Uptake Of Insulin-like Growth Factor I Research Articles

Loss of the interaction between estradiol and insulin-like growth factor I in brain endothelial cells associates to changes in mood homeostasis during peri-menopause in mice.

We recently reported that exercise increases resilience to stress in young female mice. Underlying mechanisms include an interaction of the ovarian hormone estradiol (E2) with insulin-like growth factor I (IGF-I), and an increase in the hippocampal levels of the latter. Since changes in mood regulation during aging may contribute to increasing incidence of affective disorders at older age, we determined whether the protective actions of exercise are maintained at later ages. We found that during peri-menopause, exercise no longer improves resilience to stress and even becomes anxiogenic. Furthermore, the interaction seen in young females between the E2 α receptor (ERα) and the IGF-I receptor (IGF-IR) is lost at middle-age. In addition, E2 no longer induces IGF-I uptake by brain endothelial cells, and consequently, hippocampal IGF-I levels do not increase. Treatment of middle-aged females with an ERα agonist did not recover the positive actions of exercise. Collectively, these data indicate that the loss of action of exercise during peri-menopause may be related to a loss of the interaction of IGF-IR with ERα in brain endothelial cells that cannot be ameliorated by estrogen therapy. Changes in regulation of mood by physical activity may contribute to increased appearance of affective disorders along age.

A Concerted Action Of Estradiol And Insulin Like Growth Factor I Underlies Sex Differences In Mood Regulation By Exercise

Mood homeostasis present sexually dimorphic traits which may explain sex differences in the incidence of mood disorders. We explored whether diverse behavioral-setting components of mood may be differentially regulated in males and females by exercise, a known modulator of mood. We found that exercise decreases anxiety only in males. Conversely, exercise enhanced resilience to stress and physical arousal, two other important components of mood, only in females. Because exercise increases brain input of circulating insulin-like growth factor I (IGF-I), a potent modulator of mood, we explored whether sex-specific actions of exercise on mood homeostasis relate to changes in brain IGF-I input. We found that exercise increased hippocampal IGF-I levels only in cycling females. Underlying mechanism involved activation of estrogen (E2) receptors in brain vessels that led to increased uptake of serum IGF-I as E2 was found to stimulate IGF-I uptake in brain endothelial cells. Indeed, modulatory effects of exercise on mood were absent in female mice with low serum IGF-I levels or after either ovariectomy or administration of an E2 receptor antagonist. These results suggest that sex-specific brain IGF-I responses to physiological stimuli such as exercise contribute to dimorphic mood homeostasis that may explain sex differences in affective disorders.

Spatial distribution of insulin-like growth factor binding protein-2 following hypoxic-ischemic injury

BackgroundInsulin-like growth factor binding protein-2 (IGFBP-2) regulates the bioavailability, transportation, and localization of insulin-like growth factor-I (IGF-I), an effective neuroprotectant in animal stroke models especially when administered intranasally. Therefore, determining IGFBP-2′s endogenous distribution in the normal and ischemic brain is essential in maximizing the neuroprotective potential of the intranasal IGF-I treatment approach. However, current data on IGFBP-2 is limited to mRNA and in situ hybridization studies. The purpose of this study was to determine if there are any changes in IGFBP-2 protein levels and distribution in ischemic brain and also to determine if IGFBPs play a role in the transportation of intranasally administered IGF-I into the brain.ResultsUsing an in vitro approach, we show that ischemia causes changes in the distribution of IGFBP-2 in primary cortical neurons and astrocytes. In addition, we show using the transient middle cerebral artery occlusion (MCAO) model in mice that there is a significant increase in IGFBP-2 levels in the stroke penumbra and core after 72 h. This correlated with an overall increase in IGF-I after stroke, with the highest levels of IGF-I in the stroke core after 72 h. Brain sections from stroke mice indicate that neurons and astrocytes located in the penumbra both have increased expression of IGFBP-2, however, IGFBP-2 was not detected in microglia. We used binding competition studies to show that intranasally administered exogenous IGF-I uptake into the brain is not receptor mediated and is likely facilitated by IGFBPs.ConclusionsThe change in protein levels indicates that IGFBP-2 plays an IGF-I-dependent and -independent role in the brain’s acute (neuroprotection) and chronic (tissue remodeling) response to hypoxic-ischemic injury. Competition studies indicate that IGFBPs may have a role in rapid transportation of exogenous IGF-I from the nasal tissue to the site of injury.

