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Spatiotemporal Regulation of Insulin-Like Growth Factor-1 and Its Receptor in the Brain: Is There a Role for Growth Hormone?

Year: 2017
Type: article
Abstract: Insulin-like growth factor-1 (IGF-1) is produced locally in the brain (1). Blood-borne IGF-1 may enter the brain by crossing the blood–cerebrospinal fluid (CSF) barrier (2) via megalin/low-density lipoprotein receptor–related protein 2 (3) or the blood–brain barrier via IGF-1R and low-density lipoprotein receptor–related protein–mediated transcytosis across the brain endothelial cell (4). The entry and action of IGF-1 in the brain is an important scientific question because IGF-1 action may be protective to brain cells and vessels during hypoxic-ischemic injury (5, 6) and during aging to prevent cognitive decline (7). IGF-1 and insulin resistance in the hippocampus and cerebral cortex have been described in brain tissue from patients with Alzheimer’s disease (8). Although increased IGF-1 appears protective, favorable effects of knocking down the IGF-1 receptor (IGF-1R) in Alzheimer’s disease models have been reported (9). This dichotomy presents an interesting conundrum: IGF-1 is beneficial, yet reduction of its receptor also appears advantageous. In an early paper describing IGF-1 entry into the brain, Carro et al. (2) noted that injection of IGF-1 into the CSF precluded serum-derived IGF-1 from entering the brain. The aggregate of these findings points to a unique homeostatic regulation of brain IGF-1 that responds to brain and blood-borne factors. In this issue of Endocrinology, Trueba-Saiz et al. (10) begin to unravel this question by examining the effect of circulating IGF-1 on the IGF-1R and brain-derived IGF-1 and by examining the effect of environmental enrichment to directly modulate IGF-1 and its receptor in the brain. Using a series of in vitro and in vivo experiments, Trueba-Saiz et al. (10) found that increases in serum IGF-1, achieved from bolus injection or promotion of its transport into the brain by environmental enrichment, increased brain IGF-1R phosphorylation, which in turn decreased brain IGF-1. This caused a transient increase in IGF-1 and IGF-1R messenger RNA (mRNA) in the brain before returning to baseline values. Trueba-Saiz et al. (10) describe short-term temporal changes in IGF-1 mRNA and protein alongside IGF-1R mRNA, protein, and phosphorylation and show evidence that blood-borne IGF-1 regulates brain IGF-1R in an acute and temporal manner in the 24 hours after serum IGF-1 increases. Additionally, 1 month of enriched housing induced a small yet significant increase in brain IGF-1 protein. It remains unresolved whether this increase in brain IGF-1 after enriched housing is due to a decrease in circulating IGF-1 after 1 month and subsequent reduction in brain IGF-1 degradation or whether the brain IGF-1 levels increase in response to other factors. This model begins to disentangle the complex spatiotemporal relationship between blood- and brain-derived IGF-1, allowing for future studies to investigate this regulation in the short- and long-term. Going forward, we are curious how this proposed model of brain IGF-1 and IGF-1R will evolve and whether other blood- or brain-derived factors, such as growth hormone, will play a role. Circulating growth hormone (GH) is secreted from the pituitary and exerts its actions throughout the body, notably to increase IGF-1 production at the liver and peripheral tissues, which can then feedback to inhibit GH secretion. Secretion of GH is positively regulated by (1) GH-releasing hormone (GHRH) and (2) ghrelin, which is secreted from the stomach and can stimulate GHRH at the hypothalamus or GH directly at the anterior pituitary. Hypothalamic somatostatin inhibits GH secretion from the pituitary and is also sensitive to feedback regulation. A simplified schematic of the feedback regulation of the GH–IGF-1 axis is depicted in Fig. 1. Whether these feedback mechanisms are present within the hippocampus remains to be elucidated, as indicated by the dashed lines (Fig. 1). Both GH and IGF-1 are produced locally in the brain, and there is a positive correlation between GH receptor (GH-R) and IGF-1 mRNA (11). In the brain, GH and IGF-1 expression decreases with age (11, 12). Similarly, aged humans and mice have reduced GH secretion and subsequent decreases in circulating IGF-1. It is unclear whether brain