The crosstalk between FGF21 and GH leads to weakened GH receptor signaling and IGF1 expression and is associated with growth failure in very preterm infants.

Background: Fibroblast growth factor 21 (FGF21) is an essential metabolic regulator that adapts to changes in nutritional status. Severe childhood undernutrition induces elevated FGF21 levels, contributing to growth hormone (GH) resistance and subsequent linear growth attenuation potentially through a direct action on chondrocytes. Methods: In this study, we assessed expression of the components of both GH and FGF21 pathways in rare and unique human growth plates obtained from children. Moreover, we investigated the mechanistic interplay of FGF21 on GH receptor (GHR) signaling in a heterologous system. Results: Chronic FGF21 exposure increased GH-induced GHR turnover and SOCS2 expression, leading to the inhibition of STAT5 phosphorylation and IGF-1 expression. The clinical significance of FGF21 signaling through GH receptors was tested in nutritionally driven growth failure seen in very preterm (VPT) infants right after birth. VPT infants display an immediate linear growth failure after birth followed by growth catch-up. Consistent with the in vitro model data, we show that circulating FGF21 levels were elevated during deflection in linear growth compared to catch-up growth and were inversely correlated with the length velocity and circulating IGF1 levels. Conclusions: This study further supports a central role of FGF21 in GH resistance and linear growth failure and suggests a direct action on the growth plate.

Clinical profile of Laron dwarfism - experience from a tertiary care institute in Chennai.

OBJECTIVES: Laron dwarfism is a rare genetic disorder first reported among Israeli jewish children, subsequently about 350 cases cases have been reported worldwide. We aim to describe the clinical profile of nine children with Laron dwarfism from Institute of Child Health, Chennai. METHODS: Analysis of case records from 2010 to 2018. RESULTS: Male:female ratio is 6:3. Mean age of the children at the time of diagnosis was 3 years. All children were extremely short, and mean height Z score (SD) was -7.7(0.8). All children had characteristic facies with no hypoglycaemic episodes. Microcephaly was present in four children out of which two had developmental delay. Three out of six boys had micropenis. All children had low insulin like growth factor-1 (IGF-1) and high basal growth hormone (GH) with a mean (SD) of 39.6 (11.2) ng/mL. CONCLUSIONS: Suspicion of Laron syndrome should be high when child presents with features of Growth Hormone Deficiency (GHD) with extreme stunting.

Growth Hormone and Aging.

Growth hormone (GH) secretion declines with aging (somatopause). One of the most controversial issues in aging is GH treatment of older adults without evidence of pituitary pathology. Although some clinicians have proposed reversing the GH decline in the older population, most information comes from not placebo-controlled studies. Although most animal studies reported an association between decreased GH levels (or GH resistance) and increased lifespan, human models have shown contradictory reports on the consequences of GH deficiency (GHD) on longevity. Currently, GH treatment in adults is only indicated for individuals with childhood-onset GHD transitioning to adulthood or new-onset GHD due to hypothalamic or pituitary pathologic processes.

Roles of leptin in initiation of acquired growth hormone resistance and control of metabolism in rainbow trout.

Catabolic conditions often induce concomitant changes in plasma leptin (Lep), growth hormone (GH), and insulin growth factor I (IGF-I) levels in teleost fish, but it is unclear whether these parts of the endocrine system are responding independently or functionally linked. In this study, fasted rainbow trout was used to study the effects of Lep on the GH-IGF-I system and metabolism. Fish were implanted intraperitoneally with recombinant rainbow trout Lep pellets and remained unfed. After 4 days, plasma GH levels were elevated in the Lep-treated fish in a dose-dependent manner; the expression of hepatic igf1 and plasma IGF-I levels were suppressed accordingly. In vitro Lep treatment reversed ovine GH (oGH)-stimulated expression of igf1 and igf2 in hepatocytes isolated from fasted fish, similar to the inhibitory effects of the MEK1/2 inhibitor U0126 treatment. However, Lep treatment alone had no effect on the expression of igfs or oGH-stimulated ghr2a expression in the hepatocytes. These results demonstrate an additive effect of Lep on suppression of IGF-I under catabolic conditions, indicating that Lep is likely involved in initiation of acquired GH resistance. Although the Lep-implant treatment had no effect on standard metabolic rate, it significantly suppressed gene expression of hepatic hydroxyacyl-CoA dehydrogenase, phosphoenolpyruvate carboxykinase, and glucose 6-phosphatase, which are key enzymes in lipid utilization and gluconeogenesis, in different patterns. Overall, this study indicates that the Lep increase in fasting salmonids is an important regulatory component for physiological adaptation during periods of food deprivation, involved in suppressing growth and hepatic metabolism to spare energy expenditure.

