Hepatic Insulin-like Growth Factor Research Articles

Prenatal prednisone exposure impacts liver development and function in fetal mice and its characteristics.

Prednisone, a widely used glucocorticoid drug in human and veterinary medicine, has been reported to cause developmental toxicity. However, systematic studies about the effect of prednisone on fetal liver development are still unclear. We investigated the potential effects of maternal exposure to clinically equivalent doses of prednisone during different gestational stages on cell proliferation and apoptosis, cell differentiation, glucose and lipid metabolism, and hematopoiesis in the liver of fetal mice, and explored the potential mechanisms. Results showed that prenatal prednisone exposure (PPE) could suppress cell proliferation, inhibit hepatocyte differentiation, and promote cholangiocyte differentiation in the fetal liver. Meanwhile, PPE could result in the enhancement of glyconeogenesis and bile acid synthesis and the inhibition of fatty acid β-oxidation and hematopoiesis in the fetal liver. Further analysis found that PPE-induced alterations in liver development had obvious stage and sex differences. Overall, the alteration in fetal liver development and function induced by PPE was most pronounced during the whole pregnancy (GD0-18), and the males were relatively more affected than the females. Additionally, fetal hepatic insulin-like growth factor 1 (IGF1) signaling pathway was inhibited by PPE. In conclusion, PPE could impact fetal liver development and multiple functions, and these alterations might be partially related to the inhibition of IGF1 signaling pathway.

Dietary curcumin nanoparticles improve growth performance, oxidative status and immune response of European seabass (Dicentrarchus labrax)

Abstract A 90 days of feeding trial was employed for evaluating the effects of dietary supplementation with curcumin nanoparticles (CURNPs) on growth performance, hematological and biochemical parameters, immune response, antioxidant status, and intestinal and hepatic architecture in European seabass (Dicentrarchus labrax) fingerlings. Fish (n = 300, initial body weight = 10.02 g ± 0.11g) received supplementary CURNPs at rates of 0 (control; CURNPs0), 50 (CURNPs50), 100 (CURNPs100) and 150 (CURNPs150) mg/kg diet for 90 days. Growth performance (final body weight (FBW), daily weight gain (DWG), weight gain (WG), relative growth rate (RGR), and protein efficiency ratio (PER)) and feed uptake (feed conversion rate (FCR)) were improved significantly in CURNPs (100 and 150 mg/kg)-supplemented groups. The hematological parameters red blood corpuscles (RBCs), hemoglobin (Hb), and packed cell volume (PCV) were improved significantly (p < 0.001) in CURNPs150 and CURNPs100 groups, while CURNPs150 had the lowest values of monocytes (p = 0.019) and heterophils (p < 0.005) when compared with other groups. Glucose was higher and lipid profile (total cholesterol and triglycerides) were lower in all CURNPs-supplemented groups as compared to the control group. Fish fed with CURNPS at various levels exhibited remarkable increase in digestive enzymes (amylase and lipase), immune markers (immunoglobulin G (IgG), lysozyme and phagocytic indices), and antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)). A noticeable decrease (p < 0.05) in malondialdehyde (MDA) and considerable upregulation of hepatic insulin-like growth factor 1 (IGF1) and interleukin-1beta (IL-1β) mRNA levels were found in CURNPs-supplemented fish in a dose-dependent manner. The down regulation of hepatic heat shock protein 70 (HSP70) was observed in CURNPs150. Intestinal and hepatic architectures were improved significantly by CURNPs. In conclusion, CURNPs supplementation improved growth performance, feed consumption and digestion, hematological and biochemical markers, immune response, and redox homeostasis in D. labrax. Therefore, CURNPs could be supplemented in the diets of D. labrax as a natural alternative to promote overall performance.

