REvIEwS

The blood–brain barrier as an

endocrine tissue
William A. Banks
Abstract | The blood–brain barrier (BBB) was first noted for its ability to prevent the unregulated
exchange of substances between the blood and the central nervous system (CNS). Over time,
its characterization as an interface that enables regulated exchanges between the CNS and
substances that are carried in the blood in a hormone-​like fashion have emerged. Therefore,
communication between the CNS, BBB and peripheral tissues has many endocrine-​like
properties. In this Review, I examine the various ways in which the BBB exhibits endocrine-​
related properties. The BBB is a target for hormones, such as leptin and insulin, that affect many
of its functions. The BBB is also a secretory body, releasing substances either into the blood
or the interstitial fluid of the brain. The BBB selectively allows classical and non-​classical
hormones entry to and exit from the CNS, thus allowing the CNS to be both an endocrine
target and a secretory tissue. The BBB is affected by endocrine diseases such as diabetes
mellitus and can cause or participate in endocrine diseases, including those related to thyroid
hormones and obesity. The endocrine-​like mechanisms of the BBB can extend the definition
of endocrine disease to include neurodegenerative conditions, including Alzheimer disease,
and of hormones to include cytokines, triglycerides and fatty acids.

Geriatric Research Education
and Clinical Center, Veterans
Affairs Puget Sound Health
Care System and Division
of Gerontology and Geriatric
Medicine, Department
of Medicine, University of
Washington School of
Medicine, Seattle, WA, USA.
e-​mail: wabanks1@uw.edu
https://doi.org/10.1038/
s41574-019-0213-7
The blood–brain barrier (BBB) was originally defined
by its ability to prevent the unregulated entry of blood-​
borne substances into the central nervous system (CNS).
At least three barriers are currently recognized: a vas-
cular BBB formed by brain endothelial cells; a blood–
cerebrospinal fluid (CSF) barrier formed by epithelial
cells; and a barrier formed by tanycytes, which are special
ependymal cells within the brain, that interfaces between
the circumventricular organs and other adjacent brain
tissue1. These barriers all possess tight junctions (Box 1)
that block intercellular leakage, have reduced macro­
pinocytosis and contain no fenestrae (small pores in the
cell membrane), which together all reduce intracellular
leakage (Fig. 1).
These BBBs perform many functions in addition to
that of barrier formation. Through the transport of glu-
cose, vitamins, minerals and other substances, the BBBs
supply the CNS with its nutritional needs2. Through
efflux transporters and enzymatic activities, the BBBs
help rid the brain of toxins produced there and prevent
those exogenous to the CNS from accumulating or enter-
ing the CNS in the first instance3. By regulating the influx
and efflux of informational molecules such as peptides
and regulatory proteins, and because it is a source of
informational molecules itself, the BBBs, and especially
the vascular BBB, act as interfaces in a humoral-​based
communication axis between the CNS and the blood4,5.
These extra-​barrier properties create a blood–brain
interface6 that is endowed with many endocrine-​like
properties (Fig. 2). In brief, these are the ability of brain
endothelial cells to react to both traditional hormones
and other circulating elements (thus, the barrier cells
act as classic endocrine target tissues); the ability of
barrier cells, especially brain endothelial cells, to secrete
substances into the blood that affect other cells (thus,
the barrier cells can act as classic endocrine secretory
tissues); the ability of the BBBs to transport substances
from the blood into the brain and from the brain into
the blood (thus, the BBBs selectively overcome their own
blockade, allowing the brain to act as an endocrine target
and facilitating it as an endocrine secretory tissue); the
BBBs can be targets of endocrine diseases, and the result-
ing alterations in BBB properties can underlie some of
the clinical manifestations of those endocrine diseases;
and finally, malfunctions of the BBBs can cause endo-
crine diseases. Together, these five properties provide
unique ways in which the BBB can be involved in the
treatment of endocrine diseases.
In this Review, I explore these aspects of the endo-
crine BBB. Some of these properties have many exam-
ples, and I am unable to cover them all. Therefore, this
Review focuses on the endocrine-​like properties of the
vascular BBB and defines the underlying principles that
are currently understood.

