Role Of IGF-I Research Articles

Leptin and IGF1 receptors in alpaca (Vicugna pacos) ovaries

Folliculogenesis and ovulation are regulated by gonadotrophins and other factors such as Insulin like growth factor 1 (IGF1) and leptin. In various species the presence of IGF1 receptor (IGF1R) and leptin receptor (ObR) has been detected in the ovary, but not in the alpaca. Thus, the aim of the present study was to evaluate the presence of these receptors in this tissue and analyze if the presence of these receptors in the ovary is related to the presence of a corpus luteum (CL) and if abundances, as determined by immunostaining intensity vary with follicle size. The IGF1R and ObR were identified in primary and secondary follicles, granulosa and theca interna cells of tertiary follicles and in CL. There were greater abundances of IGF1R in granulosa cells of tertiary follicles of ovaries without compared with those with CL. In both groups, the immunostaining of granulosa cells was greater than in theca interna cells. The abundance of ObR was greater in primary and secondary follicles, and theca interna cells of tertiary follicles in ovaries with than those without CL. Immunostaining of granulosa cells was greater than theca interna cells only in ovaries without CL. There were no differences in the abundance of ObR and IGF1R between primary and secondary follicles and granulosa cells of tertiary follicles, neither in ovaries with or without CL. The abundance of IGF1R was not correlated with abundance of ObR neither in ovaries with or without CL. These results indicate a possible role for IGF and leptin in ovarian function. Furthermore, these receptors could be regulated by ovarian steroid hormones because abundance of these receptors in ovaries varies depending on whether there is a CL present in the ovary.

Update in the management of acne in adolescence.

This review will update the pediatric provider on recent data on the pathogenesis and treatment of acne in adolescent patients. A special focus was made to summarize recent guidelines and fill in several identified practice gaps. Our understanding of the pathogenesis of acne is greatly expanding and data is emerging to tie diet, particularly the role of IGF-1 with inflammation in acne. Additionally, stronger recommendations to limit antibiotic usage in acne are being made worldwide. Although retinoids are considered the base of most effective acne treatment strategies, data suggests that all providers need to emphasize their importance in maintenance of acne. An effective acne management strategy targets multiple pathogenic factors in acne, using a retinoid as the foundation. Systemic antibiotics for moderate-to-severe acne should be used for acute management, then discontinued at 3-4 months, while maintaining on topical treatments. If therapy is ineffective, alternate treatments, such as combined oral contraceptives in females or isotretinoin, should be promptly employed to prevent prolonged psychological impact and cutaneous scarring.

Formoterol treatment prevents the effects of endotoxin on muscle TNF/NF-kB, Akt/mTOR, and proteolytic pathways in a rat model. Role of IGF-I and miRNA 29b

Inflammatory diseases are associated with muscle wasting as a result of an increase in proteolysis. The purpose of this study was to elucidate whether administration of a β2 adrenergic agonist, formoterol, was able to prevent the acute effects of sepsis induced by liposaccharide (LPS) injection on rat gastrocnemius muscle and to evaluate the possible roles of corticosterone, IGF-I, miR-23a, and miR-29b. For this purpose, male Wistar rats were injected with LPS and/or formoterol. Formoterol treatment decreased LPS-induced increase in serum corticosterone, TNFα upregulation, and NF-κB(p65) and Forkhead box protein O1 activation in the gastrocnemius. Atrogin-1, muscle RING-finger protein-1, microtubule-associated protein-1 light chain 3b (LC3b), and the lipidation of LC3b-I to LC3b-II were increased by LPS, and formoterol blocked these effects. Serum IGF-I and its mRNA levels in the gastrocnemius were decreased, whereas mecano growth factor and IGF binding protein 3 mRNA levels were increased in the rats injected with LPS but not in the rats that received LPS and formoterol. Similarly, LPS decreased Akt and mammalian target of rapamycin phosphorylation, and formoterol blocked these decreases. Finally, miR-29b expression in the gastrocnemius was upregulated by endotoxin injection, whereas miR-23a was not significantly different. Formoterol treatment did not significantly modify LPS-induced increase in muscle miR-29b. Furthermore, in control rats formoterol increased the expression of this miRNA. We conclude that formoterol decreases endotoxin-induced inflammation and proteolysis in rat skeletal muscle. Those responses can be a direct effect of β2 adrenergic receptor stimulation or/and of blocking the effects of LPS on corticosterone and IGF-I. Muscle miR-23a and -29b do not seem to play an important role in those responses.