Dexamethasone exposure during pregnancy triggers metabolic syndrome in offspring via epigenetic alteration of IGF1

BackgroundPrevious research has reported that prenatal exposure to dexamethasone (PDE) results in organ dysplasia and increased disease susceptibility in offspring. This study aimed to investigate the epigenetic mechanism of metabolic syndrome induced by PDE in offspring.MethodsPregnant Wistar rats were administered dexamethasone, and their offspring’s serum and liver tissues were analyzed. The hepatocyte differentiation model was established to unveil the molecular mechanism. Neonatal cord blood samples were collected to validate the phenomenon and mechanism.ResultsThe findings demonstrated that PDE leads to insulin resistance and typical metabolic syndrome traits in adult offspring rats, which originated from fetal liver dysplasia. Additionally, PDE reduced serum corticosterone level and inhibited hepatic insulin-like growth factor 1 (IGF1) signaling in fetal rats. It further revealed that liver dysplasia and functional impairment induced by PDE persist after birth, driven by the continuous downregulation of serum corticosterone and hepatic IGF1 signaling. Both in vitro and in vivo experiments confirmed that low endogenous corticosterone reduces the histone 3 lysine 9 acetylation (H3K27ac) level of IGF1 and its expression by blocking glucocorticoid receptor α, special protein 1, and P300 into the nucleus, resulting in hepatocyte differentiation inhibition and liver dysplasia. Intriguingly, neonatal cord blood samples validated the link between reduced liver function in neonates induced by PDE and decreased serum cortisol and IGF1 levels.ConclusionsThis study demonstrated that low endogenous glucocorticoid level under PDE lead to liver dysplasia by downregulating the H3K27ac level of IGF1 and its expression, ultimately contributing to metabolic syndrome in adult offspring.

Blockade of angiotensin II modulates insulin-like growth factor 1-mediated skeletal muscle homeostasis in experimental steatohepatitis

Sarcopenia is associated with mortality in patients with nonalcoholic steatohepatitis (NASH). Angiotensin II receptor blocker (ARB) has been suggested to prevent sarcopenia, but reports on its effect on NASH-derived skeletal muscle atrophy in conjunction with insulin-like growth factor 1 (IGF-1)-mediated muscle homeostasis are few. Our aim was to examine the combined effect of the ARB losartan and IGF-1 replacement on skeletal muscle atrophy in a methionine–choline deficient (MCD) diet-fed murine steatohepatitis model. The MCD-fed mice developed steatohepatitis and skeletal muscle atrophy, as indicated by the reduction of psoas muscle mass and attenuation of forelimb and hindlimb grip strength. Significantly suppressed steatohepatitis and skeletal muscle atrophy was observed after single treatment with ARB or IGF-1, and these effects were augmented after combination treatment. Treatment with ARB and IGF-1 effectively inhibited ubiquitin proteasome-mediated protein degradation by reducing forkhead box protein O1 (FOXO1) and FOXO3a transcriptional activity in the skeletal muscle. Combined ARB and IGF-1 decreased the intramuscular expression of proinflammatory cytokines (i.e., TNFα, IL6, and IL1β) and increased the Trolox equivalent antioxidant capacity and antioxidant enzymes (CAT, GPX1, SOD2, and CYTB). This antioxidant effect was based on downregulation of NADPH oxidase (NOX) 2, normalization of mitochondrial biogenesis and dynamics. Moreover, ARB increased the hepatic and plasma IGF-1 levels and improved steatohepatitis, leading to enhanced skeletal muscle protein synthesis mediated by IGF-1/ AKT/ mechanistic target of rapamycin signaling. Collectively, combined ARB and IGF-1 replacement could be a promising new therapeutic target for NASH-derived skeletal muscle wasting.

The regulation of human organic anion transporter 4 by insulin-like growth factor 1 and protein kinase B signaling

Human organic anion transporter 4 (hOAT4), mainly expressed in the kidney and placenta, is essential for the disposition of numerous drugs, toxins, and endogenous substances. Insulin-like growth factor 1 (IGF-1) is a hormone generated in the liver and plays important roles in systemic growth, development, and metabolism. In the current study, we explored the regulatory effects of IGF-1 and downstream signaling on the transport activity, protein expression, and SUMOylation of hOAT4. We showed that IGF-1 significantly increased the transport activity, expression, and maximal transport velocity Vmax of hOAT4 in kidney-derived cells. This stimulatory effect of IGF-1 on hOAT4 activity was also confirmed in cells derived from the human placenta. The increased activity and expression were correlated well with the reduced degradation rate of hOAT4 at the cell surface. Furthermore, IGF-1 significantly increased hOAT4 SUMOylation, and protein kinase B (PKB)-specific inhibitors blocked the IGF-1-induced regulations on hOAT4. In conclusion, our study demonstrates that the hepatic hormone IGF-1 regulates hOAT4 expressed in the kidney and placenta through the PKB signaling pathway. Our results support the remote sensing and signaling theory, where OATs play a central role in the remote communications among distal tissues.

