Download Multiple hypothalamic circuits sense and regulate glucose levels

Am J Physiol Regul Integr Comp Physiol 300: R47–R55, 2011.
First published November 3, 2010; doi:10.1152/ajpregu.00527.2010.
Review
Multiple hypothalamic circuits sense and regulate glucose levels
Mahesh Karnani and Denis Burdakov
Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
Submitted 12 August 2010; accepted in final form 28 October 2010
hypocretin; hypothalamus; neuron; orexin
ABOUT HALF A CENTURY AGO, subgroups of hypothalamic neurons
were found to show specialized excitatory or inhibitory firing
responses to extracellular glucose, revealing a strategy for how
the brain can directly monitor body energy status (3, 69, 70).
Glucose sensing in these glucose-excited and glucose-inhibited
neurons was not a general energy-related response, because
during examination of a large number of neurons in several
brain areas, glucose-responding cells were observed only in the
hypothalamus and brain stem, but not in other areas, such as
the thalamus or cortex (1, 60, 69, 70, 80, 83, 111). More recent
work suggests that glucose-sensing neurons may also be found
in substantia nigra (113). It is important to emphasize that the
effects of glucose on at least some of the glucose-sensing
neurons are fundamentally different form the general effects of
glucose on neuronal firing due to energy availability. While it
may be argued that glucose-excited neurons are simply a more
sensitive version of non-glucose-sensing neurons, which would
also be stimulated by glucose, especially if they are energy
depleted, glucose-inhibited neurons respond in the opposite
way to that expected from the general stimulatory fuel injection
effects of glucose, and their operation is thus clearly different
from a general energy-related effect. Glucose-sensing cells are
Address for reprint requests and other correspondence: D. Burdakov, Dept.
of Pharmacology, Univ. of Cambridge, Cambridge CB2 1PD, UK (e-mail:
[email protected]).
http://www.ajpregu.org
also found outside the brain, in tissues such as the endocrine
pancreas [glucose-excited ␤-cells and glucose-inhibited ␣-cells
(7, 81)] and the gut [glucose-excited L-cells (79)], but in this
review we will predominantly focus on a selection of recent
studies of glucose sensing in the hypothalamus. Our aim is not
to provide a comprehensive overview of mechanisms of glucose sensing in the brain and periphery, but to highlight key
findings and caveats in the recent work linking glucose sensing
to specific neurochemically defined hypothalamic neurons and
the implications of these findings for whole body glucose
homeostasis. For detailed discussions of the electrophysiological and molecular mechanisms of glucose sensing in the brain
and in peripheral glucose-sensing cells of the pancreas and the
intestine, readers are referred to other recent reviews (e.g., 6,
21, 40, 58, 54, 63, 81, 102). To put the subject into a more
general physiological perspective, we will begin with a brief
overview of the nature and sources of glucose changes in the
brain.
Physiological Fluctuations in Brain Glucose Levels
Simultaneous measurements of extracellular glucose levels
in blood and brain show that brain [glucose] is generally lower
than plasma [glucose], yet changes in blood [glucose] cause
rapid parallel changes in brain [glucose] (83, 92). A thorough
review of data on brain glucose levels (30) suggests that during
euglycemia, brain glucose levels are ⬃0.7–2.5 mM, and a
0363-6119/11 Copyright © 2011 the American Physiological Society
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Karnani M, Burdakov D. Multiple hypothalamic circuits sense and regulate
glucose levels. Am J Physiol Regul Integr Comp Physiol 300: R47–R55, 2011. First
published November 3, 2010; doi:10.1152/ajpregu.00527.2010.—The hypothalamus monitors body energy status in part through specialized glucose sensing
neurons that comprise both glucose-excited and glucose-inhibited cells. Here we
discuss recent work on the elucidation of neurochemical identities and physiological significance of these hypothalamic cells, including caveats resulting from the
currently imprecise functional and molecular definitions of glucose sensing and
differences in glucose-sensing responses obtained with different experimental
techniques. We discuss the recently observed adaptive glucose-sensing responses of
orexin/hypocretin-containing neurons, which allow these cells to sense changes in
glucose levels rather than its absolute concentration, as well as the glucose-sensing
abilities of melanin-concentrating hormone, neuropeptide Y, and proopiomelanocortin-containing neurons and the recent data on the role of ventromedial hypothalamic steroidogenic factor-1 (SF-1)/glutamate-containing cells in glucose homeostasis. We propose a model where orexin/hypocretin and SF-1/glutamate
neurons cooperate in stimulating the sympathetic outflow to the liver and pancreas
to increase blood glucose, which in turn provides negative feedback inhibition to
these cells. Orexin/hypocretin neurons also stimulate feeding and reward seeking
and are activated by hunger and stress, thereby providing a potential link between
glucose sensing and goal-oriented behavior. The cell-type-specific neuromodulatory actions of glucose in several neurochemically distinct hypothalamic circuits
are thus likely to be involved in coordinating higher brain function and behavior
with autonomic adjustments in blood glucose levels.