Starvation-induced transcription factor CREBH negatively governs body growth by controlling GH signaling.

cAMP responsive element-binding protein H (CREBH) is a hepatic transcription factor to be activated during fasting. We generated CREBH knock-in flox mice, and then generated liver-specific CREBH transgenic (CREBH L-Tg) mice in an active form. CREBH L-Tg mice showed a delay in growth in the postnatal stage. Plasma growth hormone (GH) levels were significantly increased in CREBH L-Tg mice, but plasma insulin-like growth factor 1 (IGF1) levels were significantly decreased, indicating GH resistance. In addition, CREBH overexpression significantly increased hepatic mRNA and plasma levels of FGF21, which is thought to be as one of the causes of growth delay. However, the additional ablation of FGF21 in CREBH L-Tg mice could not correct GH resistance at all. CREBH L-Tg mice sustained GH receptor (GHR) reduction and the increase of IGF binding protein 1 (IGFBP1) in the liver regardless of FGF21. As GHR is a first step in GH signaling, the reduction of GHR leads to impairment of GH signaling. These data suggest that CREBH negatively regulates growth in the postnatal growth stage via various pathways as an abundant energy response by antagonizing GH signaling.

Growth hormone and aging.

Growth hormone (GH) actions impact growth, metabolism, and body composition and have been associated with aging and longevity. Lack of GH results in slower growth, delayed maturation, and reduced body size and can lead to delayed aging, increased healthspan, and a remarkable extension of longevity. Adult body size, which is a GH-dependent trait, has a negative association with longevity in several mammalian species. Mechanistic links between GH and aging include evolutionarily conserved insulin/insulin-like growth factors and mechanistic target of rapamycin signaling pathways in accordance with long-suspected trade-offs between anabolic/growth processes and longevity. Height and the rate and regulation of GH secretion have been related to human aging, but longevity is not extended in humans with syndromes of GH deficiency or resistance. However, the risk of age-related chronic disease is reduced in individuals affected by these syndromes and various indices of increased healthspan have been reported.

A new action of peptide hormones for survival in a low-nutrient environment.

Malnutrition occurs when nutrient intake is too low for any reason and occurs regardless of gender or age. Therefore, besides loss of eating or digestive functionality due to illness, malnutrition can occur when a healthy individual undergoes an extreme diet and biases their nutrition, or when athletes exerts more energy than they can replenish through food. It has recently been reported that in Japan, the mortality rate of leaner individuals is equal to or higher than that of obese people. It is important to understand what homeostatic maintenance mechanism is behind this when the body is under hypotrophic conditions. Such mechanisms are generally endocranially controlled. We address this fundamental concern in this paper by focusing on peptide hormones. We introduce a mechanism for survival in a malnourished state via the regulation of food intake and temperature. Additionally, we will discuss the latest findings and future prospects for research on changes in the endocrine environment associated with malnutrition associated with exercise. We also review changes in next-generation endocrine environments when caused by malnutrition brought on by dieting.

Primary growth hormone insensitivity and psychomotor delay.

We report a case of short stature irresponsive to growth hormone (GH) replacement therapy. Low GH response to provocative tests and undetectable IGF-1 levels had suggested GH deficiency, while response to therapy indicated GH insensitivity. Molecular evaluation of the GH/IGF-1 axis should be performed in these cases to improve diagnosis and therapy.

Characterization of Growth Hormone Resistance in Experimental and Ulcerative Colitis.

Growth hormone (GH) resistance may develop as a consequence of inflammation during conditions such as inflammatory bowel disease, encompassing ulcerative colitis (UC). However, the specific role of the GH-insulin growth factor (IGF)-1-axis and/or the functional consequences of GH resistance in this condition are unclear. In situ hybridization targeting the GH receptor (GHR) and relevant transcriptional analyses were performed in patients with UC and in IL-10 knock-out mice with piroxicam accelerated colitis (PAC). Using cultured primary epithelial cells, the effects of inflammation on the molecular mechanisms governing GH resistance was verified. Also, the therapeutic potential of GH on mucosal healing was tested in the PAC model. Inflammation induced intestinal GH resistance in UC and experimental colitis by down-regulating GHR expression and up-regulating suppressor of cytokine signalling (SOCS) proteins. These effects are driven by pro-inflammatory mediators (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6) as confirmed using primary epithelial cells. Treatment of experimental colitis with GH increased IGF-1 and body weight of the mice, but had no effects on colonic inflammation or mucosal healing. The high transcriptional similarity between UC and experimental colitis accentuates the formation of intestinal GH resistance during inflammation. Inflammation-induced GH resistance not only impairs general growth but induces a state of local resistance, which potentially impairs the actions of GH on mucosal healing during colitis when using long-acting GH therapy.