Structure and function of a dual antagonist of the human growth hormone and prolactin receptors with site-specific PEG conjugates

Human growth hormone (hGH) is a pituitary derived endocrine protein that regulates several critical postnatal physiologic processes including growth, organ development, and metabolism. Following adulthood, GH is also a regulator of multiple pathologies like fibrosis, cancer, and diabetes. Therefore, there is a significant pharmaceutical interest in developing antagonists of hGH action. Currently there is a single FDA approved antagonist of the hGH receptor (hGHR) prescribed for treating patients with acromegaly and discovered in our laboratory almost three decades ago. Here, we present the first data on the structure and function of a new set of protein antagonists with the full range of hGH actions - dual antagonists of hGH binding to the GHR as well as that of hGH binding to the prolactin receptor. We describe the site-specific poly-ethylene-glycol (PEG) conjugation, purification, and subsequent characterization using MALDI-TOF, size-exclusion chromatography, thermostability, and biochemical activity in terms of ELISA-based binding affinities with GHR and PRLR. Moreover, these novel hGHR antagonists display distinct antagonism of GH induced GHR intracellular signaling in vitro and marked reduction in hepatic insulin-like growth factor 1 output in vivo. Lastly, we observed potent anti-cancer biological efficacies of these novel hGHR antagonists against human cancer cell lines. In conclusion, we propose that these new GHR antagonists have potential for development towards multiple clinical applications related to GH associated pathologies.

Effects of Growth Hormone on Adult Human Gonads: Action on Reproduction and Sexual Function.

Growth hormone (GH), which is commonly considered to be a promoter of growth and development, has direct and indirect effects on adult gonads that influence reproduction and sexual function of humans and nonhumans. GH receptors are expressed in adult gonads in some species including humans. For males, GH can improve the sensitivity of gonadotropins, contribute to testicular steroidogenesis, influence spermatogenesis possibly, and regulate erectile function. For females, GH can modulate ovarian steroidogenesis and ovarian angiogenesis, promote the development of ovarian cells, enhance the metabolism and proliferation of endometrial cells, and ameliorate female sexual function. Insulin-like growth factor-1 (IGF-1) is the main mediator of GH. In vivo, a number of the physiological effects of GH are mediated by GH-induced hepatic IGF-1 and local IGF-1. In this review, we highlight the roles of GH and IGF-1 in adult human gonads, clarify potential mechanisms, and explore the efficacy and the risk of GH supplementation in associated deficiency and assisted reproductive technologies. Besides, the effects of excess GH on adult human gonads are discussed as well.

Managing Estrogen Therapy in the Pituitary Patient

Growth hormone (GH) regulates metabolic and physical health in the adult human. Because the GH system is regulated by estrogens, therapeutic estrogen compounds are likely to affect metabolic health. Estrogens are available for oral and parenteral use in natural, prodrug, and synthetic formulations including selective estrogen receptor modulators (SERMs). This review covers the pharmacology of estrogen and the effects on GH action to inform judicious use in the pituitary patient. The effects on the GH system are route dependent due to first-pass hepatic metabolism. Oral but not parenteral estrogen compounds inhibit GH action, reducing hepatic insulin-like growth factor-1 (IGF-1) production, protein anabolism, and fat utilization. In patients with GH deficiency, oral estrogen therapy exacerbates the degree of hyposomatotrophism and attenuates the beneficial effects of GH replacement therapy, effects that are greater with contraceptive than replacement doses. Surveys report that less than one-fifth of hypopituitary women are appropriately replaced by a transdermal route and up to half on oral therapy are inappropriately treated with contraceptive steroids. In acromegaly, however, estrogens, especially synthetic formulations of greater potency, reduce IGF-1, improving disease control, an effect also observed in men treated with SERMs. The route-dependent effects and potency of estrogen formulations are important considerations for optimizing the management of hypogonadal patients with pituitary disease, in particular GH deficiency and acromegaly. For hypopituitary women, estrogens should be replaced by a nonoral route. For acromegaly, oral estrogen formulations can be considered as simple adjuvant therapy for disease control.