Review
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HYPOTHALAMIC GLUCOSE SENSING
Glucose-Sensing Capabilities of Neurochemically Defined
Hypothalamic Neurons
The lateral hypothalamus. Most recent work focused on
lateral hypothalamus (LH) cells that contain the peptide transmitters orexins/hypocretins, which are not expressed anywhere
else in the brain (29, 86). Orexin/hypocretin-containing neurons project widely throughout the brain, with especially dense
innervation of regions regulating arousal, metabolism, and
reward (75). Lack of orexins/hypocretins produces the symptoms of narcolepsy/cataplexy, hypophagia, hypoactivity, and
late onset obesity (23, 42). Orexin/hypocretin neurons are most
active during wakefulness and almost silent during slow-wave
AJP-Regul Integr Comp Physiol • VOL
sleep (32, 52). Several lines of evidence indicate that the
activity of orexins/hypocretin neurons promotes wakefulness,
sympathetic outflow, exploratory locomotor activity, reward
seeking, and food consumption (13, 14, 44, 53, 91, 97, 99, 100,
109). Interestingly, recent studies also suggest that underactivity and overactivity of the orexin/hypocretin system could be
linked to depression and anxiety, respectively (16, 17, 47, 98).
Whole animal studies looking at genetic markers of neuronal
activation and orexin/hypocretin mRNA expression following
in vivo manipulation of glucose levels concluded that orexin/
hypocretin neurons are activated by systemic hypoglycemia
(22, 61, 86) and could thus be glucose inhibited, especially
considering that they are not directly modulated by insulin
(110). During initial cellular level investigations of the effects
of glucose on rat LH neurons, it was found that orexin-A/
hypocretin-1 was not present in glucose-inhibited neurons (55);
and a more recent electrophysiological study also failed to
elicit responses to glucose in rat orexin/hypocretin neurons
(71). In contrast, at least three different groups independently
reported acute inhibition of orexin/hypocretin neurons by glucose, using calcium imaging in rat orexin/hypocretin neurons
(65), or whole cell patch-clamp recordings from isolated
mouse orexin/hypocretin cells (110), or mouse orexin/hypocretin cells in brain slices (41, 108).
The published discrepancies in the ability of glucose to
inhibit orexin/hypocretin neurons could, in theory, be related to
species differences (more responsive in the mouse, less responsive in the rat), which remain to be investigated in detail. If the
rat orexin/hypocretin neurons are not electrically responsive to
glucose, as suggested by the data in Ref. 71, then the calcium
imaging data, which do show glucose-induced drops in calcium concentration in ⬃ 50% of rat orexin/hypocretin neurons
(65), would suggest a possible dissociation between biochemical and electrical effects of glucose in these cells in the rat. As
an alternative to the species differences explanation, the reported absence of acute glucose responses in orexin/hypocretin
neurons in cytosol-sparing (cell-attached or perforated patch)
recordings (71), but their presence in whole cell recordings (19,
110), could in theory be explained by a currently unidentified
cytosolic factor, which suppresses the glucose-sensing ability
of these cells in in vitro preparations, but whose influence is
removed in the whole cell configuration due to the exchange of
solution between the cytosol and the pipette in this recording
mode.
The mechanism of glucose-induced inhibition of mouse
orexin/hypocretin cells is not well understood but involves
activation of background K⫹ channels (reviewed in Ref. 20).