Genetic Variation in the H19-IGF2 Cluster Might Confer Risk of Developing Impaired Renal Function.

The H19-IGF2 imprinted gene region could be implicated in the risk of developing impaired renal function (IRF). Our aim was to determine the association of several common H19-IGF2 variants and IRF in a cohort of elderly healthy individuals. The study involved 675 individuals >65 years of age, 184 with type 2 diabetes mellitus (T2DM), and 105 with IRF (estimated glomerular filtration rate [eGFR] <60). They were genotyped for two common H19 single nucleotide polymorphisms (SNPs) (rs2839698 and rs10732516), one H19-IGF2 intergenic indel (rs201858505), and one indel in the 3'UTR of the IGF2. For the H19 SNPs, we also determined the allele present in the methylated chromosome through genotyping the DNA digested with a methylation-sensitive endonuclease. None of the four H19-IGF2 variants was associated with IRF in our cohort. We found a significantly higher frequency of the 3'UTR IGF2 deletion (D) in the eGFR <60 group (p = 0.01; odds ratio = 1.16, 95% confidence interval = 1.10-2.51). This association was independent of age and T2DM, two strong predictors of IRF. In conclusion, a common indel variant in the 3'UTR of the IGF2 gene was associated with the risk of IRF. This association could be explained by the role of IGF2 in podocyte survival, through regulation of IGF2 expression by differential binding of miRNAs to the indel sequences. Functional studies should be necessary to clarify this issue.

Role of IGF1 in regulation of SOD 1 expression and mTOR/S6K signaling in heart of obese male rats

Role of IGF1 in regulation of SOD 1 expression and mTOR/S6K signaling in heart of obese male rats

Extraocular muscle regeneration in zebrafish requires late signals from Insulin-like growth factors.

Insulin-like growth factors (Igfs) are key regulators of key biological processes such as embryonic development, growth, and tissue repair and regeneration. The role of Igf in myogenesis is well documented and, in zebrafish, promotes fin and heart regeneration. However, the mechanism of action of Igf in muscle repair and regeneration is not well understood. Using adult zebrafish extraocular muscle (EOM) regeneration as an experimental model, we show that Igf1 receptor blockage using either chemical inhibitors (BMS754807 and NVP-AEW541) or translation-blocking morpholino oligonucleotides (MOs) reduced EOM regeneration. Zebrafish EOMs regeneration depends on myocyte dedifferentiation, which is driven by early epigenetic reprogramming and requires autophagy activation and cell cycle reentry. Inhibition of Igf signaling had no effect on either autophagy activation or cell proliferation, indicating that Igf signaling was not involved in the early reprogramming steps of regeneration. Instead, blocking Igf signaling produced hypercellularity of regenerating EOMs and diminished myosin expression, resulting in lack of mature differentiated muscle fibers even many days after injury, indicating that Igf was involved in late re-differentiation steps. Although it is considered the main mediator of myogenic Igf actions, Akt activation decreased in regenerating EOMs, suggesting that alternative signaling pathways mediate Igf activity in muscle regeneration. In conclusion, Igf signaling is critical for re-differentiation of reprogrammed myoblasts during late steps of zebrafish EOM regeneration, suggesting a regulatory mechanism for determining regenerated muscle size and timing of differentiation, and a potential target for regenerative therapy.

Investigating the Mechanisms of Endometrial Cancer Risk in Polycystic Ovary Syndrome: Can UK Biobank Help?

Background: UK biobank was set up to investigate the respective contributions of genetic predisposition and environmental exposure to the development of disease and recruited participants between 2006 and 2010. Our aim was to investigate the feasibility of using UK biobank for exploring the association between polycystic ovarian syndrome (PCOS) and endometrial cancer, including the role played by serum IGF-1 levels. Methods: Publicly accessible and freely available online data in the resource section of the UK biobank website were used to determine the prevalence of self reported PCOS and for assessing the quality of data on ovarian imaging and serum biomarkers. A literature review was conducted to compare rates of PCOS in UK Biobank with other populations. Results: UK biobank contains 273,469 women (age range 37-73 years) of whom 643 (0.23%) self-reported PCOS. This was compared with values ranging from 3.1 % to 19.9% obtained from 16 studies picked up by our systematic literature search. Conclusion: It is feasible to use UK biobank to conduct research into the role of IGF-1 in explaining the association between PCOS and endometrial cancer. More detailed phenotyping of women recruited into the diagnostic group of PCOS is, however, vital to underpin this research. The resulting resource would be excellent for researchers interested in exploring the long-term health risks associated with PCOS.