The Impaired Growth Induced by Zinc Deficiency in Rats Is Associated with Decreased Expression of the Hepatic Insulin-like Growth Factor I and Growth Hormone Receptor Genes

This study was conducted to determine whether dietary zinc status affects the expression of the insulin-like growth factor I and growth hormone receptor/growth hormone binding protein genes in the liver of growing rats. Weanling male Sprague-Dawley rats were randomly allotted to zinc-deficient, pair-fed or ad libitum-fed dietary treatments and fed diets containing no added zinc for 14 d. Zinc acetate was added to the deionized, distilled water (30 mg/L) provided to pair-fed and ad libitum-fed rats. As expected, zinc deficiency significantly reduced growth rate by 60% and was associated with a significantly lower serum insulin-like growth factor I concentration (46 and 67% lower than pair-fed and ad libitum-fed rats, respectively). The reduction in serum insulin-like growth factor I concentration was associated with a decrease in insulin-like growth factor I gene expression. The abundance of the 7.5-kb insulin-like growth factor I mRNA transcript in zinc-deficient and pair-fed rats was 14 and 31% that of the ad libitum-fed rats. The 0.8–1.2-kb insulin-like growth factor I transcript also was significantly lower in the zinc-deficient and pair-fed rats. In contrast, the abundance of the 1.8-kb insulin-like growth factor I transcript was unaffected by zinc deficiency. The growth hormone receptor mRNA levels of zinc-deficient and pair-fed rats were 17 and 50% and their growth hormone binding protein mRNA levels were 46 and 65% those of the ad libitum-fed rats. In summary, zinc deficiency markedly decreases expression of the insulin-like growth factor I and growth hormone receptor genes. The mechanisms that account for the decreases are obscure. Nonetheless, our results indicate that the growth retardation caused by zinc deficiency is associated with defects in the growth hormone receptor signaling pathway.

Human Growth Hormone but Not Human Insulin-Like Growth Factor-I Enhances Recovery from Neonatal Malnutrition in Rats

The ability of hormonal therapy to enhance recovery from neonatal mainutrition was assessed in rats. Pups were mainourished via maternal food restriction (60% control intake). On d 16, restricted pups (n = 50) (62% control body wt) were refed until d 20 and were given growth hormone, insulin-like growth factor-I, destripeptide [1,3] insulin-like growth factor-I, or saline (placebo). Refed-placebo pups attained 80% of control body weight by d 20. Growth hormone treatment caused a greater weight gain than refeeding alone (P ≤ 0.05). Treatment with insulin-like growth factor-I and destripeptide [1,3] insulin-like growth factor-I did not affact body weight. All three hormones increased spleen and kidney weights (P ≤ 0.05) compared with the refedplacebo group, whereas only growth hormone increased muscle weight (P ≤0.05). Mainourished pups had lower serum insulin-like growth factor-I (P ≤ 0.05) and insulin-like growth factor binding protein-3 (P ≤ 0.05), and higher serum insulin-like growth factor binding protein-2 (P ≤ 0.05) and hepatic insulin-like growth factor binding protein-2 mRNA (P ≤ 0.05) than controls. Refeeding increased serum insulin-like growth factor-I compared with restricted pups (P ≤ 0.05), and insulin-like growth factor-I treatment caused a further increased in serum insulin-like growth factor-I compared with the refedplacebo group (P ≤ 0.05). These results show that growth hormone was moderately effective at increasing body weight gain and muscle growth during recovery from mainutrition.