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Key points
• The blood–brain barrier (BBB) acts as both a secretory and target endocrine tissue.
• By regulating the transport of hormones into and out of the brain, the BBB provides a
mechanism by which the central nervous system can act as an endocrine secretory
and target tissue.
• The BBB facilitates substances not typically thought of as hormones acting in an
endocrine-​like fashion, including triglycerides, short-​chain fatty acids and
lipopolysaccharide.
• BBB function can be altered in endocrine diseases either because of adaptions to the
disease condition or because it is a disease target.
• BBB dysfunction or impairment can cause or promote the progression of endocrine or
metabolic diseases.
• The BBB is an important factor in the treatment of many diseases, often as a
therapeutic target or as a barrier that must be negotiated.
The BBB as an endocrine target
The many barrier and interface functions of the BBB
require its performance to be fine-​tuned to the needs
of the CNS and to be adaptable to the changing periph-
eral environment. As such, the BBB responds to hor-
mones, which makes it an endocrine target tissue. For
example, oestradiol modulates sodium–potassium–
chloride co-​t ransporters, and through this mech-
anism it can influence post-​stroke brain oedema7.
1,25-dihydroxyvitamin D3 regulates the expression of the
efflux transporter LDL receptor-​related protein 1 (LRP1)
and the influx transporter receptor for advanced glyca-
tion end products (RAGE)8 (of note, among the many lig-
ands of these transporters are the amyloid-​β proteins9,10).
Through the AT1 receptor, angiotensin II modi­fies BBB
permeability, including via transcytosis11,12. Thus, angi-
otensin II could be the hormone responsible for opening
the BBB during hypertensive emergencies, resulting in
hypertensive encephalopathy13.
Although insulin does not modulate GLUT1, which is
the BBB transporter for glucose, insulin has other effects
on BBB functions. For example, insulin enhances the
transport of tryptophan across the BBB, which in turn
could affect brain levels of serotonin and kynurenine,
substances that are related to sleep and depression14–16.
Insulin also regulates the activity or affects the levels of
brain endothelial cell alkaline phosphatase, glutathione
and P-​glycoprotein17–19, and insulin increases leptin trans-
port across the BBB20. The BBB transporter for insulin
itself is, in turn, regulated by several substances, including
levels of iron, cholecystokinin and triglycerides21–23.
Many other functions of the BBB are regulated in an
endocrine-​like fashion. Leptin transport is modulated
by blood-​borne glucose, triglycerides, adrenaline and
probably oestrogens20,24. Amylin alters tyrosine and tryp-
Neurovascular unit tophan transport25, the BBB efflux pump peptide trans-
A multicellular and port system 1 (PTS1) is altered by branched-​chain amino
multicomponent network that
acids26 and the mannose 6-phosphate receptor (which
is composed of neurons, glial
cells, brain endothelial cells transports some lysosomal enzymes across the neonatal
and extracellular matrix BBB) is modulated by circulating adrenaline and reti-
components. The neurovascular noic acid27–29. Evidence suggests that the decreases in the
unit is key to neurovascular expression of GLUT1 associated with a high-​fat diet are
coupling and to the delivery
of key nutrients and oxygen
rescued by vascular endothelial growth factor30.
from the circulatory system A number of substances have been proposed that
into the brain. could regulate the induction or integrity of the tight
NATURe RevIeWS | EndoCrinoLogy
Reviews
junctions, which, as mentioned earlier, are critical for
maintaining the barrier functions of the BBB. Most of
these substances are secreted from cells on the brain
side of the BBB, particularly pericytes and astrocytes.
However, some classic hormones might also have a role
in regulating tight junctions, including glucagon-​like
peptide 1 (GLP1) and transforming growth factor 1
(refs31,32). In addition to substances that could regulate
tight junctions, substances that were not traditionally
thought of as hormones circulate in the blood and affect
the function of the BBB and brain endothelial cells.
These include cytokines, triglycerides, free fatty acids
and lipopolysaccharide (LPS)32–35 (Box 2).
The aforementioned examples illustrate several prin-
ciples: barrier cells constitute an endocrine tissue that
responds to circulating factors; alterations in the BBB
affect all the known categories of BBB function (that is,
effects on barrier properties, transporters, enzymatic
activities and secretory processes); and some effects are
mediated through classic hormones, such as insulin.
Other blood-​borne effectors are not typically thought
of as hormones, such as triglycerides and LPSs, and
some effectors do not cross the intact BBB (for example,
adrenaline). Other effectors do cross, including those
with effects on other transporters. For example, insulin,
which is transported across the BBB, increases leptin
transport and triglycerides (which are also transported
across the BBB), affecting both insulin and leptin trans-
port. Thus, the scene is set for complex physiological
interactions. As a result of these endocrine effects, the
BBB is able to adapt to environmental influences that,
in turn, affect brain function. Hence, the BBB aids the
CNS in detecting and responding to environmental
conditions as presented to it through the bloodstream.
Signals coming from the CNS to the brain endothelial
cells allow the BBB to respond to the changing needs
of the brain.
The BBB as an endocrine secretory tissue
All the barrier cells are able to secrete a number of sub-
stances, but of the barrier cells, brain endothelial cells
are the most widely studied. Brain endothelial cells can
release nitric oxide, prostaglandins, cytokines and adre-
nomedullin36–41. The epithelial cells that constitute the
blood–CSF barrier and the tanycytes that form a bar-
rier between circumventricular organs and adjacent
brain tissue also have secretory functions42,43. Secretions
are both constitutive and induced and are influenced
by the other cells of the neurovascular unit44. IL-6 and
granulocyte–macrophage colony-​stimulating factor
(GM-​CSF; which is classically know as a white blood
cell growth factor) secreted from brain endothelial cells
act in an autocrine or paracrine fashion to enhance the
translocation of the HIV-1 virus across the BBB 45.
The secretions from barrier cells can also affect other
cells within the CNS. For example, brain endothelial cells
secrete fever-​mediating prostaglandins46,47 and IL-1β
and IL-6, which influence the uptake of copper and iron
by glial cells34,48.
A mechanism for intercellular crosstalk within the
CNS, and the basis for an endocrine-​like axis that con-
nects peripheral tissue events with brain functions, is
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Box 1 | The endocrinology of the blood–brain barrier
Both inside and outside the brain
Brain endothelial cells define the limits of the central nervous system (CNS) and
therefore have a luminal membrane facing into the bloodstream and an abluminal
membrane facing into brain interstitial fluid. Tight junctions cement adjoining brain
endothelial cells together, preventing intercellular diffusion (that is, blood–brain barrier
(BBB) leakage), but tight junctions also have a fence function154,155 — they block the
diffusion of proteins and lipids between the luminal and abluminal outer cell membrane
leaflets. The tight junctions endow the BBB with characteristics of polarization; that is,
the luminal surface membrane has very different transport, enzymatic and receptor
characteristics from the abluminal surface membrane. Such polarization underlies
many BBB characteristics, such as unidirectional transport or the ability to respond to a
stimulus at one surface membrane by releasing a molecule from the other membrane.
The BBB is a barrier; the BBB is a gateway
The BBB prevents the unrestricted entry of materials into the CNS. The lack of fenestrae
at the BBB, decreased macropinocytosis across the BBB and the presence of tight
junctions limit the way in which nutrients and other resources can enter the CNS.
Therefore, the BBB meets the demand for nutrient transfer with a host of transporters,
including those for glucose, amino acids, vitamins and minerals.
The BBB is constant; the BBB is ever changing
The robust barrier function of the BBB is consistent throughout the lifespan of the
healthy individual. Contrary to popular misunderstanding, the fetal barrier is not leaky
to serum proteins, nor in most studies is the healthy aged BBB114,156. Similarly, rates of
transmembrane diffusion are not different between the neonate and the adult157.
However, transport rates of amino acids differ with development, and many transporters
are altered in aged individuals. These differences are because the BBB is slave to the
needs of the brain and therefore adapts to the changing needs of the brain throughout
the lifespan — these changes can be adaptive or maladaptive and contributory
to disease.
the process by which circulating substances act at the
luminal side of brain endothelial cells to stimulate
the release of substances from these cells into brain inter-
stitial fluid that then act on other brain cells. In sum-
mary, the ability of barrier cells to secrete substances into
blood establishes an endocrine-​like axis; the ability of
barrier cells to secrete substances into the brain com-
partment in response to blood hormones establishes
a mechanism by which those hormones can influence
brain function without crossing the BBB.
The aforementioned examples illustrate several
principles: all barrier cells (endothelial, epithelial and
tanycytic) are secretory; secretions can be constitutive
or induced; for brain endothelial cells, secretions can
be into the bloodstream or into the CNS; and paracrine
and autocrine effects have been demonstrated. Whether
substances derived and released by brain endothelial cells
into the bloodstream affect distal peripheral tissues in the
classic haemocrine fashion has not been demonstrated.
Transfer of hormones across the BBB
Pathways and mechanisms. The barrier function of
the BBB would ordinarily deny water-​soluble hormones
Plasma protein binding entry to the CNS, thus making it impervious to many
The degree to which a
circulating signals. However, the BBB is permeable to
substance binds to proteins
within the blood. many hormones, which makes the CNS an endocrine
target tissue.
Choroid plexus There are many examples of circulating substances
The choroid plexus, which that cross the BBB to act on the CNS. Classic exam-
consists of modified
ependymal cells, produces the
ples of substances that cross the BBB are the steroid
cerebrospinal fluid in the hormones that cross by the non-​saturable process of
ventricles of the brain. transcellular diffusion. The rate at which these steroids
446 | AUGUST 2019 | volume 15 www.nature.com/nrendo
enter the brain is determined primarily by their lipid
solubility but is also influenced by their molecular mass
as well as the extent and type of plasma protein binding.
Accumulation within the brain is dictated by avidity of
the CNS binding receptor, especially when compared
with the avidity of binding to plasma proteins. The
presence of brain-​to-blood efflux systems can also affect
the accumulation of a substance, as demonstrated for
dehydroepiandrosterone sulfate49.
As shown by the classic studies of Geraldo David
and Tapan Anand Kumar, and of Samuel Marynick and
colleagues, the degree of uptake of steroid hormones
ranges widely, as exemplified by the accumulation of
17α hydroxyprogesterone being ~200 times greater
than that of testosterone50,51. Many of the efflux systems
that include steroid hormones among their ligands are
members of the organic anion transporting polypeptide
(OATP) and the ATP-​binding cassette (ABC) trans-
porter families49,52,53. Non-​sulfated steroids are predom-
inantly transported in the brain-​to-blood direction at
both the vascular BBB and the choroid plexus. However,
for hydrophilic sulfated steroid hormones, which are
in far greater abundance than non-​sulfated steroids,
current evidence strongly suggests that the main direc-
tion of transport is blood to brain and is mediated by
the OATPs53,54. Brain endothelial cells can also act as a
enzymatic barrier to some steroids54.
Other classic hormones, such as thyroid hormones,
insulin, leptin and ghrelin, cross the BBB by saturable
processes. Many of the major saturable transport sys-
tems, such as GLUT1, are non-​energy-requiring systems
(that is, they function via facilitated diffusion). Other
transport systems rely on pores or are transcytotic —
the latter always require energy and are variably classi­
fied as carrier-​mediated transport, receptor-​mediated
transport, receptor-​mediated transcytosis and adsorp-
tive transcytosis. A substance that is the primary ligand
for a transport system typically crosses at a rate that is
10–100-fold greater than the rate predicted on the basis
of its lipid solubility and other physicochemical charac-
teristics2. A saturable transport system also means that
the BBB can negate the effect of binding to those plasma
proteins when the BBB transporter has a higher binding
affinity than the plasma protein.
Thyroid hormones. Thyroid hormones are transported
across cell membranes by various transporters, but only
monocarboxylate transporter 8 (MCT8) and OATP1C1
are thought to be physiologically relevant55. Thyroid hor-
mone receptors do not function as BBB transporters, and
the large neutral amino acid (LNAA) transporters LAT1
and LAT2, although capable of transporting thyroid
hormones, do not seem to have a physiological role.
Evidence suggests that there are species specific dif-
ferences in the rate of thyroid hormone transfer across
the BBB. For example, in humans thyroid hormone
transfer relies on MCT8, whereas in murine endothelial
cells OATP1C1 is abundantly expressed in addition to
MCT8 (refs56,57). On the basis of mutation and knockout
studies, MCT8 in mice favours T3 transport, whereas
OATP1C1 favours T4 transport; MCT8 might also have
some efflux function56. This combination of influx and
 Reviews