Interestingly, the glucose responses of orexin/hypocretin cells
display a unique sugar selectivity, which suggests that the
sensing pathway in orexin/hypocretin cells may be distinct
from pathways involving glucose-binding proteins such as
GLUT2, hSGLT3, and SGLT1 (39). The glucose responses of
orexin/hypocretin neurons are also insensitive to glucokinase
inhibitors and cannot be mimicked by the intracellular ATP or
extracellular lactate, suggesting that they do not require conventional glucose-metabolizing machinery (39, 40).
Interestingly, at physiological temperatures, ⬃70% of orexin/
hypocretin cells exhibit only transient, or adaptive, responses to
sustained physiological rises in glucose levels (Fig. 1). Importantly, this allows orexin/hypocretin neurons to adjust their
baseline potential to background glucose levels, and thus to
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maximum of ⬃5 mM may be reached under severe plasma
hyperglycemia. In turn, plasma hypoglycemia can cause the
brain glucose to fall to 0.2– 0.5 mM. This triggers counterregulatory responses where pancreatic glucagon and adrenal catecholamine secretion, as well as hepatic glucose production, are
stimulated through activation of sympathetic nerves. Apart
from the counterregulatory responses, which are orchestrated
by glucosensors in both the brain and periphery (58, 85),
hypoglycemia also induces feeding in mammals [glucoprivic
feeding (93)]. Glucoprivic feeding has been recently suggested
to involve glucose-sensing neurons in the ventromedial hypothalamus (VMH), since it was reduced by blockade of VMH
glucokinase, a critical molecular component of some glucosesensing neurons (31).
Although brain glucose levels are generally lower than those in
the blood, it is commonly assumed that glucose concentrations
can approach those in the blood at circumventricular organs, areas
where the blood-brain barrier is highly permeable, such as the
median eminence in the hypothalamus (35). However, it has
recently been shown that this does not necessarily apply to brain
structures in close vicinity, such as the arcuate nucleus (ARC)
(31), perhaps because of tanycyte barriers separating the ARC
from the median eminence (64, 74).
Generally speaking, a meal will increase blood glucose and
thus also brain glucose, but the extent to which this happens
depends on the food. The potency of foods to increase blood
glucose is measured as the glycemic index (48), and a major
factor affecting this is the macronutrient composition of the
food. In particular, meals high in protein or fat generally have
a low glycemic index, i.e., they elevate blood glucose less than
carbohydrate-rich meals. Another source of blood glucose is
the endogenous production of glucose by the liver, which is
also under hypothalamic control as reviewed below. Hepatic
glucose production is controlled by the pancreatic hormones
insulin and glucagon as well as, but to a lesser extent, directly
by autonomic innervation (77). Insulin and parasympathetic
innervation increase hepatic glucose uptake and glycogen synthesis, whereas glucagon and sympathetic innervation promote
glycogenolysis, gluconeogenesis, and glucose release. Blood
glucose is also affected by glucose uptake into muscle and
adipose tissue, both of which are increased by insulin and
sympathetic innervation (67). Below, we will first discuss the
neurochemical identities and functional features of glucosesensing hypothalamic neurons, and then focus on recent studies
suggesting that they are key regulators of sympathetic drive
that controls uptake and release of glucose in peripheral tissues.
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HYPOTHALAMIC GLUCOSE SENSING
continue to respond to changes in glucose levels independently
of the glucose baseline (Fig. 1). We propose that, by analogy
with classical sensory organs such as the eye, this adaptation
allows orexin/hypocretin neurons to adjust their glucose sensitivity to background glucose levels (108). In other words, the
glucose dose-response curve of orexin/hypocretin cells is not
fixed, but can slide along the glucose concentration axis depending on the glucose baseline. Analysis of membrane currents and membrane resistance during the glucose adaptation
response of orexin/hypocretin cells suggests that the cellular
mechanism of this adaptation involves a time-dependent closure of the hyperpolarizing ion channels originally opened by
glucose, rather than opening of an additional population of
depolarizing channels (108). How these channels become less
active with time after they are opened by glucose is currently
unknown, but this process is highly temperature sensitive [very
slow or undetectable at room temperature but prominent at
35°C (108)]. This steep temperature sensitivity is consistent
with a process involving internalization/endocytosis of the
glucose-activated channels and/or putative glucose receptors;
AJP-Regul Integr Comp Physiol • VOL
this possibility, as well as alternative explanations (e.g., phosphorylation-induced desensitization), remain to be examined.