Embryonic thermal manipulation leads growth inhibition and reduced hepatic insulin-like growth factor1 expression due to promoter DNA hypermethylation in broilers

When broilers cannot adapt to a high-temperature environment through self-regulation, it will cause heat stress, resulting in a large number of deaths and substantial economic losses. Studies have shown that thermal manipulation (TM) during the embryonic stage can improve broilers' ability to resist heat stress later. However, different TM strategies produce different results on broilers' growth. In this study, yellow-feathered broiler eggs were selected and randomly divided into 2 groups between E10 and E18, which the control group was incubated at 37.8°C with 56% humidity, and the TM group was subjected to 39°C with 65% humidity. After hatching, all broilers were reared normally until slaughtered at 12 d of age (D12). During D1 to D12, body weight, feed intake, and body temperature were recorded. The results showed that TM significantly decreased (P < 0.05) the final body weight, weight gain, and average daily feed intake of broilers. Meanwhile, the serum levels of Triiodothyronine (T3) and free T3 were significantly decreased in the TM group (P < 0.05). The expressions of hepatic growth regulation-associated genes, growth hormone receptor (GHR), insulin-like growth factor1, and 2 (IGF1 and IGF2) were significantly down-regulated in the TM group (P < 0.05). In addition, TM altered hepatic DNA methylation, resulting in a significant increase (P < 0.05) in the methylation of the IGF1 and GHR promoter regions. The above results indicated that TM during the embryonic stage decreased the serum thyroid hormone level and increased the methylation level of the IGF1 and GHR promoter regions to down-regulate the expression of growth-related genes, resulting in early growth inhibition of broilers.

Effects of fasting on FOXO3 expression as an anti-aging biomarker in the liver

BackgroundAging is a multifactorial degenerative process that can be modulated by fasting through activation of the Fork-head transcription factor of the O class 3 (FOXO3), which plays an important role in increasing lifespans. However, the effects of different fasting durations on the expression of FOXO3 in the liver has not yet been reported. ObjectiveThis study analyzed the effects of different fasting durations on the FOXO3 expression and its pathway by measuring sirtuin1 (SIRT1), insulin-like growth factor-1 (IGF-1), and superoxide dismutase (SOD) activity in the liver. MethodsNew Zealand white rabbits were used to mimic the effects of fasting on humans. The rabbits were divided into the control, intermittent fasting (IF), and prolonged fasting (PF) groups. Both fasting groups were interspersed with the non-fasting phase for 8 h. This treatment was conducted for 6 days. On Day 7, all the rabbits were sacrificed, and their livers were taken to measure the FOXO3 and SIRT1 mRNA expressions, the IGF-1 protein level, and the SOD activity level. ANOVA, multiple comparison, and Pearson's correlation were performed for statistical analysis. ResultsThe FOXO3 and SIRT1 mRNA expressions were significantly higher in the IF group than in the control group. The FOXO3 expression was also 2.5 times higher in the IF group than in the PF group. There was a positive correlation between the FOXO3 and SIRT1 mRNA expressions. The IGF-1 protein level was significantly lower in the IF and PF groups than in the control group. The SOD-specific activity level was significantly higher in the IF group than in the control and PF groups. ConclusionsIntermittent fasting significantly increased the FOXO3 and SIRT1 mRNA expressions and the SOD activity level in the livers of the rabbits and significantly decreased the circulating and hepatic IGF-1. Therefore, intermittent fasting may give a protective intervention effect towards aging.

The Optimum Dietary Phenylalanine Requirement of Hybrid Grouper (Epinephelusfuscoguttatus ♀ × Epinepheluslanceolatus ♂) Juveniles: Effects on Growth Performance, Gut Micromorphology, and Antioxidation.