a efflux transport is consistent with an early study in mice

Membrane protein
Nonpolarized cell finding that T3 crosses mainly in the blood-​to-brain
direction and T4 is dominated by an efflux system58.
Substrate Deiodinases are abundantly expressed in the brain59
and they are thought to have a major role not only in
Cytoplasm the conversion of T4 to T3 but also in the catabolism of
thyroid hormones to inactive forms. Finally, free iodide
is rapidly transported out of the brain60,61. MCT8 and
OATP1C1 are also abundantly expressed in the choroid
Substrate binding plexus. When injected into the lateral ventricle, however,
Cell membrane:
inner leaflet leads to response T3 and T4 penetrate only into the periventricular area.
Such limited periventricular distribution is the rule for
Nucleus
substances injected into the CSF62,63. As such, it is likely
that the choroid plexus is a source of thyroid hormones
Vesicle for brain regions that are in contact with the CSF.

Cell membrane: Insulin. Insulin is a classic hormone that in mammals is

outer leaflet secreted predominantly by a single tissue, the pancreas.
Insulin is transported across the BBB by a saturable
Exocytosis Endocytosis Extracellular fluid system64–66. In the periphery, insulin acts as a metabolic
hormone, inducing the uptake and metabolism of glu-
cose by tissues that express GLUT4, such as muscle, adi-
b pose tissues and the liver. Transport of glucose across
Brain Transcytosis Abluminal Abluminal the BBB, however, depends on the non-​insulin-sensitive
contents response GLUT1, and few brain cells possess GLUT4. Many of
the properties of CNS insulin are more mitogenic (that
Endothelial cell is, they are involved in growth) than metabolic (such
Tight Tight junctions
junction separate luminal as being used for energy); it seems as if peripheral and
and abluminal
contents CNS insulin have followed separate evolutionary paths67.
It should be noted, however, that studies that investi-
gate the actions of substances, not just hormones, on the
CNS often administer pharmacologically relevant doses,
Endocytosis Exocytosis therefore the elucidated actions on the CNS might not
Luminal Luminal
contents response
Activated occur physiologically. In addition, any substance that is
Blood receptor
injected into the CSF will eventually enter the blood-
stream as the CSF is reabsorbed. Studies have shown
Lipid that substances injected into the CSF can be found
Protein
peripherally in the blood. In some cases, those levels are
the same as if the substance had been given as an intra­
venous infusion68,69. Ironically, then, the effects produced
Abluminal outer after an intracerebroventricular injection can actually on
Abluminal membrane leaflet lipids occasion be mediated at peripheral sites of action.
membrane Research published between 1984 and 1992 reported
protein Inner membrane
leaflet lipid that CNS insulin influenced feeding and blood glucose
levels; however, the effects were paradoxical to those
Luminal Luminal outer of insulin-​induced hypoglycaemia70,71. That is, CNS
membrane membrane insulin inhibits feeding, elevates blood glucose and even
protein leaflet lipid
reduces blood insulin. Therefore, insulin is one of several
hormones that have paradoxical CNS effects, raising the
possibility that they act as their own counter-​regulatory
hormones72.
CNS insulin acts in the hypothalamus to control
Fig. 1 | The presence and architecture of tight junctions results in polarization ~50% of hepatic glucose production by stimulating
of the brain endothelial cell. a | Endocytosis, membrane protein distribution and sympathetic outflow to the liver73,74. Although, it is
receptor response in a nonpolarized cell all occur in a single extracellular environment. insulin’s mitogenic-​like effects on brain cells and its
b | Tight junctions create polarization so that the extracellular environment is divided possible use in the treatment of Alzheimer disease that
into luminal (blood) and abluminal (brain) spaces. Transcytosis (blood–brain barrier
have raised the most excitement of late75. As mentioned
penetration) and exocytosis can occur. Receptor activation can result in a response on
the luminal or abluminal side of the cell. Inset shows that the fence function of tight previously, the actions of insulin in the CNS are more
junctions prevents the exchange of luminal and abluminal outer membrane leaflet mitogenic than metabolic and resemble more closely
contents, allowing for unique populations of lipids and proteins. The fence function those of the ancestral insulins than those of peripheral
extends only to the outer leaflet and therefore does not divide the inner leaflet into insulin76. Insulin administered to the brains of healthy
distinct luminal and abluminal regions. humans, cognitively impaired humans or mouse models