Because orexin/hypocretin neurons are thought to stimulate
wakefulness and signal reward deficiency, their inhibition by
glucose may, in theory, be involved in anxiolytic, rewarding,
and soporific effects of sugar ingestion (reviewed in Ref. 18),
as well as in the regulation of blood glucose levels (see
Hypothalmic Glucose-Sensing Neurons as Regulators of Peripheral Glucose Handling). In terms of arousal and reward,
there is a theory that proposes a functional separation of the
orexin/hypocretin system into a lateral population that regulates reward and a medial population that regulates arousal
(43). At least in the mouse, inhibition of orexin/hypocretin
cells by glucose does not appear to follow such a clear
topographic separation; the glucose responses are observed in
most if not all orexin/hypocretin cells across both lateral and
medial parts of the lateral hypothalamic area, suggesting that
glucose may affect both arousal and reward-related parts of the
orexin/hypocretin system (108). However, analysis of the time
course of glucose responses in mouse hypothalamus suggests
that the medial group of orexin/hypocretin cells contains a
greater proportion of adaptive orexin/hypocretin neurons than
the lateral group (108). It is thus tempting to speculate that
adaptive and nonadaptive glucose-sensing responses may be
differentially involved in arousal or reward.
Another population of widely projecting lateral hypothalamic cells use the peptide transmitter melanin-concentrating
hormone (MCH) (10). Although, like orexins/hypocretins,
MCH is often considered an appetite-promoting transmitter, in
many other respects the physiological roles of MCH neurons
appear to be the opposite of those of orexin/hypocretin cells. In
mice, knockout of MCH increases energy expenditure and
reduces body weight (88), and these characteristics are also
seen in animals lacking the MCH receptor -1 (MCH1R) (57).
Central injection of MCH in rats increases the quantities of
rapid eye movement and especially slow-wave sleep (106),
while deletion of MCH or MCH1R in mice leads to increased
wheel-running activity (115). These data suggest that endogenous MCH promotes sleep and suppresses locomotor activity
and energy expenditure, i.e., the opposite of actions of orexins/
hypocretins. It should be noted that, while MCH neurons are
often referred to as appetite promoting, their role in the control
of food intake is not entirely clear cut. For example, in mice,
knockout of MCH increases food intake during the day but
decreases it at night with the net daily result being a reduction
in food intake (88). Although most (57, 78, 82), but not all
(76), studies show that brain injections of MCH increase food
intake, mice lacking the MCH receptor actually exhibited
increased food intake (24, 57). Feeding-related effects of MCH
thus appear to be complex, and may be influenced by its
possible roles in anxiety and depression (15, 37). A closely
related issue, which remains to be resolved, is whether MCH
neurons are a functionally homogenous population or comprise
subsets of cells with different profiles of ion channels and
receptor expression and differential projection patterns, giving
rise to several different behavioral roles, as recently proposed
for orexin/hypocretin neurons (43).
Examination of the effects of changes in glucose on the
electrical excitability of MCH neurones using whole cell recordings in mouse brain slices suggests that most MCH neurones are directly and dose-dependently depolarized and ex300 • JANUARY 2011 •
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Fig. 1. Adaptive glucose-sensing in orexin/hypocretin neurons. A: identification of an orexin/hypocretin neuron in a mouse brain slice by postrecording
immunocytochemistry (left, orexin cell labelled with Neurobiotin is arrowed;
right, the same arrowed cell is labelled with an orexin-A antibody). Scale
bar ⫽ 50 ␮m; both images are shown at the same magnification. B: a mouse
orexin/hypocretin cell is transiently inhibited by glucose but then adapts its
membrane potential back to baseline despite the continuing presence of
elevated glucose. C: this adaptation allows an orexin/hypocretin cell to respond
to a second change in glucose levels. (Composited from Figs. 1, 4, and 5 of
Ref. 108 with permission from Proc Natl Acad Sci USA).