The optimum phenylalanine (Phe) requirement for hybrid grouper (Epinephelusfuscoguttatus ♀ × Epinepheluslanceolatus ♂) juveniles was determined through an 8-week growth trial. A total of seven isoenergetic (340 kcal per 100 g of dry matter), isonitrogenous, and isolipidic diets were made, containing 8.2 (Phe 8.2), 9.2 (Phe 9.2), 10.1 (Phe 10.1), 11.2 (Phe 11.2), 13.3 (Phe 13.3), 15.2 (Phe 15.2), and 17.3 g/kg (Phe 17.3), respectively. Triplicate tanks of juvenile fish (about 16.7 g/fish) were fed each experimental diet twice daily until apparent satiation. The results indicated that different dietary Phe levels significantly influenced weight gain percentage (WG), feed efficiency (FE), protein efficiency ratio (PER), as well as, productive protein value (PPV). Fish fed Phe 8.2 had the lowest WG or PPV among all experimental treatments. Furthermore, the optimal dietary Phe level increased fold height, width, enterocyte, and microvillus height of fish. The Phe 10.1 group exhibited higher growth hormone (GH) expression in the pituitary compared to other groups. Expression of hepatic insulin-like growth factor-1 (IGF-1) and growth hormone receptor 1 (GHR1) displayed a similar pattern of variation to that of GH. The Phe 13.3 group had lower expression of S6 kinase 1 (S6K1) and target of rapamycin (TOR) than other groups. In addition, fish fed Phe 10.1 had lower levels of nuclear factor erythroid 2 (Nrf2) and heat shock protein 70 (HSP70) in the head kidney, and Cu/Zn-superoxide (Cu/ZnSOD) dismutases in the midgut compared to fish fed other Phe levels. Generally, optimal Phe content in the diet of hybrid grouper was estimated to be 12.7 g/kg of dry matter (27.3 g/kg of dietary protein), and at this level, the feed utilization, gut micromorphology, and immunity of fish were also elevated.

Dietary glycerol monolaurate improves bone growth through the regulation of IGF-1 in the fish model

Glycerol monolaurate (GML) has the potential of antibacterial and growth-promoting in food. Recent research reported that GML could significantly increase the body index of fish, but whether GML can exert growth-promoting ability via regulating bone metabolism remains unknown. This study explored the effects of GML on the bone growth of fish models and its mechanisms by analyzing the expression of insulin-like growth factor 1(IGF-1). The micro-CT scanning results showed that the dietary supplementation of 750 mg/kg GML significantly increased the body length and bone mineral density, and improved the bone microarchitecture parameters of the caudal vertebrae of zebrafish (Danio rerio). The centrum part of the vertebra was easier to respond to the regulatory effect of GML than the neural arch and the haemal arch. Mechanistically, the content of serum IGF-1, the expression of osteogenic differentiation-related genes, and genes involved in IGF-1/PI3K/Akt signaling pathway were significantly increased. The liver proteomic analysis showed the consistent results that GML supplementation could up-regulate the expression of hepatic IGF-1, and that energy metabolism and growth and development-related metabolic pathways were implicated in the GML bone growth boosting effects. These findings highlight that GML could be used as a functional food additive to improve bone growth and health.

Pregelatinized starch improves growth and mitigates adverse liver/intestinal histomorphology in largemouth bass, Micropterus salmoides, juveniles

The growth and well-being of carnivorous fish, such as largemouth bass Micropterus salmoides, can be compromised by excessive dietary starch but this may depend on starch type and degree of gelatinization. In a 2 × 2 factorial design, largemouth bass were fed diets containing 20 % raw corn starch (RCS), raw sweetpotato flour (RSP), pregelatinized corn starch (PGCS) or pregelatinized sweetpotato flour (PGSP) and their growth, muscle biochemical composition, liver/intestinal histopathology, and expression of genes responsible for growth and fatty acid metabolism were analyzed. Some indicators of pellet quality were also measured showing that pregelatinized starches significantly improved (P < 0.05) water stability, water absorption index, and water solubility index while significantly reducing bulk density. Gelatinization significantly improved (P < 0.05) weight gain and FCR (1073 % and 0.84, respectively) over their raw starch forms (892 % and 1.02, respectively), which was correlated with significantly upregulated (P < 0.05) hepatic insulin-like growth factor-1. Neither starch type or gelatinization had any significant effect on the muscle proximate or mineral composition, but MUFA was significantly (P < 0.05) in the RCS treatment, which corresponded with significantly lower hepatic expression of fatty acid synthase. Gelatinization significantly upregulated lowest (P < 0.05) hepatic expression of cholesterol 7 alpha-hydroxylase. Histopathological damage and inflammation occurred in the liver and distal intestine, respectively, of fish fed raw starch diets but not for the PG types. Results indicate that pregelatinizing both starch sources significantly improved growth and feeding efficiency in largemouth bass juveniles while causing no adverse histopathology compared to either raw starch sources.