NATURe RevIeWS | EndoCrinoLogy volume 15 | AUGUST 2019 | 447

Reviews
Brain Blood-to-brain passage
of hormones across the
BBB allows the brain to
be an endocrine target
BBB
Receptor
The BBB is a target for The BBB secretes
circulating substances substances into the
secreted by other tissues circulation that
affect other tissues
Blood
Fig. 2 | The vascular blood–brain barrier as an endocrine tissue. The vascular blood–brain barrier (BBB) is a target
for circulating substances in the blood7,8,11,12,17–19. In addition to this, the vascular BBB secretes substances into the blood
that act in autocrine, paracrine and haemocrine fashions34,36–41,45–48 and it regulates the exchange of informational
substances between the central nervous system and the blood50,51,55,64–66,80,81, resulting in humorally mediated brain–body
communication.
of Alzheimer disease results in rapid improvement in
cognition and has effects on neuronal survival, plasticity
of synapses, dendritic arborization and the formation of
neuronal circuits77–79.
Ghrelin. Ghrelin is illustrative of other hormones
that are predominantly synthesized in the periphery
but are capable of crossing the BBB80,81 in quantities
sufficient to influence CNS function. Aside from having
effects on feeding and energy expenditure, ghrelin also
has effects on cognition, synaptic function, neuronal
survival and neurogenesis (effects that are shared by
insulin and leptin)82–85.
Fibroblast growth factors. Fibroblast growth factors
(FGFs) are a large family of regulatory proteins with
many functions, including endocrine functions. FGF2
(basic FGF), FGF19 (human homologue of mouse
FGF15, henceforth referred to as FGF15/FGF19) and
FGF21 have all been shown to cross the BBB, and there
is preliminary evidence for FGF1 (acidic FGF) cross-
ing86–89. In many cases, the ability of a peripherally
administered FGF to cross the BBB underlies its ability in
part or in whole to induce CNS effects, including those
on analgesia86, circadian behaviour90 and metabolism91.
FGF15/FGF19 and FGF21 can circulate as hormones
and have acute metabolic effects that are mediated, at
least in part, through the liver and adipose tissues91. Both
FGF15/FGF19 and FGF21 increase energy expenditure
and decrease plasma insulin, glucose and triglyceride
concentrations in the liver in obese animals, but in a
chronic setting these effects, as well as weight loss, are
predominantly mediated through the CNS. Part of the
CNS effect of FGF15/FGF19 and FGF21 is mediated
through sympathetic outflow from the CNS to brown
fat. Peripherally administered FGF1 also acts within the
CNS to decrease hyperglycaemia92.
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Autocrine Paracrine Blood-to-brain
effects effects passage of
substances across
the BBB allows the
brain to act as an
endocrine
secretory tissue
The glucose-​n ormalizing effect of FGF1 is not
dependent on weight loss, reduced food intake, changes
in basal glucose turnover or production rate, glucose
uptake by heart or adipose tissues or changes in blood
insulin or glucagon levels. Unlike FGF15/FGF19, FGF1
has little or no effect on the hypothalamic–pituitary–
adrenal axis and only has acute effects on sympa-
thetic outflow92. Instead, FGF1 administered by intra­
cerebroventricular injection was shown to increase
hepatic and skeletal muscle uptake of glucose, a process
that probably occurred via an insulin receptor-​dependent
mechanism92.
Leptin. The examples of BBB–hormone transport path-
ways that I have provided in this Review so far mostly
relate to brain endothelial cells and the vascular BBB. It is
worth noting, however, that although the epithelial bar-
rier cells of the choroid plexus and tanycytes found at the
circumventricular organs share characteristics with brain
endothelial cells and the vascular BBB, each barrier results
in unique distribution patterns for the hormones or other
substances it transports93,94. The unique regional distri-
bution patterns are a result of the very low diffusion rates
within brain tissue. Furthermore, the low diffusion
rates from the CSF into brain tissue means that when a
substance is introduced into the CSF it is fairly evenly dis-
tributed throughout cranial CSF, but diffusion from the
CSF into adjacent brain tissue is poor. As a result of this
poor diffusion, a substance transported into the CSF by
the choroid plexus remains mostly periventricular60,62,63,95.
In theory, the three barriers (the vascular BBB, the
blood–CSF barrier and the tanycytic barrier at the cir-
cumventricular organs) work in harmony to support
brain function, but there are some examples of how these
barriers would affect a specific hormone or influence a
given brain region (Box 3; Fig. 3). Studies in rodents that
investigated how peripheral leptin is distributed in the