Role of androgen receptor on cyclic mechanical stretch-regulated proliferation of C2C12 myoblasts and its upstream signals: IGF-1-mediated PI3K/Akt and MAPKs pathways

ObjectsTo detect the effects of androgen receptor (AR) on cyclic mechanical stretch-modulated proliferation of C2C12 myoblasts and its pathways: roles of IGF-1, PI3K and MAPK. MethodsC2C12 were randomly divided into five groups: un-stretched control, six or 8 h of fifteen percent stretch, and six or 8 h of twenty percent stretch. Cyclic mechanical stretch of C2C12 were completed using a computer-controlled FlexCell Strain Unit. Cell proliferation and IGF-1 concentration in medium were detected by CCK8 and ELISA, respectively. Expressions of AR and IGF-1R, and expressions and activities of PI3K, p38 and ERK1/2 in stretched C2C12 cells were determined by Western blot. Results①The proliferation of C2C12 cells, IGF-1 concentration in medium, expressions of AR and IGF-1R, and activities of PI3K, p38 and ERK1/2 were increased by 6 h of fifteen percent stretch, while decreased by twenty percent stretch for six or 8 h ②The fifteen percent stretch-increased proliferation of C2C12 cells was reversed by AR inhibitor, Flutamide. ③The increases of AR expression, activities of PI3K, p38 and ERK1/2 resulted from fifteen percent stretch were attenuated by IGF-1 neutralizing antibody, while twenty percent stretch-induced decreases of the above indicators were enhanced by recombinant IGF-1. ④Specific inhibitors of p38, ERK1/2 and PI3K all decreased the expression of AR in fifteen percent and twenty percent of stretched C2C12 cells. ConclusionsCyclic mechanical stretch modulated the proliferation of C2C12 cells, which may be attributed to the alterations of AR via IGF-1-PI3K/Akt and IGF-1-MAPK (p38, ERK1/2) pathways in C2C12 cells.

The role of IGF-1 and the distribution of body fat in decreasing the number of prostate rebiopsies

ObjectiveTo assess the usefulness of IGF-1 and internal organ fat measured by bioelectrical impedance audiometry to avoid rebiopsies in patients with persistently high prostate-specific antigen (PSA) levels. Material and methodA prospective study was conducted with 92 patients who underwent prostate rebiopsy due to high PSA levels with negative results in the rectal examination and a lack of preneoplastic lesions. The patients previously had their IGF-1 levels measured and had undergone an impedance audiometry test using the abdominal Fat Analyzer AB-140 TANITA system. We calculated the receiver operating characteristic (ROC) curves for the PSA levels, %PSA, internal organ fat and IGF-1 and PSA density. ResultsTwenty-five patients were diagnosed with prostate cancer. These patients had significantly higher PSA, PSAd and IGF-1 values and a tendency toward higher internal organ fat levels and lower %PSA readings (p=.001, p=0.003, p=0.001, p=0.24 and p=0.28, respectively). The ROC curve showed an area under the curve for IGF-1 and PSA of 0.82 and 0.81, respectively. Using the cutoff points for 95% sensitivity and using the 3 criteria as an indication of rebiopsy, 74% of the biopsies would have been spared, leaving undiagnosed only 1 patient with clinically significant cancer—Gleason score>7 (4+3). The positive and negative predictive values for the set of variables were higher than for each one separately (PPV: 66/NPV: 63). The cost of both determinations was 82 euros. ConclusionsOur results suggest that measuring IGF-1 could significantly decrease the number of unnecessary rebiopsies in an inexpensive and safe manner.

