REVIEW
Serum insulin-like growth factor I in brain function
Eva Carro and Ignacio Torres-Aleman
Cajal Institute, CSIC, Madrid, Spain(Received for publication on December 21, 2005)(Revised for publication on May 8, 2006)(Accepted for publication on May 8, 2006)

Abstract. Insulin-like growth factor I (IGF-I) is present at high concentrations in the circulation.
Tissue-speciﬁc genetic ablation has shown that the majority of serum IGF-I is secreted by liver cells,
although all major organs synthesize it. IGF-I is an important signal during development, including
brain growth. Although the biological role of IGF-I in organs such as muscle or ovary is reasonably
well established, its biological signiﬁcance in the adult brain is far from clear. In this regard, while
local IGF-I synthesis decreases during brain development, protein levels remain relatively constantthroughout life until old age, where a decline is found, not only in the brain but also in the bloodstream. This mismatch between declining local synthesis early after birth and steady protein levels may
be explained by the ability of serum IGF-I to access the brain across the blood-brain-barrier. This
peripheral IGF-I input to the brain is a physiologically meaningful process of potential impact in brain
diseases. Numerous brain mechanisms are regulated by serum IGF-I. Many of these, such as cell energy modulation or growth and survival are common to other IGF-I target tissues but there are also a
number of brain-speciﬁc mechanisms regulated by IGF-I which likely underlie the ability of serum
IGF-I to modulate the major function of the brain: cognition. We propose that serum IGF-I forms partof the mechanisms involved in the ‘‘cognitive reserve’’ concept of brain responses to homeostasis
breakdown. Based on IGF-I pleiotropy not only in brain but elsewhere, we consider that loss of IGF-I
function is an important step towards disease. (Keio J Med 55 (2): 59–63, June 2006)
Key words: insulin-like growth factors, brain, blood-brain-barrier, neurodegenerative illness

sulin, and due to its importance in endocrine loops, thebiological role of IGF-I is probably the best studied.
IGF-I is a multifaceted growth factor acting as aclassical hormone in the somatotropic axis under thecontrol of pituitary growth hormone (GH) and as a local humoral factor in all tissues. Genetic manipulationin mice has shown that absence of IGF-I is lethal perinatally, although a reduced number of IGF-I null animals, albeit infertile, survive to adulthood.5 While thereason for the latter is not clear, the existence of other
IGFs in mammals may explain partial rescue. A seminal
work from D LeRoith’s laboratory6 showed that circulating IGF-I is mostly produced by the liver, and more
importantly, that body growth does not depend on it
since serum IGF-I deﬁcient animals (LID mice) shownormal body size. However, LID mice show not only
speciﬁc metabolic defects as expected based on previous observations, but also a wide range of neurologicalcomplications,7 pointing to new aspects of blood-borne

Introduction
The insulin-like growth factors (IGFs) appeared
early in phylogeny (around 600 million years ago1) andexpanded through gene duplication1 to include over 30
different molecules in invertebrate species (C. elegans)to around 10 in vertebrates (man). In simple organisms IGFs are circumscribed to neural tissues, where
they control feeding behavior, energy balance, and cell
growth and are also probably involved in longevity determination.2 In mammals, although a lower number of
IGFs have so far been characterized, their biologicalrole has expanded. Firstly, mammals produce IGFs not
only in the brain, but in all tissues, and while neuralcontrol of energy balance and feeding behavior is still
performed through brain insulin pathways,3 the IGFs
participate not only in regulation of body size, but inmany other physiological processes, including life-spancontrol,4 that are slowly been unveiled. Apart from in-

Reprint requests to: Dr. Ignacio Torres-Aleman, Cajal Institute, Avda. Dr. Arce, 37. 28002. Madrid, Spain, e-mail: torres@cajal.csic.es
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Carro E and Torres-Aleman I: IGF-I and the brain