The Effect of Commercial Genetic Selection on Somatotropic Gene Expression in Broilers: A Potential Role for Insulin-Like Growth Factor Binding Proteins in Regulating Broiler Growth and Body Composition.

The somatotropic axis influences growth and metabolism, and many of its effects are a result of insulin-like growth factor (IGF) signaling modulated by IGF-binding proteins (IGFBPs). Modern commercial meat-type (broiler) chickens exhibit rapid and efficient growth and muscle accretion resulting from decades of commercial genetic selection, and it is not known how alterations in the IGF system has contributed to these improvements. To determine the effect of commercial genetic selection on somatotropic axis activity, two experiments were conducted comparing legacy Athens Canadian Random Bred and modern Ross 308 male broiler lines, one between embryonic days 10 and 18 and the second between post-hatch days 10 and 40. Gene expression was evaluated in liver and breast muscle (pectoralis major) and circulating hormone concentrations were measured post-hatch. During embryogenesis, no differences in IGF expression were found that corresponded with difference in body weight between the lines beginning on embryonic day 14. While hepatic IGF expression and circulating IGF did not differ between the lines post-hatch, expression of both IGF1 and IGF2 mRNA was greater in breast muscle of modern broilers. Differential expression of select IGFBPs suggests their action is dependent on developmental stage and site of production. Hepatic IGFBP1 appears to promote embryonic growth but inhibit post-hatch growth at select ages. Results suggest that local IGFBP4 may prevent breast muscle growth during embryogenesis but promote it after hatch. Post-hatch, IGFBP2 produced in liver appears to inhibit body growth, but IGFBP2 produced locally in breast muscle facilitates development of this tissue. The opposite appears true for IGFBP3, which seems to promote overall body growth when produced in liver and restrict breast muscle growth when produced locally. Results presented here suggest that paracrine IGF signaling in breast muscle may contribute to overall growth and muscle accretion in chickens, and that this activity is regulated in developmentally distinct and tissue-specific contexts through combinatorial action of IGFBPs.

Sprint training interacts with body mass to affect hepatic insulin-like growth factor expression in female green anoles (Anolis carolinensis)

Locomotor performance is a key predictor of fitness in many animal species. As such, locomotion integrates the output of a number of morphological, physiological, and molecular levels of organization, yet relatively little is known regarding the major molecular pathways that bolster locomotor performance. One potentially relevant pathway is the insulin and insulin-like signaling (IIS) network, a significant regulator of physiological processes such as reproduction, growth, and metabolism. Two primary hormones of this network, insulin-like growth factor 1 (IGF1) and insulin-like growth factor 2 (IGF2) are important mediators of these processes and, consequently, of life-history strategies. We sprint-trained green anole (Anolis carolinensis) females to test the responsiveness of IGF1 and IGF2 hepatic gene expression to exercise training. We also tested how sprint training would affect glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and eukaryotic elongation factor 2 (EEF2). The former is a crucial enzyme for glycolytic function in a cell, and the latter is necessary for protein synthesis. Resistance exercise forces animals to increase investment of resources towards skeletal muscle growth. Because IGF1 and IGF2 are important hormones for growth, and GAPDH and EEF2 are crucial for proper cellular function, we hypothesized that these four genes would be affected by sprint training. We found that sprint training affects IGF and EEF2 expression, such that larger sprint-trained lizards express hepatic IGF1, IGF2, and EEF2 to a lesser extent than similarly sized untrained lizards. These results demonstrate that the IIS, and pathways connected to it, can react in a size-dependent manner and are implicated in the exercise response in reptiles.

Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial.