lnteracciones de la respuesta del eje somatotrófco en la amenorrea hipotalámica funcional relacionada con la desnutrición / The activity of the somatotrophic function in Functional Hypothalamic Amenorrhea (FHA) related to undernourishmant

La función somatotrófica en la amenorrea hipotalámica funcional (AHF) exhibe un aumento central de su actividad y paradojalmente, el comportamiento hormonal periférico, el metabolismo intermedio y varios aspectos clínicos pueden ser compatibles con los observados en la insuficiencia del eje somatotrófico. Los niveles basales y la secreción diaria de GH son altas, pero su perfil pulsátil es irrregular. En virtud de ello, se produce una resistencia a la GH, con disminución de los receptores de la hormona, que, sumado al descenso de la proteína ligadora de GH (GH binding protein, GHBP), alteran su capacidad de estimular en el hígado las síntesis de IGF-I, IGFBP-3 y la de la subunidad acido-lábil. Ello disminuye la disponibilidad de IGF-I libre en los tejidos. Por otro lado, los IGFBP-1 y IGFBP-2 aumentan significativamente. Si bien estos péptidos son regulados por la GH, aparentemente resulta ser más importante su correlación inversa con la actividad de la insulina (que se encuentra disminuida en estas pacientes) y con el bajo aporte proteico de las dietas. El aumento de los niveles séricos de estos péptidos también contribuye al descenso de la IGF-I libre. Las alteraciones en la dinámica de secreción inducen a una reducción de la concentración de la leptina (una adipokina) y al aumento de la ghrelina (la cual, a su vez, facilita la secreción de GH) y presentan una destacada incidencia en el metabolismo intermedio de estas pacientes desnutridas. Estos cambios hormonales pueden ser interpretados como un mecanismo de adaptación homeostática tendiente a preservar la disponibilidad de los nutrientes energéticos. En relación a ello, existe inicialmente un predominio de la lipólisis, seguido de proteólisis a nivel muscular. Si la restricción dietética continúa, se desarrolla en el hígado y en el tejido muscular, un proceso de neoglu-cogénesis utilizando como sustrato, las proteínas y los NEFA. Ello es seguido por la glugenólisis que aporta glucosa. No obstante, el aumento de los ácidos grasos libres y eventualmente la aparición de cuerpos cetónicos cuando la alimentación es muy restringida, sugieren la presencia de acidosis metabólica. Este estadio clínico implica un aumento del riesgo cardiovascular y la posibilidad de muerte prematura o súbita, una eventualidad latente en las pacientes con AHF y desnutridas. El autor declara no poseer conflictos de intereses.

The activity of the somatotropic function in Functional Hypothalamic Amenorrhea (FHA) is increased at the central level, and paradoxically, the peripheral hormonal behaviour, intermediate metabolism and several clinical aspects may be similar to those observed in somatotropic axis deficiency. Baseline and daily GH secretion levels are high, but its pulsatile profile is irregular. This results in resistance to GH, i.e., downregulation of hormone receptors, which, together with the decrease in GH binding protein (GHBP), impair GH ability to stimulate the synthesis of IGF-I, IGFBP-3 and the acid-labile subunit in the liver. This causes a decrease in the availability of free IGF-I in tissues. In addition, IGFBP-1 and IGF-BP2 significantly increase. Even if these peptides are regulated by GH, their inverse correlation with insulin activity (which is decreased in these patients) and the low protein diet, respectively, appear to be more important factors. The increase in the serum levels of these peptides also contributes to the decrease in free IGF-I. Alterations in secretory patterns lead to a decrease in leptin concentration (an adipokine) and to an increase in Ghrelin, which, in turn, facilitates GH secretion and has a remarkable incidence in intermediate metabolism in these undernourished patients. These hormonal changes can be interpreted as a mechanism of homeostatic adaptation tending to preserve availability of energetic nutrients. Thus, there is an initial predominance of lypolisis followed by proteolysis at muscle level. If dietary restriction continues, a process of neoglucogenesis occurs in the liver and muscle tissue, with proteins and free fatty acids (NEFAs) being used as substrates. This is followed by glucogenolysis, which produces glucose. However, the increase in NEFAs and the potential presence of ketone bodies in highly restricted diets, suggest the presence of metabolic acidosis. This clinical condition implies an increased cardiovascular risk and the possibility of premature death, a potential outcome in undernourished patients with FHA. No competing financial interests exists.