Circulating Insulin-Like Growth Factor I Mediates the Protective Effects of Physical Exercise against Brain Insults of Different Etiology and Anatomy

Physical exercise ameliorates age-related neuronal loss and is currently recommended as a therapeutical aid in several neurodegenerative diseases. However, evidence is still lacking to firmly establish whether exercise constitutes a practical neuroprotective strategy. We now show that exercise provides a remarkable protection against brain insults of different etiology and anatomy. Laboratory rodents were submitted to treadmill running (1 km/d) either before or after neurotoxin insult of the hippocampus (domoic acid) or the brainstem (3-acetylpyridine) or along progression of inherited neurodegeneration affecting the cerebellum (Purkinje cell degeneration). In all cases, animals show recovery of behavioral performance compared with sedentary ones, i.e., intact spatial memory in hippocampal-injured mice, and normal or near to normal motor coordination in brainstem- and cerebellum-damaged animals. Furthermore, exercise blocked neuronal impairment or loss in all types of injuries. Because circulating insulin-like growth factor I (IGF-I), a potent neurotrophic hormone, mediates many of the effects of exercise on the brain, we determined whether neuroprotection by exercise is mediated by IGF-I. Indeed, subcutaneous administration of a blocking anti-IGF-I antibody to exercising animals to inhibit exercise-induced brain uptake of IGF-I abrogates the protective effects of exercise in all types of lesions; antibody-treated animals showed sedentary-like brain damage. These results indicate that exercise prevents and protects from brain damage through increased uptake of circulating IGF-I by the brain. The practice of physical exercise is thus strongly recommended as a preventive measure against neuronal demise. These findings also support the use of IGF-I as a therapeutical aid in brain diseases coursing with either acute or progressive neuronal death.

Circulating Insulin-Like Growth Factor I Mediates Exercise-Induced Increases in the Number of New Neurons in the Adult Hippocampus

Although the physiological significance of continued formation of new neurons in the adult mammalian brain is still uncertain, therapeutic strategies aimed to potentiate this process show great promise. Several external factors, including physical exercise, increase the number of new neurons in the adult hippocampus, but underlying mechanisms are not yet known. We recently found that exercise stimulates uptake of the neurotrophic factor insulin-like growth factor I (IGF-I) from the bloodstream into specific brain areas, including the hippocampus. In addition, IGF-I participates in the effects of exercise on hippocampal c-fos expression and mimics several other effects of exercise on brain function. Because subcutaneous administration of IGF-I to sedentary adult rats markedly increases the number of new neurons in the hippocampus, we hypothesized that exercise-induced brain uptake of blood-borne IGF-I could mediate the stimulatory effects of exercise on the adult hippocampus. Thus, we blocked the entrance of circulating IGF-I into the brain by subcutaneous infusion of a blocking IGF-I antiserum to rats undergoing exercise training. The resulting inhibition of brain uptake of IGF-I was paralleled by complete inhibition of exercise-induced increases in the number of new neurons in the hippocampus. Exercising rats receiving an infusion of nonblocking serum showed normal increases in the number of new hippocampal neurons after exercise. Thus, increased uptake of blood-borne IGF-I is necessary for the stimulatory effects of exercise on the number of new granule cells in the adult hippocampus. Taken together with previous results, we conclude that circulating IGF-I is an important determinant of exercise-induced changes in the adult brain.