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AJP-Regul Integr Comp Physiol • VOL
excited cells, are GABAergic; however, the GABAergic
marker GAD is not expressed in a clear relationship to glucosesensing capacity (49, 59). Recent data show that most VMH
neurons express a protein called steroidogenic factor-1 (SF-1)
and that SF-1-expressing neurons have key roles in glucose
homeostasis (103, 114). However, how SF-1 expression relates
to glucose-excited and glucose-inhibited neurons of the VMH
is currently unclear, although there is some interesting recent
data that indirectly suggest that some of the glucose-inhibited
VMH neurons may express SF-1 and glutamate (see discussion
at the end of Hypothalmic Glucose-sensing Neurons as Regulators of Peripheral Glucose Handling). Perhaps the most
critical issue to resolve here is how gene expression and
glucose-sensing identities of VMH neurons relate to their
projection targets, since there is emerging evidence that different subregions of the VMH are differentially connected to
other key feeding centers, such as the ARC (96).
Need for Better Functional and Molecular Markers of
Glucose Sensing
After glucose sensing has been linked to specific populations
of vital neurons described above, more and more researchers
have moved into this field, creating an increasing demand for
clear criteria for classifying neurons as glucose excited and
glucose inhibited. In terms of functional experiments, a key
source of uncertainty stems from the fact that glucose is used
as an energy fuel by all neurons, either directly or indirectly by
stimulating lactate production by astrocytes (71, 73). Thus,
experimental alterations of glucose levels can often elicit
general energy-related and/or neuroprotective responses that
are unrelated to specific glucose sensing. An example of this is
silencing of neurons by very low glucose, which is a widespread response found in both glucose-sensing and non-glucose-sensing neurons and often involving neuroprotective
opening of ATP-inhibited K (KATP) channels, and consequent
hyperpolarization, induced by the fall in glucose (and thus
cytosolic ATP) levels (9, 60). Although in glucose-excited
neurons the hyperpolarization induced by 0 mM glucose is
likely to be much faster than in non-glucose-sensing neurons,
and thus the speed of hyperpolarization has been used by some
researchers to identify glucose-sensing cells, this criterion can
be very sensitive to experimental variables such as location of
cells in the recording chamber and in the tissue (for brain slice
recording). For these reasons, a more robust, and more physiological, criterion for classifying a glucose-excited neuron as
glucose sensing would perhaps be a test of whether its firing
can be significantly affected by changes in extracellular glucose in the physiological glucose range in the brain, e.g., 1 to
2.5 mM (83), although there is currently no agreement on how
large the effects on firing should be to pass this qualifying test.
As mentioned in the introduction, the functional definition of
glucose-inhibited neurons is much more clear, because their
membrane potential responses to glucose occur in the opposite
direction (hyperpolarization) from the general energy-related
effects of glucose (depolarization).
In terms of molecular definitions of brain glucose-sensing
cells, no molecules unique to glucose-sensing cells have yet
been identified. Several markers of glucose-sensing ability
have been proposed, including KATP channels, glucokinase,
AMP kinase, and the GLUT2 transporter (25, 101, 111), but
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cited by glucose within the physiological concentration window (19). Based on the above-mentioned effects of MCH on
locomotor activity and body energy balance, these data imply
that glucose-induced excitation of MCH neurones may promote sleep and suppress energy expenditure. To the best of our
knowledge, the glucose-sensing abilities of MCH neurons have
not yet been examined in species other than mouse or with
different recording techniques.
ARC of the hypothalamus. This hypothalamic region is
currently probably the best understood in terms of the control
of appetite and metabolism. The generally accepted model is
that the ARC of the hypothalamus, neuropeptide Y (NPY)
neurons promote weight gain by stimulating appetite and
suppressing energy expenditure, whereas ARC proopiomelanocortin (POMC) neurones cause weight loss by inhibiting
feeding and stimulating energy expenditure (26, 87). A key
feature of this model is that NPY and POMC neurons are
oppositely regulated by signals of body energy status, such as
leptin (26 –28, 87, 105). Whether the NPY and POMC neatly
correspond to glucose-inhibited and glucose-excited neurons,
respectively, which would fit in nicely into the above model, is
still debated. For example, Muroya et al. (66) concluded that
94% of ARC cells that decreased their calcium levels in
response to glucose were immunoreactive for NPY. Whole cell
patch-clamp recordings also indicated that a significant proportion (40%) of NPY neurons are glucose inhibited (34). But,
in contrast, perforated patch recordings of Claret et al. (25)
failed to show inhibitory effects of glucose on NPY cells.