Expression and functional role of Bone Morphogenetic Proteins (BMPs) in cyclical corpus luteum in buffalo (Bubalus bubalis)

The role of growth factors in the modulation of ovarian function is an interesting area of research in reproductive biology. Recently, we have shown the expression and role of IGF, EGF, VEGF and FGF in the follicle and CL. Here, we report the presence of Bone Morphogenetic Proteins (BMPs) and their functional receptors in the corpus luteum (CL) of buffalo. The bubaline CL was classified into four stages according to the morphology and progesterone (P4) concentration. The qPCR, immunoblot and immunohistochemistry studies revealed that BMP2 and BMP Receptors (BMPR1A, BMPR1B and BMPR2) were significantly upregulated during the mid stage whereas BMP4 and BMP7 were upregulated during the early stage of CL (P<0.05). Studies on primary luteal cell culture (LCC) using mid CL showed a significant time and concentration dependent effect of BMP4 and BMP7 (P<0.05). At 100ngml−1, the BMPs maximally stimulated the transcripts of StAR, CYP11A1 and 3βHSD that paralleled with P4 accretion in the media (P<0.05). Further, the BMP4 as well as BMP7 upregulated the transcripts of PCNA and downregulated CASPASE3 in the LCC at the same concentration (P<0.05). Though the combined effect of BMP4 and 7 was significantly higher (P<0.05) than that of individual one, it was not additive. In conclusion, the expression of BMPs and their receptors were dependent on the stages of CL in the buffalo. Treatment of LCC with BMPs in vitro confirmed the presence of functional receptors that stimulated the P4 production and luteal cell survival. Moreover, the results support the concept that the upregulation of P4 and its biosynthetic pathway enzymes such as CYP11A1, StAR and 3βHSD in the CL is likely due to the autocrine and /or paracrine effects of BMP4 and BMP7 under physiological milieu.

Circulating Insulin-Like Growth Factor I Regulates Its Receptor in the Brain of Male Mice.

The role of IGF-1 and its receptor (IGF-1R) in brain pathology is still unclear. Thus, either reduction of IGF-IR or treatment with IGF-1, two apparently opposite actions, has proven beneficial in brain diseases such as Alzheimer's dementia. A possible explanation of this discrepancy is that IGF-1 down-regulates brain IGF-1R levels, as previously seen in a mouse Alzheimer's dementia model. We now explored whether under normal conditions IGF-1 modulates its receptor. We first observed that in vitro, IGF-1 reduced IGF-1R mRNA levels in all types of brain cells including neurons, astrocytes, microglia, endothelial cells, and oligodendrocytes. IGF-1 also inhibited its own expression in neurons and brain endothelium. Next, we analyzed the in vivo actions of IGF-1. Because serum IGF-1 can enter the brain, we injected mice with IGF-1 ip. As soon as 1 hour after the injection, decreased hippocampal IGF-1 levels were observed, followed by increased IGF-1 and IGF-1R mRNAs 6 hours later. Because environmental enrichment (EE) stimulates the entrance of serum IGF-1 into the brain, we analyzed whether a physiological entrance of IGF-1 also produced changes in brain IGF-1R. Stimulation of IGF-1R by EE triggered a gradual decrease in hippocampal IGF-1 levels. After 6 hours of EE exposure, IGF-1 levels reached a significant decrease in parallel with increased IGF-1R expression. After longer times, IGF-1R mRNA levels returned to baseline. Thus, under nonpathological conditions, IGF-1 regulates brain IGF-1R. Because baseline IGF-1R levels are rapidly restored, a tight control of brain IGF-1R expression seems to operate under physiological conditions.

Is there a role for IGF-1 in the development of second primary cancers?

Cancer survival rates are increasing, and as a result, more cancer survivors are exposed to the risk of developing a second primary cancer (SPC). It has been hypothesized that one of the underlying mechanisms for this risk could be mediated by variations in insulin‐like growth factor‐1 (IGF‐1). This review summarizes the current epidemiological evidence to identify whether IGF‐1 plays a role in the development of SPCs. IGF‐1 is known to promote cancer development by inhibiting apoptosis and stimulating cell proliferation. Epidemiological studies have reported a positive association between circulating IGF‐1 levels and various primary cancers, such as breast, colorectal, and prostate cancer. The role of IGF‐1 in increasing SPC risk has been explored less. Nonetheless, several experimental studies have observed a deregulation of the IGF‐1 pathway, which may explain the association between IGF‐1 and SPCs. Thus, measuring serum IGF‐1 may serve as a useful marker in assessing the risk of SPCs, and therefore, more translational experimental and epidemiological studies are needed to further disentangle the role of IGF‐1 in the development of specific SPCs.

INSULIN-LIKE GROWTH FACTOR 1 UNDER CONDITIONS OF THE BRAIN VASCULAR DISEASES.