Circulating Insulin-Like Growth Factor I Mediates Effects of Exercise on the Brain

Physical exercise increases brain activity through mechanisms not yet known. We now report that in rats, running induces uptake of blood insulin-like growth factor I (IGF-I) by specific groups of neurons throughout the brain. Neurons accumulating IGF-I show increased spontaneous firing and a protracted increase in sensitivity to afferent stimulation. Furthermore, systemic injection of IGF-I mimicked the effects of exercise in the brain. Thus, brain uptake of IGF-I after either intracarotid injection or after exercise elicited the same pattern of neuronal accumulation of IGF-I, an identical widespread increase in neuronal c-Fos, and a similar stimulation of hippocampal brain-derived neurotrophic factor. When uptake of IGF-I by brain cells was blocked, the exercise-induced increase on c-Fos expression was also blocked. We conclude that serum IGF-I mediates activational effects of exercise in the brain. Thus, stimulation of the uptake of blood-borne IGF-I by nerve cells may lead to novel neuroprotective strategies.

Hepatic production and intestinal uptake of IGF-I: response to infection.

The role of the liver and gut in contributing to the infection-induced fall in circulating insulin-like growth factor I (IGF-I) was examined in chronically catheterized conscious dogs. Two weeks before study, catheters and Doppler flow probes were implanted to assess hepatic and gut balance of IGF-I. To control nutrient intake, dogs were placed on total parenteral nutrition (TPN) as their sole caloric source. After dogs received TPN for 5 days, net hepatic and intestine IGF-I balances were assessed. A hypermetabolic infected state was then induced by the intraperitoneal implantation of a fibrin clot containing Escherichia coli. TPN was continued, and organ IGF-I balance was assessed 24 and 48 h after induction of infection. Arterial IGF-I levels were significantly decreased following infection (111 +/- 18, 62 +/- 10, and 63 +/- 8 ng/ml before and 24 and 48 h after, respectively). Net hepatic IGF-I output decreased markedly (221 +/- 73, to 73 +/- 41 and 41 +/- 17 ng. kg-1. min-1 before and 24 and 48 h after, respectively). The infection-induced decrease in hepatic IGF-I output could not be explained by concomitant alterations in plasma cortisol or insulin levels. The gut demonstrated a net uptake of IGF-I before infection (178 +/- 29 ng. kg-1. min-1). However, after infection, intestinal IGF-I uptake was completely suppressed (-10 +/- 15 and -8 +/- 36 ng. kg-1. min-1). In summary, infection decreases net hepatic IGF-I release 65-80% and completely suppresses net IGF-I uptake by the intestine. As a consequence of these reciprocal changes in IGF-I balance across the liver and intestine, splanchnic production of IGF-I was unchanged by infection. These data suggest that changes in the clearance and/or production of IGF-I by extrasplanchnic tissues contribute to the infection-induced decrease in circulating IGF-I levels.

Role of Astroglia and Insulin-Like Growth Factor-I in Gonadal Hormone-Dependent Synaptic Plasticity