IGF-I on brain function. This unexpected phenotypeof LID mice underscores the biologically relevance oftransport of blood-borne IGF-I into the brain throughthe blood-brain-barrier (BBB).
Although during years several laboratories reported
passage of serum hormones across the BBB,8,9 including IGF-I,9 these ﬁndings were broadly disregarded dueto the dominating notion that the BBB establishes aphysiological sealing of the brain. Fortunately, this oldfashioned concept is slowly being reverted and the ideaof protein trafﬁc at the blood-brain junction is now
incorporated into brain physiology networks.10 In thecase of serum IGF-I, we may consider that the brain isjust one more target organ. The following sections will
illustrate this notion further.
The Choroid Plexus Epithelium: Port of Entry of
Blood-Borne IGF-I
The BBB comprises the tight junction-sealed endothelium of brain vessels and the similarly sealed epithelium of choroid plexus, a specialized ventricularorgan highly irrigated with normal fenestrated vessels(Fig. 1). Both brain barrier constituents are enrichedin IGF-I receptors.11 Detailed studies have shown thatthe choroid plexus is a major route of entry of systemic IGF-I into the brain: accumulation of intracarotid
injected digoxigenin-labelled IGF-I is readily observedin this epithelium and cerebrospinal ﬂuid (CSF) whilebrain vessels showed no staining.12 Furthermore, whenthe IGF-I receptor in the choroid plexus is inhibited byviral delivery of a dominant negative form of thereceptor, blood to CSF translocation of IGF-I is fully

blocked13 and blood-borne IGF-I signaling on brain
parenchyma is drastically reduced (Fig. 2). These observations leave open the role of the IGF-I receptor inbrain vessels and surrounding glial end-feet.14 While
serum IGF-I is an important growth signal for brain
vessels,15 the presence of IGF-I receptors in glial endfeet located outside the sealed endothelium suggeststhat blood-borne IGF-I may reach its glial receptors.
Alternatively, glial receptors may be activated by IGF-I
synthesized by the endothelium, which shows a high
IGF-I mRNA content.16
Once serum IGF-I translocates into the CSF throughthe choroid plexus, the mechanism that allows accumulation of IGF-I in target neurons throughout the brain
at very speciﬁc locations12 remains undetermined. At
any rate, IGF-I present in the CSF accumulates in speciﬁc periventricular cell types17 and intraventricularadministration of IGF-I and many other growth factors,
has proved neuroprotective,18 which clearly indicatesthat CSF-derived growth factors are able to reachtarget neurons throughout the brain. Both the brain
and the CSF have high levels of IGF-binding proteins(IGFBPs), in particular IGFBP-2.19 These carrier proteins are known to participate in translocation of circulating IGFs to target organs20 but in the case of CSF-tobrain IGF-I transport, this remains to be shown. At any
rate, other serum-derived proteins, including insulin,that lacks a binding protein system,20 are translocatedto the CSF and eventually accumulate in brain parenchyma through poorly described pathways.21
Serum-derived IGF-I is present in all brain areas.12
Since the adult brain synthesizes very low levels of IGFI and only in very speciﬁc locations,22 most brain IGF-I

Fig. 1 Schematic representation of blood-brain barriers (BBB) at the brain endothelium (the blood-brain barrier) and at the choroid plexus
epithelium (the blood-CSF barrier). In both specialized tight junction-sealed cell linings there is abundant expression of IGF-I receptors, suggesting that the BBB is a target of serum IGF-I.

Keio J Med 2006; 55 (2): 59–63

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Fig. 2 The choroid plexus is a major site of entrance of serum IGF-I into the brain. Adult rats were infected in the choroid plexus with adominant-negative IGF-I receptor (KR)-bearing viral vector (a control group received the empty viral vector: HIV group) and after 2 months
received a systemic injection (carotid artery) of 10 mg IGF-I. Note that while HIV-infected rats show increased levels of active Akt (phosphoAkt: pAkt, a kinase downstream of the IGF-I receptor) in hippocampus or choroid plexus as compared to saline-injected rats (controls),
animals with IGF-I receptor blockade (KR) not only showed impaired responses in choroid plexus, as expected, but also in the hippocampus.
Thus, intact IGF-I receptor function at the choroid plexus is needed for systemic IGF-I to modulate Akt function in hippocampus. Representative blots and densitometry histograms are shown. Control rats receiving IGF-I responded identically to HIV rats receiving IGF-I. *P < 0.05
by Student’s t-test.