Background/AimsWe aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD).MethodsAn exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy.ResultsDPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels.ConclusionsThe DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.

Dietary vitamin C affects growth, antioxidant status and serum immune parameter of juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂) fed low fishmeal diets

Ascorbic acid (Vitamin C - VC) is one of the essential micronutrients required for normal growth and physiology of fish. In this research, the optimum dietary VC requirement of juvenile hybrid grouper (Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂) was evaluated in a comparative feeding trial and subsequent oxidative stress test. Six isoenergetic (340 kcal/kg), isoproteic (49%) and isolipidic (7%) experimental diets were supplemented with graded amounts of L-ascorbyl-2-polyphosphate (analyzed VC concentrations of 76, 86, 104, 126, 137 and 152 mg/kg dry matter) and hand-fed to fish (initial weight of 15 ± 0.1 g/fish (means ± S.D.)) in three replicate cages twice a day (08:00 h and 16:30 h) to apparent satiation for 7 weeks. Percent weight gain (WG%), together with the VC concentrations in liver and head kidney, were elevated with increasing dietary VC contents, reaching a plateau in the VC137 treatment. The optimal dietary VC requirement of hybrid grouper was estimated to be 148 mg/kg dry matter based on broken-line regression analysis of WG%. Serum immunoglobulin M (IgM) concentrations and the relative mRNA expression of hepatic insulin-like growth factor-1 (IGF-1) displayed a similar variation tendency as WG%. At the transcriptional level, the activity of Nrf2-Keap1 pathway was up-regulated by VC supplementations, with the VC104 treatment showing the highest value. In summary, the optimal dietary VC requirement for the highest value of WG% of juvenile hybrid grouper was 148 mg/kg dry matter, and appropriate dietary VC supplementation improved oxidation resistance and serum IgM concentrations of the fish.

The Impact of Curcumin on Growth Performance, Growth-Related Gene Expression, Oxidative Stress, and Immunological Biomarkers in Broiler Chickens at Different Stocking Densities.

Simple SummaryThe primary goal of global poultry production is to optimize the amount of chicken produced per square meter of floor area. Consequently, stocking density (SD) and curcumin supplementation on broiler performance were investigated. Our results revealed that supplemental curcumin improved birds’ growth, behaviours, and immunity by lowering oxidative stress, enhancing humoral immune response, and modulating the suppression of growth-related gene expressions in broilers raised in high stocking density circumstances.Curcumin’s antioxidant properties reduce free radicals and may improve broiler growth. Therefore, the influence of stocking density (SD) and administration of curcumin in the diet on broiler performance was explored to clarify the impact of HSD and curcumin on the performance of growth, behavioural patterns, haematological, oxidant/antioxidant parameters, immunity markers, and the growth-related genes expression in broiler chickens. A total of 200 broiler chickens (Cobb 500, 2-weeks old) were allotted into 4 groups; SD (moderate and high) and curcumin (100 and 200 mg/kg diet)-supplemented HSD, respectively. Behavioural observations were performed. After a 28-day experimental period, tissue and blood samples were collected for analysis. Expressions of mRNA for insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), myostatin (MSTN), and leptin in liver tissues were examined. HSD birds exhibited lower growth performance measurements, haematological parameters, circulating 3,5,3-triiodothyronine and thyroxine levels, antioxidant activities (GSH-Px, catalase, superoxide dismutase), immunoglobulins (A, G, M), and hepatic GHR and IGF-1 expression values. However, HSD birds even had an increment of serum corticosterone, malondialdehyde, pro-inflammatory cytokine (TNF-a, IL-2, IL-6) levels, hepatic leptin and MSTN expression. Moreover, HSD decreased drinking, feeding, crouching, body care, and increased standing and walking behaviour. The addition of curcumin, particularly at a 200 mg/kg diet, alleviated the effect of HSD through amending growth-related gene expression in the chickens. In conclusion, curcumin can enhance birds’ growth performance, behavioural patterns, and immunity by reducing oxidative stress and up-regulating the growth-related gene expressions of broilers under stressful conditions due to a high stocking density.