Box 2 | The blood–brain interface expands the definition of hormones
Hormones were originally defined as substances secreted by glandular tissues, but the
definition has long been extended to include secretions from non-​glandular tissues.
Some substances not traditionally thought of as hormones interact with the blood–brain
barrier (BBB) in an endocrine-​like fashion.
Cytokines
Cytokines are transported across the vascular BBB and are secreted by brain endothelial
cells and the epithelial cells of the blood–cerebrospinal fluid (CSF) barrier. With regard
to the BBB, cytokines have autocrine, paracrine and haemocrine modes of action. The
endocrine-​like interactions between the BBB and cytokines are a major component of
the neuroimmune axis and participate in the central nervous system (CNS)-mediated
effects of circulating cytokines, including feeding, sleep, thermogenesis and fever, pain
perception and the progression of neurodegenerative diseases104.
Triglycerides, free fatty acids and short-​chain fatty acids
Triglycerides act at the BBB to regulate the transport of leptin, ghrelin and insulin. They
also cross the BBB to induce resistance to leptin and insulin at their CNS receptors. Free
fatty acids, such as palmitate and arachidonate, cross the BBB, where they participate
in membrane turnover and signalling. Free fatty acids act at the hypothalamus to affect
the expression of feeding hormones such as galanin and orexin. Short-​chain fatty acids
(such as acetate, propionate and butyrate) connect the microbiome to the brain.
Gut bacteria act on dietary fibre to produce these short-​chain fatty acids, which enter
the blood and cross the BBB to affect brain functions.
Lipopolysaccharides
Lipopolysaccharides (LPSs) have potent effects on the BBB. For example, they can alter
the function of BBB transporters; induce the release of prostaglandins, nitric oxide and
cytokines from the BBB; and disrupt the BBB104. LPSs can translocate across the gut
after physiological events, such as intense running, and circulate in blood under normal
conditions. The presence of LPSs in the blood in physiological conditions raises the
possibility of them having physiological roles, which might be mediated through their
effects on the BBB; however, as colonizing bacteria are the source of LPSs, rather than
the human host, LPSs would be better described as a vitamin, albeit one with hormonal
effects, analogous to vitamin D.
arcuate nucleus following transport across the BBB in a
fed and non-​fed state offer some interesting examples
of how the three barriers can interact (Fig. 3). In the fed
state, leptin is transported across the vascular BBB by
brain endothelial cells at the rate of ~5.9 × 10−4 ml/g, or
~20 times faster than albumin80. In addition to the vas-
cular BBB, a second source of leptin is transported across
the choroid plexus and into the CSF69,96.
As mentioned earlier, owing to low diffusion rates
from the CSF to the brain, tissue concentrations of
BBB-​t ransported leptin decrease dramatically and
logarithmically from the ventricular surface63 so that
leptin remains mainly in the periventricular region of
the arcuate nucleus69. The study by Berislav Zlokovic
and colleagues96, which was conducted in rats, reported
a transport rate at the choroid plexus that was ten times
higher than the transport rate found by Naoko Nonaka
and colleagues97 in the mouse. One explanation could be
that the rat, with its larger arcuate nucleus and therefore
its larger diffusional distances, requires higher rates of
leptin transport into the CSF than the mouse.
A third pathway that leptin can take to the arcuate
nucleus tissue is via diffusion across the leaky BBB of the
median eminence. Leptin that enters the CNS via this
route is subsequently transported by tanycytes into the
CSF and arcuate nucleus tissue. Without this transport
function, the barrier function of the tanycytes would
prevent leptin from diffusing from the median eminence
into the CSF or arcuate nucleus93.
NATURe RevIeWS | EndoCrinoLogy
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Dramatic changes occur in these systems with food
restriction. After 24 h of fasting, leptin transport across
the vascular BBB increases98, the tanycytic barrier extends
further along the ventricle and some of the brain endo­
thelial cells in the arcuate nucleus closest to the median
eminence lose barrier function93. Whereas these events
probably increase leptin levels in the arcuate nucleus
after 24 h of fasting, the changes at 48 h act in unison to
decrease leptin action, resulting in leptin deficiency, leptin
peripheral resistance and leptin central resistance. By 48 h
of fasting, serum leptin levels are decreased, the leptin
transport rate across the vascular BBB is greatly decreased
and there is resistance at the leptin receptor. The latter
two events — inhibition of leptin transport and receptor
binding — are mediated at least in part by triglycerides,
which are greatly increased in the blood with starvation
and are transported across the BBB33,99 (Fig. 3).
The CNS can contribute levels of a substance in the
blood. Such substances enter the bloodstream not only
through efflux transporters located at the vascular BBB
and choroid plexus but also with the reabsorption of CSF
into the bloodstream. Indeed, because of this efflux, sub-
stances injected into the lateral ventricles of the brain
can produce blood levels that resemble that of an intra-
venous infusion68. The renowned neuroendocrinologist
Seymour Reichlin showed that on stimulation, the CNS
can be an impressive source of blood cytokines100–102.
Others have shown that corticotropin-​releasing hormone
given into the lateral ventricle of the brain can enter the
circulation in amounts sufficient to modulate splenic
secretion of IL-1β100.
The microbiota. Once in the bloodstream, the secreted
products of the gut microbiota might have many effects
on BBB functions and the neuroimmune axes in which
the BBB participates103,104. In addition, the products
of the microbiome, as exemplified by the short-​chain
fatty acids, cross the BBB to exert effects on the CNS.
A 2016 study showed that short-​chain fatty acids cross-
ing the BBB increase microglial activation to the extent
that the nature of the microbiome could be a risk factor
for Parkinson disease105.
The brain as an endocrine tissue. As detailed in this
section, a number of fundamental principles govern
the transfer of hormones across the BBB. First, every
major class of hormone (steroids, peptides, regulatory
proteins and thyroid hormones) has representatives that
cross the BBB at physiologically relevant levels. Second,
a variety of transfer mechanisms across the BBB exist,
with transcellular diffusion and blood-​to-brain satura-
ble transporters being the best understood mechanisms.
Third, for some hormones, brain-​to-blood transporters,
plasma protein binding, enzymatic barrier function or
CNS receptor affinity is a major or the major determi-
nant of CNS uptake or retention. Furthermore, in many
cases, the protein acting as the hormone’s receptor is not
the same protein acting as its transporter.
This section elucidated several other points. As illus-
trated by leptin, the various barrier systems (endothelial–
vascular, epithelial–CSF and tanycytic–CSF–circum-
ventricular organ) have ‘spheres of influence’; that is,
volume 15 | AUGUST 2019 | 449
Reviews
Allan–Herndon–Dudley