Gonadal hormones exert a critical influence over the architecture of specific brain areas affecting the formation of neuronal contacts. Cellular mechanisms mediating gonadal hormone actions on synapses have been studied extensively in the rat arcuate nucleus, a hypothalamic center involved in the feed-back regulation of gonadotropins. Gonadal steroids exert organizational and activational effects on arcuate nucleus synaptic connectivity. Perinatal testosterone induces a sexual dimorphic pattern of synaptic contacts. Furthermore, during the preovulatory and ovulatory phases of the estrous cycle there is a transient disconnection of inhibitory synaptic inputs to the somas of arcuate neurons. This synaptic remodeling is induced by estradiol, blocked by progesterone, and begins with the onset of puberty in females. Astroglia appear to play a significant role in the organizational and the activational hormone effects on neuronal connectivity by regulating the amount of neuronal membrane available for the formation of synaptic contacts and by releasing soluble factors, such as insulin-like growth factor I (IGF-I), which promote the differentiation of neural processes. Recent evidence indicates that gonadal steroids and IGF-I may interact in their trophic effects on the neuroendocrine hypothalamus. Estradiol and IGF-I promote the survival and morphological differentiation of rat hypothalamic neurons in primary cultures. The effect of estradiol depends on IGF-I, while the effects of both estradiol and IGF-I depend on estrogen receptors. Furthermore, estrogen activation of astroglia in hypothalamic tissue fragments depends on IGF-I receptors. These findings indicate that IGF-I may mediate some of the developmental and activational effects of gonadal steroids on the brain and suggest that IGF-I may activate the estrogen receptor to induce its neurotrophic effects on hypothalamic cells. In addition, IGF-I levels in the neuroendocrine hypothalamus are regulated by gonadal steroids. IGF-I levels in tanycytes, a specific astroglia cell type present in the arcuate nucleus and median eminence, increase at puberty, are affected by neonatal androgen levels, show sex differences, and fluctuate in accordance to the natural variations in plasma levels of ovarian steroids that are associated with the estrous cycle. These changes appear to be mediated by hormonal regulation of IGF-I uptake from blood or cerebrospinal fluid by tanycytes. These results suggest that tanycytes may be involved in the regulation of neuroendocrine events in adult rats by regulating the availability of IGF-I to hypothalamic neurons. In summary, IGF-I and different forms of neuron–astroglia communication are involved in the effects of estradiol on synaptic plasticity in the hypothalamic arcuate nucleus.

Regulation of the insulin-like growth factor system by insulin in burn patients

The aim of the present investigation was to determine whether there is a net uptake of insulin-like growth factor I (IGF-I) or IGF-binding proteins (IGFBPs) by the leg after burn injury and to elucidate the regulatory role of insulin exerted on this system under in vivo conditions in burn patients. Studies were performed on nine patients after burn injury (approximately 60% body surface area). Each patient was studied twice during a continuous infusion of a carbohydrate-rich enteral diet. Blood was collected simultaneously from the femoral artery and vein for the measurement of various elements of the IGF system after 7 days of enteral diet alone (basal period) and after 7 days of the enteral diet plus the infusion of insulin (insulin period). Data from these patients were compared to values in age-matched fed healthy volunteers. During the basal period, burn patients demonstrated a significant reduction in the venous concentration of IGF-I and an increase in both IGFBP-1 and -2 compared to control values. Insulin produced a significant 15% increase in the IGF-I concentration in burn patients, but decreased the circulating levels of IGFBP-1 by 50%. The IGF-I and IGFBP-1 concentrations at the end of the insulin period were still significantly different from those in control subjects. Burn patients also exhibited a marked reduction in intact IGFBP-3 and the acid-labile subunit under basal conditions, and these alterations were not reversed by insulin. Under basal conditions, all burn patients had a positive arterio-venous (A-V) difference for IGF-I across the leg. The A-V difference was increased 50% in response to insulin. The net uptake of IGF-I by the leg was 2.4 micrograms/min under basal conditions, and as leg blood flow also tended to increase in response to insulin, IGF-I uptake was elevated more than 3-fold during the insulin period. No A-V difference across the leg was detected for IGFBP-1, -2, or -3 in burn patients. In conclusion, burn injury in humans produces dramatic and sustained alterations in various components of the IGF system that persist despite adequate nutritional support. Our data indicate the presence of a net uptake of IGF-I by the leg in burn patients that may serve to counteract the catabolic state.

Regulation of the insulin-like growth factor system by insulin in burn patients.