The system insulin-like growth factors (IGF) occupies an important place in the development and growth of the central nervous system (CNS). Gene expression of insulin-like growth factor I (IGF-1) and IGF-1 receptor are represented in all parts of the brain and are heavily concentrated in the cerebral vessels. IGF-1 is involved in neuro-, angiogenesis, in the stimulation of cell proliferation, and repair responses to damage for both the central and peripheral nervous system. IGF- 1 exerts antioxidant, anti-inflammatory and protective effects on the CNS. The review discusses the importance and the role of IGF-I in vascular diseases of the brain, in particular, aneurysms, the ischemic stroke, the aneurysmal subarachnoid hemorrhage, as well as neuroprotection.

Contradicting interplay between insulin-like growth factor-1 and miR-486-5p in primary NK cells and hepatoma cell lines with a contemporary inhibitory impact on HCC tumor progression

In this study, an impaired natural killer (NK) cell cytolytic activity in 135 hepatocellular carcinoma (HCC) patients parallel to a reduced expression level of insulin-like growth factor (IGF)-1 in NK cells of HCC patients has been revealed. Ectopic expression of miR-486-5p, a direct upstream regulator of IGF-1, restored the endogenous level of IGF-1 in NK cells of HCC patients, thus augmenting its cytolytic activity against Huh7 cells in an opposite manner to the IGF-1 siRNAs. Unorthodoxly, over-expression of miR-486-5p in target hepatocytes resulted in the repression of IGF-1, suppression of Huh7 cells proliferation and viability in a similar pattern to the IGF-1 siRNAs. Therefore, this study highlights a potential role of IGF-1 in modulating cytolytic potential of NK cells of HCC patients. miR-486-5p acts in a cell-specific manner, differentially modulating IGF-1 expression in NK cells and their target hepatocytes with a contemporary inhibitory impact on HCC progression.

A histological and immunohistochemical study of the effects of N-acetyl cysteine on retinopathy of prematurity by modifying insulin-like growth factor-1

Retinopathy of prematurity (ROP) is a vasoproliferative disorder that occurs in premature infants and may lead to permanent visual impairment. We investigated both the possible protective role of N-acetyl cysteine (NAC) for preventing ROP and the role of IGF-1 in the disorder. Forty-five newborn rats were divided into three groups. Group 1 was raised in room air as controls. Group 2 was exposed to 60% oxygen for 14 days after birth, then transferred to room air. Group 3 was exposed to the same conditions as group 2, but received intraperitoneal injections of NAC on postnatal days 7–17. After 35 days, both eyes of all rats were processed for histology. Some sections were stained with hematoxylin and eosin to assess structural changes and other sections were immunostained to determine the location of IGF-1. Frozen sections also were prepared and stained for adenosine triphosphatase to detect retinal blood vessels. Compared to the controls, more blood vessels, many of which were abnormal, and increased IGF-1 expression were observed in group 2. In group 3, abnormal blood vessels and IGF-1 expression were less evident. NAC appeared to be an effective vascular-protective agent for ROP by decreasing IGF-1 expression.

Differential effects of IGF-1 deficiency during the life span on structural and biomechanical properties in the tibia of aged mice.

Advanced aging is associated with the loss of structural and biomechanical properties in bones, which increases the risk for bone fracture. Aging is also associated with reductions in circulating levels of the anabolic signaling hormone, insulin-like growth factor (IGF)-1. While the role of IGF-1 in bone development has been well characterized, the impact of the age-related loss of IGF-1 on bone aging remains controversial. Here, we describe the effects of reducing IGF-1 at multiple time points in the mouse life span--early in postnatal development, early adulthood, or late adulthood on tibia bone aging in both male and female igf (f/f) mice. Bone structure was analyzed at 27 months of age using microCT. We find that age-related reductions in cortical bone fraction, cortical thickness, and tissue mineral density were more pronounced when IGF-1 was reduced early in life and not in late adulthood. Three-point bone bending assays revealed that IGF-1 deficiency early in life resulted in reduced maximum force, maximum bending moment, and bone stiffness in aged males and females. The effects of IGF-1 on bone aging are microenvironment specific, as early-life loss of IGF-1 resulted in decreased cortical bone structure and strength along the diaphysis while significantly increasing trabecular bone fraction and trabecular number at the proximal metaphysis. The increases in trabecular bone were limited to males, as early-life loss of IGF-1 did not alter bone fraction or number in females. Together, our data suggest that the age-related loss of IGF-1 influences tibia bone aging in a sex-specific, microenvironment-specific, and time-dependent manner.