These discrepancies appear to show a similar methodology
correlation to discrepancies in the studies of orexin/hypocretin
neurons noted above: in both NPY and orexin/hypocretin cells,
glucose-induced inhibition appears to be readily observed in
whole cell recordings but, paradoxically, not in the less invasive perforated patch recordings. Interestingly, for arcuate
glucose-excited POMC neurons, the differences in the literature appear to follow the opposite methodology correlation.
Specifically, Fioramonti et al. (34) did not observe any glucose
responses in most POMC neurons when using the cytosoldisrupting whole cell recordings. In contrast, using the cytosolpreserving loose patch or perforated patch recordings shows
that the majority of POMC neurons are excited by glucose in
the physiological concentration range (25, 46, 72). We would
like to propose that the operation of glucose-excited neurons
requires a highly diffusible cytosolic messenger [presumably
ATP (59), but see Ref. 2] and can thus be particularly easily
disrupted especially in small cells by experimental techniques
that wash out the cytosol (such as the whole cell recording with
large-tipped pipettes). In contrast, glucose-inhibited neurons
use a completely different (but as yet undetermined) intracellular signaling pathway (see Refs. 39 and 40), and we would
like to speculate that this pathway is boosted in whole cell
recordings, possibly due to diffusion of a suppressor substance(s) away from cytosol into the pipette.
Ventromedial nucleus of the hypothalamus. This hypothalamic area is probably the most studied in terms of brain
glucose sensing and has long been known to contain both
glucose-excited and glucose-inhibited neurons. However, in
terms of neurochemistry of glucose sensing, the ventromedial
nucleus of the hypothalamus (VMH) is currently understood
much less than the ARC and LH. Single cell gene expression
analysis suggests that some VMH neurons, including glucose-
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HYPOTHALAMIC GLUCOSE SENSING
the correlation between the expression of these proteins and the
brain locations of glucose-sensing neurons is imperfect (5, 49,
50). For glucose-inhibited neurons, the need for molecular
markers is particularly critical since even the final effector
channels remain to be defined in exact molecular detail (20). It
is probably accurate to say that it is currently unknown exactly
what makes glucose-sensing neurons distinct from other neurons at the molecular level.
Hypothalamic Glucose-Sensing Neurons as Regulators of
Peripheral Glucose Handling
AJP-Regul Integr Comp Physiol • VOL
direct infusion of orexin-A/hypocretin-1 into the medial hypothalamus. This was interpreted as simultaneous increase in
glucose utilization and production, since it was also observed
that glucose uptake by muscle was increased. Orexins/hypocretins promoted glucose uptake and insulin-dependent glycogen synthesis in skeletal muscle by a mechanism involving
␤2-adrenoreceptors on non-myocyte cells of skeletal muscle,
suggesting that orexin/hypocretin cells could activate this
mechanism through sympathetic nerves.
Based on these studies, it can be concluded that at least some
of the orexin/hypocretin neurons control key peripheral mediators of glucose homeostasis via the sympathetic nerves. It
remains to be examined whether some subsets of orexin/
hypocretin neurons [for example, medial vs. lateral (43)] are
more important for this. We propose that these findings (90,
112) could mean that the activity of orexin/hypocretin neurons
promotes shuttling of glucose from liver to muscle, as would
be useful in foraging that is thought to be stimulated by the
orexin/hypocretin system (110). Thus, it is possible that the
glucose inhibition of orexin/hypocretin cells provides negative
feedback in a circuit that consists of orexin/hypocretin cells,
sympathetic nerves, the pancreas, and the liver (Fig. 2). Since
MCH cells decrease heart rate and thermogenesis via the
sympathetic nervous system (8) and glucose increases their
activity (19), they might also be involved in this putative
feedback loop. It is noteworthy that MCH neurons also project
polysynaptically via the sympathetic ganglia to the adrenal
medulla, white and brown adipose tissue, and the liver (51, 68,
95). However, to the best of our knowledge, it is not yet known
Fig. 2. Hypothetical model integrating the physiological roles of glucoseinhibited lateral hypothalamus (LH) and ventromedial hypothalamus (VMH)
neurons (see text for details). Arrows indicate stimulation (or increased levels),
t-bars show inhibition. VTA, ventral tegmental area; LC, locus coeruleus;
TMN, hypothalamic tuberomammillary nucleus; CRF, corticotropin-releasing
factor; SF-1 steroidogenic factor-1.