Fig. 3 Impaired IGF-I signaling at the BBB by aging, inappropriate diet, sedentary life, stress, inﬂammatory mediators associated to illnesses,
and inheritance may underlie the inﬂuence of all these factors in development of Alzheimer’s disease. Diminished serum IGF-I input at thechoroid plexus may lead to increased amyloid (Ab) levels due to impaired clearance,28 tauopathy and cognitive loss due to reduced levels ofbrain IGF-I in addition to IGF-I/Insulin resistance in nerve cells (glia and neurons). In brain vessels, reduced IGF-I receptor function will leadto decreased brain angiogenesis15 and consequently to impaired energy support to brain cells, that in conjunction to altered IGF-I/Insulin
signaling will worsen the metabolic balance and in this way further contribute to cell impairment.

in the adult is probably from peripheral origin.23 Although this suggestion may appear premature at ﬁrst
glance, many observations support it. A biological signiﬁcance of peripheral IGF-I in brain function is supported by the presence of IGF-I receptors and IGFBPs
in all brain areas, including many devoid of detectable
IGF-I mRNA.24 Systemic administration of IGF-I elicits a wide variety of central effects, including increases

in neuronal activity,12,25 hippocampal neurogenesis,26
expression of growth factors and early genes,22 resilience to insults27 or amyloid b clearance,28 just to namea few (see below). As discussed elsewhere,29 not only
IGF-I, but other neuroactive humoral signals arise
also from the periphery even though they may also
be synthesized locally by brain cells; i.e., hormonal
steroids.

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Serum IGF-I Couples Physical Activity andBrain Function
A prominent role of serum IGF-I in the response tophysical exercise has long been recognized. Exerciseinduced muscle growth is mediated by serum IGFI,30,31 and many other aspects of the adaptive response
to exercise, including changes in brain function, involve
circulating IGF-I.32 Indeed, and as recently emphasized,33 brain health relies on physical activity. The
mechanisms involved in the beneﬁcial effects of exercise on brain function require serum IGF-I as a criticaleffector,32 and form part of the phenotypic expression of the exercise-driven human genome.34 In otherwords, physical activity (highly reduced in present-day
sedentary societies) is a physiological stimulus needed
to provide the brain with peripheral trophic support.
Although the mechanism underlying increased transport of serum IGF-I into the brain in response to exercise is not known, exercise-induced increase in brain
blood ﬂow is in all probability involved.
A particularly relevant aspect of serum IGF-I in thiscontext is its probable role in building a ‘‘cognitive reserve’’; i.e., the activity-dependent processes whereby
the brain builds up new functional (cognitive, motor . . .)skills allowing to eventually cope better with (cognitive,
motor . . .) damaging stimuli since more functional
resources are available. This concept stems from theobservation that increased mental or physical activity
reduces the risk of neurodegeneration.35 Exerciseinduced resilience to insult requires serum IGF-I27 andserum IGF-I is needed not only for exercise-induced
adult hippocampal neurogenesis but also for basal neurogenesis26 and synaptic plasticity: mutant mice withlow serum IGF-I levels lack hippocampal long-term
potentiation, which is restored upon chronic systemic
IGF-I therapy to the mice (unpublished observations).
All these observations clearly indicate that serum IGF-I
is necessary for building experience-dependent functional plasticity since this process involves synaptic
plasticity and, as hypothesized elsewhere36 probably
also newly formed neurons. Although highly speculative at present, declining serum IGF-I associated toaging may underlie cognitive loss commonly found inaged individuals37 due to diminished functional plasticity as a consequence of lower neurogenetic rate andsynaptic plasticity capabilities. Notably, the latter two
deﬁcits are common in old age.38,39
Conclusion
The IGFs constitute an ancient family of growth factors involved in the control of energy expenditure andin this way affect cell growth, body size and even longevity. This classical role refers to the major actions ofthese peptides when evaluated at an organism level.
However, when analyzed at tissue level, new speciﬁcroles are slowly been unveiled. In the case of IGF-I, aprominent role in brain function is gaining increasing
acceptance. The fact that not only brain IGF-I, but also
blood-borne (mostly liver-derived) IGF-I affects brain
physiology and disease may appear at ﬁrst as a novel
way to regulate brain activity through peripheral signals, but feedback mechanisms between the brain andthe periphery should be two-sided.

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