Young at Heart.

Theagingprocesshasa significant effecton the structure and function of the cardiovascular system. Also, an age-dependent increase in the prevalence of cardiovascular disease, hypertension, and heart failure is clinically observed. Experimentally, a plethora of cellular adaptations in the cardiovascular system are associated with aging. These changes broadly include increased sympathetic nerve activity (in part due to increased circulating catecholamines), increased cardiac responsiveness to the renin-angiotensin system, increased extracellular remodeling with increased cardiac fibrosis, increased reactive oxygen substrate production, and decreased functioning of autophagy (1). Over time, these cellular changes lead to arrest of normal cell cycle progression, loss of cardiomyocytes, cardiac hypertrophy, and altered diastolic functioning with impaired myocardial perfusion, a process broadly referred to as cardiac senescence. The GH/IGF-1 axis is a principal mediator of growth and metabolism with an established role in aging. In humans, after 60 years of age, there is a significant decline in circulating levels of both GH and IGF-1. Recognition of this phenomenon, known as “somatopause,” led to the proposal that replacement of GH and IGF-1 may mitigate the effects of aging (2). Indeed, this has spurred to the production of several dubious “supplements,” from deer antler preparations to amino acid mixtures, that tout antiaging effects and superficially appear to be related to GH and IGF-1. However, animal studies have demonstrated quite opposite results. Studies in Drosophila, worms, and rodents have established increased longevity with disruption of the GH/IGF-1 axis. For example, mice with diminished GH levels or with a GH receptor gene disruption (GHRKO) have increased longevity (3). Indeed, GHRKO mice are currently the longest lived mouse line with a mouse reaching a lifespan of almost 5 years (http://www. methuselahfoundation.org/). The relationship with IGF-1 and aging is more nuanced. Mice with a complete deletion of IGF-1 receptor (IGF-1R) exhibit a high degree of mortality (4), whereas female mice heterozygous for a mutated IGF-1R allele have an increased lifespan (5). Likewise, decreasing bioavailability of IGF-1 through deletion of the metalloproteinase PAPP-A (responsible for cleaving IGF-1 from IGF-binding protein 4) also increases lifespan (6). The role of IGF-1 in the myocardium is equally layered. Overexpression of skeletal muscle IGF-1 in mice using the -actin promoter/enhancer results in high levels of IGF-1 in muscle and heart without a concomitant increase in circulating IGF-1. These mice develop concentric ventricular hypertrophy before 10 weeks of age with no decline in cardiac function. After 10 weeks, however, the chronic effects of high IGF-1 manifest as ventricular stiffening, loss of ventricular compliance, decreased cardiac function, and cardiac fibrosis (7). Cardiac-specific deletion of IGF-1R (CIGF1RKO) has been reported to result in normal cardiac development but an attenuated response to exercise induced hypertrophy in 13to 15-week-old mice (8). This may be due, in part, to an up-regulation of AMP kinase action and subsequent antagonism of mammalian target of rapamycin/S6 kinase mediated hypertrophy (8). Inducible, cardiac-specific IGF-1R gene disrupted mice demonstrate varying results depending on the age of disruption. IGF-1R disruption in 3-month-old mice does not lead to any functional changes measured by in vivo pressure measurement or magnetic resonance imaging (9). Disruption at 11 months of age, however, is associated with an approximate 25% decrease in ventricular developed

Neuron-derived insulin-like growth factor (IGF)-I is necessary for normal cognition and hedonic activity of mice