GH regulates brain IGF-1 production. Additionally, it is unknown whether peripheral (pituitary-secreted) GH and IGF-1 (from the liver) feedback to inhibit both GH and IGF-1 production in the brain. Interestingly, the Ames dwarf mouse harbors a single point mutation of a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1), which leads to a failure of the Pit-1 lineage of pituitary cells, including lactotropes, somatotropes, and thyrotropes (13). The Ames mouse is reported to have 0.001% to 1% complement of normal somatotropes in the pituitary such that it has defective GH production in the pituitary and decreased IGF-1 production in the liver; however, this mouse has increased hippocampal GH and IGF-1, as well as downstream Akt and CREB signaling, compared with normal control mice (14). Behavioral studies demonstrate that although normal animals exhibit the expected decline of memory with age, old Ames dwarf mice do not show any deficits in memory retention when compared with young normal or young dwarf mice (15). Trueba-Saiz et al. (10) comment on the liver-specific Igf1-null (LID) mouse and attribute this animal’s decreased IGF-1R activation to decreased blood–brain barrier transport of IGF-1 due to low serum IGF-1 concentrations [75% lower than normal (16)]. Earlier studies described similar brain IGF-1 concentrations in sedentary female LID mice compared with control mice (17); however, in our review of the literature, we were unable to find reports of hippocampal GH production in LID mice. There are a variety of mouse models probing components of the GH–IGF-1 axis [reviewed by Junnila et al. (16)], and the bulk of this research focuses on the effects at the liver or in the periphery. Given the newfound knowledge on balancing blood- and brain-derived IGF-1, it is curious whether GH, of brain or blood origin, fits into the regulation of brain IGF-1 concentrations. Perhaps the involvement of brain-derived GH stimulates the long-term increases in brain IGF-1 observed after 1 month of enrichment housing? Regardless, more work investigating the production, regulation, and interplay of GH, GH-R, IGF-1, and IGF-1R in the brain is warranted. Schematic of growth hormone and IGF-1 axis. At the hypothalamus, GHRH and somatostatin (SS) regulate GH release from the anterior pituitary. GH action at the liver stimulates IGF-1 secretion, which can act on peripheral tissues. Ghrelin is secreted from the stomach and promotes GH secretion through direct action at the pituitary or indirectly through its actions on hypothalamic regulatory hormones. Circulating IGF-1 from the liver enters the hippocampus and has actions described by Trueba-Saiz et al. (10). It is unknown how circulating GH, ghrelin, or IGF-1 may affect hippocampal GH or GH-R. It is also unknown how circulating GH and ghrelin may affect the pathway described by Trueba-Saiz et al. (10). Canonical signaling cascades are shown with solid lines. An arrowhead indicates stimulation, and a bar-headed lines indicates inhibition. Unknown actions of hippocampal GH and GH-R are surrounded by dashed lines. Additionally, unknown signaling cascades are indicated by dashed lines. It is also important to note that other factors may be involved in brain GH and IGF-1 production and action. As indicated in Fig. 1, GH secretion from the pituitary is regulated, and this may be at play in the hippocampus as well. Hypothalamic GH expression has also been reported (18, 19), although its physiological role and regulation remain to be elucidated. GHRH and its receptor are predominantly expressed in the hypothalamus, with trace GHRH receptor mRNA in the cerebral cortex (20, 21). In contrast, ghrelin acts through the growth hormone secretagogue receptor, which is more widely expressed in the brain and is present in the hippocampus (22, 23). Although little is known regarding GHRH and ghrelin regulation of hippocampal GH, other factors have been implicated. Hippocampal GH and IGF-1 expression is sexually dimorphic (11). Early studies of hippocampal GH found that transient increases in estrogen during estrus and diestrus correlated with increased GH protein and GH-R and IGF-1 mRNA compared with proestrus (11). Ovariectomized female subjects had GH mRNA expression similar to male subjects, and exogenous estrogen replacement elicited a marked increase in hippocampal GH and a decrease in GH-R and IGF-1 mRNA (11). Later work expanded on this