the distribution of a hormone within the CNS differs
syndrome depending on the barrier it has crossed. Leptin is also
A condition resulting from an example of how BBB–hormone transporters are not
deficient thyroid hormone static but are regulated by peripheral events, including
transport across the blood–
brain barrier characterized
by other hormones.
by cognitive impairment, lack In some cases, the effect of a hormone on the CNS
of speech and hypotonia. is complementary to its peripheral action (CNS insu-
lin’s effect on hepatic glucose production); in other
cases, it can be contradictory so that in the CNS the
hormone acts in counter-​regulatory fashion to its
peripheral effects (CNS insulin’s ability to increase
blood sugar and suppress appetite). In addition to
these outcomes, the effects induced in the CNS by a
hormone can seem unrelated to those of its peripheral
actions (CNS insulin’s effect on cognition). As with
the other endocrine functions of the BBB, substances
acting in a hormone-​like fashion include those not
typically classified as hormones and have actions that
are not typically thought of as endocrine (triglycerides
and leptin resistances). Furthermore, a blood-​borne
hormone might exert an effect in the periphery that
is dependent on a CNS site of action (insulin’s effect
on CNS-​mediated hepatic glucose output). In this
case, the blood-​to-brain transfer of a hormone and
the subsequent CNS action is part of a more complex
brain–body interaction.
Research has also shown that brain-​to-blood transfer
mechanisms (such as transporters and CSF reabsorp-
tion) can, under some circumstances, contribute mark-
edly to blood levels of a hormone as illustrated by leptin,
cytokines and potassium. In addition, products from the
Box 3 | Three barriers and their spheres of influence
This Review has emphasized the vascular blood–brain barrier (BBB). This barrier is the
best studied of the three main barriers and fits most readily into an endocrine model
given that hormones are by definition blood-​borne. It is of note, however, that two
other arms of the BBB, which are composed of epithelial cells and tanycytes, also have
endocrine-​like functions. In addition, areas of the brain in which capillaries lack barrier
functions (known as the circumventricular organs) have access to hormones much the
way peripheral tissues do. The circumventricular organs are connected to other regions
of the brain by afferent and efferent nerves so that signals received in these non-​barrier
regions of the brain can be relayed to other regions.
Hormones that enter the circumventricular organs are not able to diffuse to adjacent
brain regions nor to the cerebrospinal fluid (CSF) because of a delimiting tanycytic
barrier (Fig. 3). The cells that form the tanycytic and epithelial barriers have transporter
functions and the epithelial cells of the choroid plexus have secretory properties
as well158,159.
The distribution of a hormone within the central nervous system (CNS) is greatly
influenced by which barrier a hormone has used to enter the CNS, creating unique
spheres of influence for each barrier. For example, hormones that leak into the space
between the capillary plexus and epithelial cells of the choroid plexus can influence
epithelial cell function or be transported into the CSF. Hormones that leak into
the circumventricular organs, aside from influencing the brain cells within the
circumventricular organs, also have the potential of influencing the delimiting
tanycytes or of being transported into adjacent brain tissue or CSF. Substances
that enter the CSF have very limited diffusion into the brain and are mainly in the
periventricular and other CSF-​contacting areas. Likewise, substances diffusing
across the tanycytic barrier are mainly confined to the adjacent tissue.
The vascular BBB could homogeneously distribute a hormone throughout the brain,
but most hormones that cross the vascular BBB demonstrate a heterogeneous pattern
because of differences in transport, efflux and degradation rates. A fourth pattern of
distribution occurs for hormones or hormone analogues that have very long half-​lives
in blood as they can enter using the extracellular pathways160.
450 | AUGUST 2019 | volume 15 www.nature.com/nrendo
gut microbiome such as short-​chain fatty acids can cross
the BBB to influence the CNS.
The BBB as a target of endocrine disease
Both the BBB and the blood–retinal barrier are disrupted
in diabetes mellitus in both humans and animal models
of diabetes106,107. In streptozotocin-​induced diabetes, BBB
disruption is progressive, involving bigger lesions and
more regions of the brain with disease duration107. Blood–
retinal barrier disruption, which results in diabetic
retinopathy, is the leading cause of blindness in Western
countries. BBB disruption also occurs in diabetes
mellitus. Disruption in the occipital cortex can contrib-
ute to the visual deterioration108 seen in diabetes. BBB
disruption is closely linked with cognitive impairments109
and precedes cognitive impairment110.
In both BBB and blood–retinal barrier disruption, the
main cause of disruption seems to arise from pericytic
glucotoxicity111,112. Pericytes, which are instrumental in
instructing brain endothelial cells to form and maintain
barrier functions113,114, take up glucose in an insulin-​
independent manner so that at high levels more glucose
enters the tricarboxylic acid (TCA) cycle, producing
more ATP but also increasing oxidative stress. This oxi-
dative stress is blamed for pericyte death, which leads
to BBB disruption and blood–retinal barrier disruption.
Pericyte loss has been proposed to have a role in other
types of brain diseases with a BBB component, including
Alzheimer disease, cerebral cavernous malformation and
methamphetamine toxicity115–117.
In addition to pericyte integrity, other aspects of
the BBB can be affected by diabetes mellitus or obesity.
Leptin, choline and insulin transport, as well as the efflux
transporter LRP1, are decreased in diabetes mellitus or
with obesity98,118–121. Furthermore, the expression of
numerous proteins by brain endothelial cells, such as
cytoskeletal proteins, enzymes and transport-​related
proteins, is decreased with obesity122. The lipid com-
position of brain endothelial cells is not altered in the
brains of patients with diabetes mellitus or obesity, but
brain endothelial cells in the brains of these individuals
do have increased oxidative damage123.
Hyperhomocysteinaemia is also associated with BBB
disruption124. Evidence suggests that disruption is via the
N-​methyl-d-​aspartate receptor, a finding that is consist-
ent with homocysteine being an agonist for this receptor.
As for diabetes mellitus, BBB disruption precedes the
cerebral pathology found in this condition125.
In summary, barrier and transporter functions can
be altered in the brains of patients with endocrine and
meta­bolic diseases. Furthermore, barrier dysfunction
leads to clinical disease, as exemplified by blindness
resulting from blood–retinal disruption and cognitive
changes resulting from BBB disruption.
The BBB as a cause of endocrine disease
Thyroid-​ h ormone-related conditions. Impaired
expression of MCT8, the main BBB transporter of
thyroid hormones in humans, results in Allan–Herndon–
Dudley syndrome55. Brain lesions are present prenatally.
Interestingly, mice with an MCT8 deficiency do not
show altered brain structures or evidence for cognitive
 Reviews