The role of IGF-I and indoleamine-2,3-dioxygenase (IDO)1 in animal behavior is an expanding field, with IGF-I and IDO1 having opposing roles. IGF-I is anti-depressive, whereas IDO1 mediates several depression-like behaviors. The cellular sources, or targets, of IGF-I and IDO1 underpinning these roles remain poorly characterized. Mice with lox-P gene inserts targeting Igf1, Ido1 or type-1-IGF receptor (Igf1r) were bred to mice expressing Cre-recombinase in neurons (Neu-Cre) or myeloid-derived cells (My-Cre) to generate knockdown models. We hypothesized that neuronal IGF-I acts on glial IGF1R’s to modulate behavior and cognition, and central IDO1 is required for depression-like behaviors. Cognition was assessed using object and social discrimination tests (ODT, SDT) to evaluate recognition and exploration of novel objects or mice, respectively. Igf1-Neu-Cre mice did not discriminate novel over familiar objects 1 and 24 h post-training, whereas Igf1r-Neu-Cre and Ido1-Neu-Cre mice performed poorly at 24 h. With My-Cre strains, only Igf1r-My-Cre mice underperformed at 1 h. Knockdown of Igf1, Igf1r or Ido1 did not diminish performance in the SDT or anxiolytic activity (zero-maze open-field activity). Igf1-My-Cre mice took longer to establish a preference for sucrose in the two-bottle preference test of anhedonia, and Igf1-Neu-Cre mice had a prolonged recovery period following peripheral LPS administration. These results suggest neuronal and myeloid-derived IGF-I are necessary for hedonic activity, whereas neuronal IGF-I, IGF1R and IDO1 and myeloid IGF1R support optimal cognitive performance in the ODT.

The role of IGF-1 in neurodegenerative diseases

The role of IGF-1 in neurodegenerative diseases

Abstract 5081: The IGF axis regulates hepatic stellate cell recruitment and activation during colorectal carcinoma liver metastasis

Abstract Background: The hepatic stellate cells (HSC) play a major role in orchestrating the liver's fibrogenic (wounding) response and have been identified as an important player in the prometastatic microenvironment in the liver. Here we analyzed the role of the IGF axis in the recruitment and activation of HSC during the early stages of colorectal carcinoma (CRC) liver metastasis. Methods: Murine CRC MC-38 cells were inoculated via the intrasplenic/portal route into female mice with a conditional liver IGF-1 deletion (iLID), induced by a single tamoxifen (Tx) injection 2 days or 3 weeks earlier. Vehicle (sunflower oil) injected iLID mice or Tx - injected wild type mice were used as controls. Experimental liver fibrosis was achieved by repeated carbon tetrachloride (CCl4) administration. The stromal response of the liver was analyzed using immunohistochemistry with emphasis on HSC recruitment and activation. In addition, in vitro assays were utilized to explore the role of IGF-1 in HSC activation. Results: In iLID mice treated with Tx, a 75% reduction in circulating IGF-1 levels could be observed within 24 hr and it persisted for the duration of the experiments. When injected with MC-38 cells, 3 weeks post Tx injection, these mice developed significantly fewer liver metastases than non-treated controls, while no reduction in the number of metastases was seen in WT mice injected with Tx or in oil-injected iLID controls. Interestingly, we observed that Tx treatment 48 hr prior to tumor injection, failed to reduce liver metastasis in iLID mice, although their circulating IGF-1 levels were markedly reduced, suggesting that the loss of direct paracrine IGF-1 effects on the tumor cells was not sufficient to inhibit tumor growth in the liver and that other effects on the hepatic microenvironment were at play. Analysis of HSC recruitment and activation subsequently revealed a significant reduction in HSC activation around micrometastases as compared to controls. This was evident as early as 3 days post tumor inoculation, persisted for the duration of the experimental period (16-18 days) and corresponded with reduced IGF-1 receptor and Akt activation in these cells. In vitro studies confirmed that IGF-1 could directly activate isolated HSC and rescue them from serum-depletion induced apoptosis. Finally, in iLID mice with sustained IGF-1 depletion, a significant reduction in HSC-mediated collagen deposition was observed following continuous treatment with CCl4, confirming the role of IGF-1 in HSC activation in a second tumor-free model. Conclusion: Our results show that a sustained reduction in circulating IGF-1 levels altered HSC recruitment and activation to tumor sites and reduced tumor cell growth in the liver. We identify IGF-1 as a regulator of HSC function and the response of the microenvironment to invading cancer cells, thereby affecting metastatic expansion. Supported by CIHR Grant MOP 81201 (to PB) and MICRTP Fellowship (to MCF). Note: This abstract was not presented at the meeting. Citation Format: Maria C. Fernandez, Roni F. Rayes, Jun Xu, Tatiana Kisseleva, Shoshana Yakar, Pnina Brodt. The IGF axis regulates hepatic stellate cell recruitment and activation during colorectal carcinoma liver metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5081. doi:10.1158/1538-7445.AM2015-5081