Although the information provided by single-center experiences is more homogeneous, these studies usually comprise a limited number of patients and thus, frequently lack statistical power. AREAS COVERED: Registry-based Information regarding the epidemiology, clinical presentation, biochemical and imaging diagnosis, as well as therapeutic outcome and mortality in acromegaly is critically analyzed. EXPERT OPINION: By gathering data from multiple centers in a specific Country, these registries generate important insights into the real-life behavior of this condition, that should be considered, both, in international consensus meetings and in the design of local, Country-specific diagnostic and therapeutic strategies.

IGFBP7 Fuels the Glycolytic Metabolism in B-Cell Precursor Acute Lymphoblastic Leukemia by Sustaining Activation of the IGF1R-Akt-GLUT1 Axis.

Increased glycolytic metabolism plays an important role in B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL). We previously showed that IGFBP7 exerts mitogenic and prosuvival effects in ALL by promoting IGF1 receptor (IGF1R) permanence on the cell surface, thus prolonging Akt activation upon IGFs/insulin stimulation. Here, we show that sustained activation of the IGF1R-PI3K-Akt axis concurs with GLUT1 upregulation, which enhances energy metabolism and increases glycolytic metabolism in BCP-ALL. IGFBP7 neutralization with a monoclonal antibody or the pharmacological inhibition of the PI3K-Akt pathway was shown to abrogate this effect, restoring the physiological levels of GLUT1 on the cell surface. The metabolic effect described here may offer an additional mechanistic explanation for the strong negative impact seen in ALL cells in vitro and in vivo after the knockdown or antibody neutralization of IGFBP7, while reinforcing the notion that it is a valid target for future therapeutic interventions.

Effect of growth rates on hormonal and pubertal status in Nellore heifers early weaned.

This study aimed to determine the effect of growth rates on the hormonal status and puberty onset. Forty-eight Nellore heifers were weaned at 3.0 ± 0.1 (means ± standard error of the mean) months old were blocked according to body weight at weaning (84 ± 2 kg) and randomly assigned to treatments. The treatments were arranged in 2 × 2 factorial according to the feeding program. The first program was high (H; 0.79 kg/day) or control (C; 0.45 kg/day) average daily gain (ADG) from 3rd to 7th month of age (growing phase I). The second program was also high (H; 0.70 kg/day) or control (C; 0.50 kg/day) ADG from the 7th month until puberty (growing phase II), resulting in four treatments: HH (n = 13), HC (n = 10), CH (n = 13), and CC (n = 12). To achieve desired gains, heifers in high ADG program were fed ad libitum dry matter intake (DMI), and the control group was offered around 50% of ad libitum DMI of high group. All heifers received a diet with similar composition. Puberty was assessed weekly by ultrasound examination, and the largest follicle diameter was evaluated every month. Blood samples were collected to quantify leptin, insulin growth factor-1 (IGF1) and luteinizing hormone (LH). At 7 months of age, heifers in high ADG were 35 kg heavier than the control. Heifers in the HH had greater DMI compared with CH in phase II. The puberty rate at 19 months old was greater in the HH treatment (84%) than in the CC (23%), but there was no difference between HC (60%) and CH (50%) treatments. Heifers from HH treatment had greater serum leptin concentration than others at 13 months old, and serum leptin was greater in HH compared with CH and CC at 18 months old. High heifers in phase I had greater serum IGF1 concentration than the control. In addition, HH heifers had a greater diameter of the largest follicle than CC. There was no interaction between phases and age in any variable relative to the LH profile. However, the heifers' age was the main factor that increased the frequency of LH pulse. In conclusion, increasing ADG was associated with greater ADG, serum leptin and IGF-1 concentration, and puberty onset; however, LH concentration was affected mainly by age of the animal. The increasing growth rate at younger age made heifers more efficient.

Function and form of the shoulder in congenital and untreated growth hormone deficiency.

OBJECTIVES: The shoulder is the most mobile joint in the entire human body. During arm elevation, it requires the integrity of a set of muscles, bones, and tendons. Individuals with short stature often need to raise their arms above the shoulder girdle and may have functional restriction or shoulder injuries. The impact of isolated GH deficiency (IGHD) on joints remains not well defined. The purpose of this work is to evaluate the function and structure of the shoulder in short-statured adult individuals with untreated IGHD due to the same homozygous mutation in the GHRH receptor gene. METHODS: A cross-sectional study (evidence 3) was carried out in 20 GH-naive IGHD subjects and 20 age-matched controls. They completed the disabilities of the arm, shoulder, and hand (DASH) questionnaire and shoulder ultrasound (US). Thickness of the anterior, medial, and posterior portions of the supraspinatus tendon and of subacromial space was measured, and the number of individuals with tendinosis or tearing of the supraspinatus tendon was registered. RESULTS: DASH score was similar between IGHD and controls, but IGHD subjects complained less of symptoms (p = 0.002). The number of individual with tears was higher in the controls (p = 0.02). As expected, the absolute US measurements were lower in IGHD, but the magnitude of the reduction was most pronounced in the thickness of the anterior portion of the supraspinatus tendon. CONCLUSION: Adults with lifetime IGHD do not have functional shoulder restrictions, complain less of problems in performing upper extremity activities, and have fewer tendinous injuries than controls.