a Fed state b 24 h fasted c 48 h fasted

Central insulin
CSF Choroid plexus resistance
Arcuate nucleus Arcuate nucleus
Arcuate
nucleus
cell

Leptin
Leptin Triglyceride
receptor

Capillary ↓ Leptin
↑ Triglyceride
Ventromedial region Ventromedial region levels

Epithelial cell Leaky

Ependymal
cell

Tanycyte

Leaky
Median eminence

Fig. 3 | Blood-​to-brain transport of leptin into the arcuate nucleus: integration of signals and changes with feeding
state. a | In the fed state, blood-​derived leptin (blue dots) reaches the arcuate nucleus by transport across local capillaries
with barrier function80, transport across the epithelial cells of the choroid plexus into cerebrospinal fluid (CSF) with
subsequent leakage into brain tissue across leaky ependymal cells69,96 and transport into CSF and adjacent brain tissue by
the tanycytic barrier after leakage into the median eminence93. b | Three changes found at 24 h of fasting are an extension
of the tanycytic barrier into the ventricular region, an increase in the blood–brain barrier (BBB) transport rate of leptin
and the conversion of some capillaries in the ventromedial region of the arcuate nucleus to a leaky state93,98. c | At 48 h of
fasting, leptin blood levels are greatly reduced, blood triglycerides are elevated, blood triglycerides impair leptin transport
across the BBB contributing to peripheral leptin resistance and triglycerides cross the BBB to interfere with activation
of the leptin receptor, contributing to central leptin resistance33,93,98,99.

impairments. This lack of pathology in MCT8-deficient
mice is thought to be caused by the higher expression
of OATP1C1 in mice56,57. OATP1C1 favours the trans-
port of T4, but high levels of deiodinases in brain con-
vert T4 to T3. Mice lacking both MCT8 and OATP1C1
have delayed cerebellar development, reduced mye-
lination and other pathologies consistent with CNS
hypothyroidism56.
Interestingly, in humans, MCT8 deficiency results
in a very different clinical presentation from cretin-
ism, another form of thyroid deficiency that has roots
in maternal iodine deficiency126. Cretinism and MCT8
deficiency have many differences in disease course; for
example, cretinism results in maternal and fetal whole-​
body thyroid hormone deficiency, whereas MCT8
deficiency has a paradoxical stage during the perinatal
period of cerebral hyperthyroidism. Cerebral hyper­
thyroidism does not occur in MCT8-deficient mice that
also have a knockout of LAT2 (ref.127), suggesting that
LAT2 might be an important transporter of T3 in neo-
nates and might even be upregulated during this period
in the absence of MCT8.

NATURe RevIeWS | EndoCrinoLogy volume 15 | AUGUST 2019 | 451

Reviews
Box 4 | What controls feedback outside a negative feedback loop?
The concept of the negative feedback loop is central to classic endocrinology. Such a
loop results in the fine-​tuning of the levels of the effector hormone and the end point.
A classic example of a feedback loop is the relationship between glucose and insulin.
Insulin levels in blood increase when blood glucose levels rise, which results in glucose
levels returning to within the normal range. With the decrease in blood glucose levels,
the stimulus for insulin secretion is abated and blood insulin levels also return to
previous values.
Insulin has actions within the central nervous system (CNS), and there must also be
an optimal level of brain insulin. The actions of insulin in the brain are more mitogenic
than metabolic and are not coupled to its effects on blood glucose, thus there is a
dissociation in the control of end points. In other words, the optimization of blood
insulin levels for the control of blood glucose does not ensure that brain insulin levels
are optimized for its CNS functions. This theoretical dilemma exists for other hormones
that are totally, or mainly, produced in the periphery but have actions in the CNS
that are not connected to their peripheral feedback mechanisms, including leptin
and ghrelin.
Glucose and insulin. Impaired transport of glucose
and insulin across the BBB have each been proposed
as important factors in Alzheimer disease128. Impaired
transport of glucose across the BBB certainly results in
cognitive impairments, seizures and ketosis as exem-
plified by the GLUT1 deficiency syndrome129. Despite
having an elevated serum insulin level, patients with
Alzheimer disease have a decreased level of insulin
in the CSF as well as a decreased CSF:serum ratio for
insulin, suggestive of a defect in the BBB transport
of insulin130. Insulin resistance in the CNS, so-​called
type 3 diabetes mellitus, can occur independently of
peripheral insulin resistance131; indeed, the relationship
and interactions between these two spheres of insulin
resistance are largely unexplored (Box 4). Tine Sartorius
and colleagues132 have noted that in comparison with
young mice, aged mice have a delayed increase in cor-
tical brain activity after the peripheral, but not after the
central, administration of insulin, suggesting that an
impaired transport of insulin across the BBB could be
a contributor to CNS insulin resistance132.
Leptin and leptin resistance. The BBB is directly invol­
ved in peripheral leptin resistance and is indirectly
involved in central leptin resistance, thus contributing
to obesity, the metabolic syndrome and diabetes mellitus.
Leptin is secreted primarily by adipose cells and is trans-
ported across the BBB by a saturable system80,133. Leptin’s
rate of transport into the arcuate nucleus area of the
hypothalamus is particularly high but is also robust into
the hippocampus134. A loss of the anoretic effects of leptin
results in profound obesity in both rodents and humans
— leptin-​deficient mice at 10 months of age weigh more
than three times their leptin-​replete littermates, and
leptin-​deficient humans have BMIs in the low 50s135,136.
Leptin-​deficient humans and animals are exqui-
sitely sensitive to treatment with leptin. For example, 18
months of leptin replacement therapy resulted in BMI
levels decreasing from an average of 51.2 to 26.9 (ref.135).
Leptin deficiency is rare in humans, with cohorts of
individuals in Turkey135 and Paraguay137. Elevated blood
leptin levels in the face of obesity are common in humans
and can result from attenuated transport at the BBB,
resistance at the leptin receptor or deficits in signalling
452 | AUGUST 2019 | volume 15 www.nature.com/nrendo
downstream of the leptin receptor138–140. Resistance at
the BBB occurs early with the onset of obesity and likely
participates in a positive feedback-​loop-like fashion to
promote obesity.
The mechanisms underlying the development, pro-
gression and maintenance of obesity and leptin resist-
ance have been influenced by evolutionary pressures to
acquire excess calories and to retain them as fat. Wild-​
living adult primates have fat masses of ~6% of their
body weight141, which is about the same as seen in per-
sons with anorexia nervosa142. Hunter-​gatherers typically
have BMIs of ~19 (ref.143). In other words, the evolution-
ary struggle has been to acquire a caloric reserve to see
the individual through times when caloric acquisition
falls short of immediate requirements and not to avoid
obesity and its metabolic consequences.
These evolutionary pressures can be seen in the BBB
pharmacokinetic curves for leptin80,134. Leptin transport
across the BBB is saturable, which means that the rela-
tionship between serum and CNS leptin levels resem-
bles a hyperbolic curve. Where this hyperbolic curve is
linear, the blood concentrations of leptin are such that
they produce the greatest proportional increases in CNS
leptin levels. As blood leptin levels increase, the curve
flattens (loses linearity), which results in a smaller pro-
portion of blood leptin entering the CNS134,144. This loss
of linearity is the pharmacokinetic proximal cause and
an immediate cause of peripheral resistance to leptin.
The loss of linearity for both rodent brain levels of leptin
and human CSF levels of leptin occurs between 5 and
10 ng/ml (refs134,145), a level typically associated with
ideal body weight146. As such, leptin resistance is already
occurring in humans at levels of BMI that Western med-
icine has traditionally labelled ideal body weight, but not
at levels seen in wild-​living primates or hunter-​gatherers.
Thus, saturable transport at the BBB of a hormone
adds an additional level of potential resistance to that
of a classic resistance syndrome. In non-​barrier tissues,
receptor resistance can be addressed by increased pro-
duction of the hormone until either the response returns
to normal or hormone production reaches its max-
imum. However, when the hormone crosses the BBB
by a saturable mechanism, the BBB can act as a choke
point. Saturation of the transporter at the BBB limits
how much hormone can enter the brain, and that limit
can be insufficient to raise brain tissue levels to those
needed to overcome receptor resistance. In the case of
leptin, peripheral resistance is the term used to denote
the inability of the BBB to deliver sufficient amounts
of hormone to the brain to overcome brain receptor
(central) resistance.
Triglycerides are a cause of peripheral leptin resist-
ance, and elevation of triglycerides is the classic dyslipi-
daemia of the metabolic syndrome. Triglycerides (Fig. 3)
act at the brain endothelial cell barrier to decrease the
rate of leptin transport across the BBB, thus they are
capable of contributing to peripheral leptin resistance33.
Triglycerides are also transported across the BBB and
can act at the CNS leptin receptor to induce central
leptin resistance99. Thus, the BBB as either a target or
a conduit is involved in both peripheral and central
leptin resistance.
 Reviews