The aim of the present investigation was to determine whether there is a net uptake of insulin-like growth factor I (IGF-I) or IGF-binding proteins (IGFBPs) by the leg after burn injury and to elucidate the regulatory role of insulin exerted on this system under in vivo conditions in burn patients. Studies were performed on nine patients after burn injury (approximately 60% body surface area). Each patient was studied twice during a continuous infusion of a carbohydrate-rich enteral diet. Blood was collected simultaneously from the femoral artery and vein for the measurement of various elements of the IGF system after 7 days of enteral diet alone (basal period) and after 7 days of the enteral diet plus the infusion of insulin (insulin period). Data from these patients were compared to values in age-matched fed healthy volunteers. During the basal period, burn patients demonstrated a significant reduction in the venous concentration of IGF-I and an increase in both IGFBP-1 and -2 compared to control values. Insulin produced a significant 15% increase in the IGF-I concentration in burn patients, but decreased the circulating levels of IGFBP-1 by 50%. The IGF-I and IGFBP-1 concentrations at the end of the insulin period were still significantly different from those in control subjects. Burn patients also exhibited a marked reduction in intact IGFBP-3 and the acid-labile subunit under basal conditions, and these alterations were not reversed by insulin. Under basal conditions, all burn patients had a positive arterio-venous (A-V) difference for IGF-I across the leg. The A-V difference was increased 50% in response to insulin. The net uptake of IGF-I by the leg was 2.4 micrograms/min under basal conditions, and as leg blood flow also tended to increase in response to insulin, IGF-I uptake was elevated more than 3-fold during the insulin period. No A-V difference across the leg was detected for IGFBP-1, -2, or -3 in burn patients. In conclusion, burn injury in humans produces dramatic and sustained alterations in various components of the IGF system that persist despite adequate nutritional support. Our data indicate the presence of a net uptake of IGF-I by the leg in burn patients that may serve to counteract the catabolic state.

Interaction of the signalling pathways of insulin-like growth factor-I and sex steroids in the neuroendocrine hypothalamus.

Among the numerous endocrine signals that affect the central nervous system, sex steroids play an important role. It has been recently postulated that part of the effects of these hormones on the brain may be mediated by trophic factors, such as insulin-like growth factor I (IGF-I). Both estradiol and IGF-I increase the survival and differentiation of developing fetal rat hypothalamic neurons in culture. The effect of estradiol is blocked by the pure estrogen receptor antagonist ICI 182,780, by an antisense oligonucleotide to the estrogen receptor, and by an antisense oligonucleotide to IGF-I. In turn, the effect of IGF-I is blocked by ICI 182,780 and by the antisense oligonucleotide to the estrogen receptor. These findings indicate that estrogen-induced activation of the estrogen receptor in developing hypothalamic neurons requires the presence of IGF-I and that both estradiol and IGF-I use the estrogen receptor to mediate their trophic effects on hypothalamic cells. In vivo, sex steroids affect IGF-I levels in the endocrine hypothalamus. IGF-I levels in tanycytes, a specific subtype of glial cells present in the arcuate nucleus and median eminence, are sexually dimorphic in the rat, increase with the onset of puberty, and are regulated by perinatal and adult levels of sex steroids. These changes may be due to hormonal modifications of IGF-I uptake by tanycytes from blood or cerebrospinal fluid. Therefore, this type of glial cell appears to play a central role in the interaction of sex steroids and IGF-I in the hypothalamus.

Insulin-like Growth Factor-I and Its Complexes in Normal Human Articular Cartilage: Studies of Partition and Diffusion

Insulin-like growth factor-I (IGF-I) plays a major role in cartilage homeostasis. Our objective was to study the penetration of IGF-I, both alone and bound to serum proteins, into the different zones of normal human cartilage using radioactively labeled IGF-I. The uptake of free IGF-I was higher than that predicted on the basis of excluded volume calculations and showed concentration dependence: we attributed this to reversible binding of the hormone to the tissue. Since the extent of binding was much higher than that calculated for binding to cell receptors, we concluded that IGF-I binds to matrix components. The kinetics of desorption of IGF-I from cartilage confirmed our conclusions regarding binding. The degree of uptake of IGF-I protein complexes prepared by labeling human serum with [125I]IGF-I showed that such complexes are largely excluded from normal cartilage and that the amounts present in the tissue are too low to affect proteoglycan metabolism.