Effect of sires' expected progeny difference for scrotal circumference and juvenile ADG on the puberty of crossbred beef heifers.

The early attainment of puberty in heifers is essential for the profitability of the cow-calf farm. This study aimed to evaluate the impact of juvenile average daily gain (ADG) and sire's expected progeny difference (EPD) on puberty of crossbred beef heifers. Sixty Angus × Nellore heifers early weaned (age = 102 ± 4.3 d; initial BW = 103 ± 4.7 kg) were used in a 2 × 2 factorial arrangement. The factor 1 was the sire's EPD for scrotal circumference, in which heifers born from sires with positive EPD were considered precocious (P), and heifers born from sires with negative EPD were considered non-precocious (NP). The factor 2 was the high (HG; ADG = 0.9 kg; ad libitum) and medium ADG (MG; ADG = 0.7 kg) from 3rd to 7th month of age (1st phase). After 1st phase until puberty, all heifers were fed ad libitum (2nd phase). Statistical analysis was performed by SAS. There was an interaction between factors for DMI in the 1st phase (P = 0.02), which PHG heifers had higher DMI than NPHG. There was no effect on puberty rate, BW, age and BCS at puberty comparing HG vs. MG. However, favorable sires' EPD for scrotal circumference induced a higher proportion of puberty (P 87% vs. NP 59%) at 15 months of age. Thus, the ADG in juvenile age did not affect puberty rate, but sires with positive EPD increased puberty rate of Angus × Nellore heifers in heifers fed a high gain diet.

Central growth hormone action regulates neuroglial and proinflammatory markers in the hypothalamus of male mice.

Growth hormone (GH) action in specific neuronal populations regulates neuroendocrine responses, metabolism, and behavior. However, the potential role of central GH action on glial function is less understood. The present study aims to determine how the hypothalamic expression of several neuroglial markers is affected by central GH action in male mice. The dwarf GH- and insulin-like growth factor-1 (IGF-1)-deficient Ghrhrlit/lit mice showed decreased mRNA expression of Nes (Nestin), Gfap, Iba1, Adgre1 (F4/80), and Tnf (TNFα) in the hypothalamus, compared to wild-type animals. In contrast, transgenic overexpression of GH led to high serum GH and IGF-1 levels, and increased hypothalamic expression of Nes, Gfap, Adgre1, Iba1, and Rax. Hepatocyte-specific GH receptor (GHR) knockout mice, which are characterized by high serum GH levels, but reduced IGF-1 secretion, showed increased mRNA expression of Gfap, Iba1, Tnf, and Sox10, demonstrating that the increase in GH levels alters the hypothalamic expression of glial markers associated with neuroinflammation, independently of IGF-1. Conversely, brain-specific GHR knockout mice showed reduced expression of Gfap, Adgre1, and Vim (vimentin), indicating that brain GHR signaling is necessary to mediate GH-induced changes in the expression of several neuroglial markers. In conclusion, the hypothalamic mRNA levels of several neuroglial markers associated with inflammation are directly modulated by GHR signaling in male mice.

Fasting and prolonged food restriction differentially affect GH secretion independently of GH receptor signaling in AgRP neurons.

Growth hormone (GH) receptor (GHR) is abundantly expressed in neurons that co-release the agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). Since ARHAgRP/NPY neurons regulate several hypothalamic-pituitary-endocrine axes, this neuronal population possibly modulates GH secretion via a negative feedback loop, particularly during food restriction, when ARHAgRP/NPY neurons are highly active. The present study aims to determine the importance of GHR signaling in ARHAgRP/NPY neurons on the pattern of GH secretion in fed and food-deprived male mice. Additionally, we compared the effect of two distinct situations of food deprivation: 16 h of fasting or four days of food restriction (40% of usual food intake). Overnight fasting strongly suppressed both basal and pulsatile GH secretion. Animals lacking GHR in ARHAgRP/NPY neurons (AgRP∆GHR mice) did not exhibit differences in GH secretion either in the fed or fasted state, compared to control mice. In contrast, four days of food restriction increased GH pulse frequency, basal GH secretion, and pulse irregularity/complexity (measured by sample entropy), whereas pulsatile GH secretion was not affected in both control and AgRP∆GHR mice. Hypothalamic Ghrh mRNA levels were unaffected by fasting or food restriction, but Sst expression increased in acutely fasted mice, but decreased after prolonged food restriction in both control and AgRP∆GHR mice. Our findings indicate that short-term fasting and prolonged food restriction differentially affect the pattern of GH secretion, independently of GHR signaling in ARHAgRP/NPY neurons.