BBB transporter dysfunction and endocrine disease.
In summary, BBB transporter dysfunction occurs for a
wide range of substances including thyroid hormones,
glucose, insulin and leptin. Dysfunction of BBB trans-
porters results in changes in a wide range of symptoms,
including cerebral hypothyroidism, cognitive impair-
ment, metabolic dysfunctions and obesity. To date, the
clearest connections between BBB transporters and dis-
ease exist for substances the brain does not synthesize
or can synthesize only in limited amounts. The involve-
ment of the BBB in an endocrine disease might be due
to the primary loss of a transporter, as exemplified by
Allan–Herndon–Dudley syndrome, or as a downstream
event of the disease or condition that modulates the
transporter, as exemplified by hypertriglyceridaemia
and the metabolic syndrome.
Endocrine BBB and treatment of diseases
The multiple facets of the endocrine BBB that make it
vulnerable to being a target or a cause of endocrine dis-
ease also suggest roles for it in the treatment of endocrine
diseases. Clearly, the role of the BBB as a transporter of
hormones into the CNS, which allows the CNS to act as
an endocrine target tissue, presents many possibilities.
Phenylketonuria. Phenylketonuria results from a defec-
tive metabolism of the LNAA phenylalanine. The other
LNAAs share with phenylalanine a transporter across
the BBB, therefore an excess of circulating phenylalanine
results in both an increase in brain phenylalanine and a
decrease in brain levels of other LNAAs caused by com-
petitive inhibition147. CNS symptoms can arise both as
a result of toxic levels of phenylalanine and because of a
deficiency in neurotransmitter substrates. Although the
disease is typically treated with diets low in phenylala-
nine, several studies have advocated treating with a mix-
ture of LNAAs, which would both block phenylalanine
from crossing the BBB in high amounts and increase the
uptake of LNAAs that act as precursors to neurotrans-
mitters148,149. A similar strategy has also been advocated
for maple syrup urine disease, in which branched-​chain
LNAAs accumulate in the brain148.
Diabetes mellitus and insulin resistance. The poten-
tial merit of the delivery of FGFs to the brain for the
treatment of diabetes mellitus is clear from the work dis-
cussed above. Indeed, the discovery92 that when doses
of FGFs one-​tenth of an effective peripheral dose are
delivered into the brain they reverse (apparently per-
manently) mild to moderate levels of hyperglycaemia in
some models of moderate obesity shows the potential of
combining the endocrine brain and the endocrine BBB.
Modifications to transporters, theoretically exemplified
by the ability of α-​adrenergics to overcome peripheral
leptin resistance or triglycerides to enhance transport
of insulin and ghrelin, could enable increased access of
endogenous hormones to the CNS23,33,150.
Peripheral insulin resistance, impaired transport of
glucose and insulin across the BBB and central insulin
resistance are all implicated in Alzheimer disease. Dual
incretin receptor agonists (twincretins) directed at GLP1
and glucose-​dependent insulinotropic polypeptide that
can cross the BBB are able to improve peripheral glucose
control and improve the BBB transport of glucose151–153.
Whether they can affect CNS insulin resistance or affect
insulin transport across the BBB is yet to be published.
GLP1 has also been proposed to prevent diabetic disrup-
tion of the BBB by limiting the oxidative stress that arises
from the hyperglycaemic conditions31.
Conclusions
The BBB performs as both an endocrine target and an
endocrine secretory tissue. By selectively regulating the
exchange between the CNS and the blood of traditional
hormones as well as other informational molecules, the
BBB also allows the CNS to act as both an endocrine tar-
get and an endocrine secretory tissue. The BBB is a target
for some endocrine diseases and is an active participant
in the onset and promulgation of endocrine disease; as a
result, the BBB can also be key to the treatment of some
endocrine diseases. Finally, the view of the BBB as an
endocrine tissue expands the list of hormones to include
cytokines, lipids and even LPSs.
Published online 24 May 2019

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Competing interests
The author declares no competing interests.
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Reviewer information
Nature Reviews Endocrinology thanks B. Levin, D. Begley
and V. Prevot, and the other anonymous reviewers, for their
contribution to the peer review of this work.
volume 15 | AUGUST 2019 | 455