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Although ARC neurons send signals to key central and
peripheral regulators of energy balance (95, 62), the roles of
glucose sensing in the POMC and NPY cells in glucose
homeostasis remain somewhat unclear, despite recent attempts
to inactivate NPY/POMC glucosensing through targeted genetic manipulations [(25, 72), but see discussion in Refs. 54
and 40]. In orexin/hypocretin and MCH neurons, an equivalent
analysis has not been performed due to the lack of knowledge
of molecular components of glucose sensing in these cells (19,
20, 38). However, the original study by Yamanaka et al. (110)
that described the intrinsic inhibitory responses of orexin/
hypocretin cells to glucose also observed a lack of fastinginduced stimulation of arousal in mice lacking orexins/hypocretins, suggesting that disinhibition of orexin/hypocretin cells
by falling glucose may have a role in the initiation of foraging.
In this section, we will not discuss the involvement of glucosesensing neurons in behavior and higher brain function further
but instead discuss recent findings on their interactions with
peripheral tissues relevant to glucose homeostasis, focusing in
particular on recent work on control of glucose homeostasis by
LH orexin/hypocretin neurons and VMH SF-1 neurons.
As reviewed in Refs. 33 and 104, orexin/hypocretin neurons
can control basal metabolic rate in addition to alertness and
reward seeking. Intracerebroventricular administration of orexinA/hypocretin-1 increases energy expenditure even in anaesthetized rats (107). A number of experiments (4, 89) showed that
intracerebroventricular or intrathecal administration of orexin/
hypocretin stimulates sympathetic outflow and increases
plasma epinephrine and norepinephrine levels. Anatomical
data employing pseudorabies virus transsynaptic tract tracing
(36, 51, 95) or electron microscopy and cholera toxin B subunit
tracing (56), show that orexin/hypocretin cells project polysynaptically to various sympathetic outflow systems. Two recent
papers have demonstrated the potential physiological significance of these findings in relation to glucose homeostasis.
The data of Yi et al. (112) suggested that orexin/hypocretin
neurons, especially those in the perifornical area, can stimulate
endogenous glucose production and increase blood glucose
through sympathetic nervous control. They retrodialyzed bicuculline into the LH and found that orexin/hypocretin neurons
were specifically activated in the perifornical area. This led to
stimulation of hepatic glucose production, which was inhibited
by intracerebroventricular pretreatment with an orexin/hypocretin receptor antagonist. An increase in endogenous glucose
production was also induced by intracerebroventricular injection of orexin-A/hypocretin-1, and this increase was inhibited
by hepatic sympathetic denervation.
On the other hand, Shiuchi et al. (90) found no change in
blood glucose, but increase in glucose turnover rate, upon
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Perspectives and Significance
Many glucose-sensing neurons of the hypothalamus have
now been assigned neurochemical identities and are beginning
to be linked to specific higher and lower functions of the
nervous system (Fig. 2). Most, if not all, of the glucose-sensing
neurons of the hypothalamus are well placed to affect peripheral glucose utilization in liver, muscle, and adipose tissue
through the autonomic nervous system (Fig. 2). This might
give a general rationale for their ability to sense changes in
glucose levels as a feedback regulation of their control of these
organs. Our hypothesis would predict that glucose-excited
neurons inhibit sympathetic input to key peripheral regulators
of glucose homeostasis, whereas glucose-inhibited neurons
would stimulate it. It remains a challenge to find molecular
markers and mechanisms that are unique to glucose-sensing
cells. In our view, this is one of the key current obstacles in
assessing the relative importance of the multiple circuits involved in hypothalamic glucose sensing and in investigating
how specific features of brain glucose-sensing cells, such as its
adaptive time course in some neurons (Fig. 1), relate to the
regulation of glucose homeostasis and behavior.
GRANTS
Work in the authors’ laboratory has been funded by the European Research
Council (FP7). M. Karnani was also supported by the Osk. Huttunen Foundation.
AJP-Regul Integr Comp Physiol • VOL
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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