dimorphic expression by thoroughly examining the wide distribution of GH throughout the brain and describing the estrogen-induced increases in GH in the medial preoptic area and arcuate nucleus via estrogen receptor α (24). Additionally, increased preoptic area GH expression and increased body weight were observed in female subjects with 2 X chromosomes as compared with female subjects with 1 X chromosome (18). It is interesting that the changes in response to estrogen in the brain on GH and IGF-1 parallel the changes in the liver due to exogenous estrogen administration, which leads to the reduction of serum IGF-1 from the liver and to alteration of the sex-specific profile of GH secretion (25, 26). This is likely due to estrogen’s action to attenuate GH-R expression and signal transduction (27). Gonadal steroids likely play a part in the regulation of brain GH and IGF-1 and are important to consider while investigating this potential feedback loop. How IGF-1 transports itself through the brain to access various cell types is unknown. Blood-borne IGF-1 bound to insulin-like growth factor–binding protein (IGFBP)-3 is able to cross the brain endothelial cell after IGFBP-3 degradation by matrix metalloproteinase-9 (4). Compounds that are able to cross the highly restrictive brain endothelial cell subsequently enter the Virchow-Robin space (VRS), a paravascular space where CSF flows. The VRS represents a mixture of CSF secreted from the choroid plexus and blood-borne substances that cross the endothelial cell. Recent imaging studies investigating the vectoral flow of CSF through the VRS (28, 29) highlight its importance when considering the transport of proteins to and throughout the brain interstitial fluid. After IGF-1’s entry to the VRS, it is unclear whether it is transported as free IGF-1 or bound to IGF-1 binding proteins present in the brain. IGFBP-2, -5, and -6 have been reported in the CSF (30, 31), and binding proteins (including IGFBP-3) may be increased in response to hypoxic-ischemic injury (5, 32). IGF-1 and IGFBPs may act in concert to elicit cellular responses (33). Do circulating IGFBPs in CSF bind to IGF-1 that has recently crossed the brain endothelial cell? In response to increases in serum-derived IGF-1, is there differential expression of IGFBPs that contribute to the short-term decreases in brain IGF-1? How IGF-1 from brain or blood origin circulates through the brain interstitial fluid or CSF to reach target cells remains unknown and is an opportunity for future study. Finally, the mechanisms regulating the short-term degradation and longer-term increases of brain IGF-1 in response to increases in circulating IGF-1 or its transport into the brain remain to be elucidated. Thus, we are unable to infer whether enrichment-induced increases in brain IGF-1 are due to increased IGF-1 transport into brain, decreased brain IGF-1 degradation, or increased brain IGF-1 production. Moreover, from whole-brain studies, it is unknown which cell population is contributing to these concentration changes. Given the variable responses to IGF-1 treatment observed between cell types in vitro and the recent understanding that IGF-1 may affect astrocyte glucose handling (34, 35), understanding IGF-1 metabolism in specific cell populations is necessary to fully understand the importance of IGF-1R activation and subsequent alterations in IGF-1R and IGF-1 production. The recent findings in this issue of Endocrinology regarding IGF-1 entry into the brain and its short-term effects on brain IGF-1 and IGF-1R are intriguing. Trueba-Saiz et al. (10) nicely expand upon previous knowledge of brain IGF-1 action and metabolism. However, we believe these findings are merely the tip of the iceberg and look forward to future work that will continue to illuminate the regulation and effect of IGF-1 in the brain. cerebrospinal fluid growth hormone growth hormone receptor growth hormone–releasing hormone insulin-like growth factor–binding protein insulin-like growth factor-1 insulin-like growth factor-1 receptor liver-specific Igf1-null messenger RNA Virchow-Robin space This work was supported in part by National Institutes of Health Grant F31 DK104521 to S.M.G. Disclosure Summary: M.O.T. is the founder of Ammonett Pharma. S.M.G. has nothing to disclose.
DOI: 10.1210/en.2016-1884
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W2606135710
FWCI: 0.644
Cites: 35
Cited by: 4
Related to: 10