hypothalamic-autonomic control of energy homeostasis
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BioquimicaTRANSCRIPT
REVIEW
Hypothalamic-autonomic control of energy homeostasis
Patricia Seoane-Collazo1,2• Johan Fernø1,3
• Francisco Gonzalez4,5•
Carlos Dieguez1,2• Rosaura Leis6
• Ruben Nogueiras1,2• Miguel Lopez1,2
Received: 23 December 2014 / Accepted: 6 June 2015
� Springer Science+Business Media New York 2015
Abstract Regulation of energy homeostasis is tightly
controlled by the central nervous system (CNS). Several
key areas such as the hypothalamus and brainstem receive
and integrate signals conveying energy status from the
periphery, such as leptin, thyroid hormones, and insulin,
ultimately leading to modulation of food intake, energy
expenditure (EE), and peripheral metabolism. The auto-
nomic nervous system (ANS) plays a key role in the
response to such signals, innervating peripheral metabolic
tissues, including brown and white adipose tissue (BAT
and WAT), liver, pancreas, and skeletal muscle. The ANS
consists of two parts, the sympathetic and parasympathetic
nervous systems (SNS and PSNS). The SNS regulates BAT
thermogenesis and EE, controlled by central areas such as
the preoptic area (POA) and the ventromedial, dorsome-
dial, and arcuate hypothalamic nuclei (VMH, DMH, and
ARC). The SNS also regulates lipid metabolism in WAT,
controlled by the lateral hypothalamic area (LHA), VMH,
and ARC. Control of hepatic glucose production and pan-
creatic insulin secretion also involves the LHA, VMH, and
ARC as well as the dorsal vagal complex (DVC), via
splanchnic sympathetic and the vagal parasympathetic
nerves. Muscle glucose uptake is also controlled by the
SNS via hypothalamic nuclei such as the VMH. There is
recent evidence of novel pathways connecting the CNS and
ANS. These include the hypothalamic AMP-activated
protein kinase–SNS–BAT axis which has been demon-
strated to be a key modulator of thermogenesis. In this
review, we summarize current knowledge of the role of the
ANS in the modulation of energy balance.
Keywords Hypothalamus � Autonomic nervous system �Energy balance
Introduction
Energy homeostasis is crucial to the maintenance of health
in an organism and is precisely controlled by the central
nervous system (CNS) which receives and integrates sig-
nals of energy status from the periphery and in response
modulates food intake and energy expenditure (EE) [1–5].
In conditions such as obesity and its comorbidities, an
imbalance in these signals can occur, weakening the
counterregulation that controls energy status [6]. Thus,
& Patricia Seoane-Collazo
& Miguel Lopez
1 NeurObesity Group, Department of Physiology, CIMUS,
University of Santiago de Compostela-Instituto de
Investigacion Sanitaria, 15782 Santiago de Compostela,
Spain
2 CIBER Fisiopatologıa de la Obesidad y Nutricion
(CIBERobn), 15706 Santiago de Compostela, Spain
3 Department of Clinical Science, K. G. Jebsen Center for
Diabetes Research, University of Bergen, 5021 Bergen,
Norway
4 Department of Surgery, CIMUS, University of Santiago de
Compostela-Instituto de Investigacion Sanitaria,
15782 Santiago de Compostela, Spain
5 Service of Ophthalmology, Complejo Hospitalario
Universitario de Santiago de Compostela,
15706 Santiago de Compostela, Spain
6 Unit of Investigation in Nutrition, Growth and Human
Development of Galicia, Pediatric Department (USC),
Complexo Hospitalario Universitario de Santiago (IDIS/
SERGAS), Santiago de Compostela, Spain
123
Endocrine
DOI 10.1007/s12020-015-0658-y
obesity is characterized by a positive energy balance and
increased fat mass which ultimately triggers coronary dis-
ease, type II diabetes, non-alcoholic hepatic steatosis, bil-
iary disease, and certain types of cancer [6–8]. On the other
hand, cancers and diseases such as rheumatoid arthritis
may cause a negative energy balance and cachexia, leading
to a marked reduction in body weight and higher mortality
due to tissue wasting [9–12].
The autonomic nervous system (ANS) innervates and
regulates metabolic organs and plays an important role in
physiological responses to endogenous and exogenous
stimuli. The ANS consists of two parts, the sympathetic
nervous system (SNS) and the parasympathetic nervous
system (PSNS) [13–16]. Traditionally, the SNS has been
associated with catabolic responses and the PSNS with
anabolic responses [14–17]. Under some physiological
circumstances, both the SNS and PSNS can be activated or
inhibited at the same time, but usually when one is acti-
vated the other is inhibited [18]. Adipose tissue is known to
be innervated by the SNS, whereas PSNS innervation to
some fat depots is still controversial [19, 20]. The liver and
pancreas are innervated by splanchnic sympathetic and
vagal parasympathetic nerves [14, 21–23], while skeletal
muscle also receives both sympathetic and parasympathetic
innervation [18].
Autonomic modulation of adipose tissue: BATthermogenesis versus WAT lipolysis
Adipose tissue is a key regulator of energy homeostasis and
can be classified into two types: (1) brown adipose tissue
(BAT), a specialized tissue that dissipates energy in the
form of heat through non-shivering thermogenesis (NST),
and (2) white adipose tissue (WAT), traditionally associ-
ated with energy storage but for the last two decades also
recognized as an important endocrine tissue [24–26].
Autonomic modulation of BAT thermogenesis
BAT is a specialized tissue responsible for heat production
through NST. Physiological activation of BAT occurs
when the organism needs extra heat, but BAT can also be
activated in response to particular diets [26–29]. Until
recently, BAT was considered to be important only in
small or hibernating mammals and in newborn humans.
Recent studies have challenged that view by using positron
emission and computed tomographic (PET-CT) scans to
identify functional BAT in adult humans [30–33], and BAT
is now recognized as a potential target organ in the treat-
ment of obesity [27, 28, 34]. In rats, there are several
brown fat pads: cervical, mediastinal, perirenal, and peri-
cardial, as well as interscapular BAT which is the principal
BAT depot in rodents [26–28, 35]. In addition, brown
adipocytes are found in WAT, a phenomenon known as
‘browning’ [36–38]. All BAT depots receive sympathetic
innervation, but only mediastinal and pericardial BAT
appears to receive parasympathetic innervation [36, 39].
The CNS is able to control BAT function via the ANS.
BAT is activated by increased firing rate in sympathetic
nerves, which leads to the release of noradrenaline (NA)
and activation of BAT b-adrenergic receptors, mainly b3-
receptors [26–29]. Activation of adrenergic receptors trig-
gers cAMP production by adenylyl cyclase and subsequent
activation of protein kinase A (PKA) and p38 MAPK
kinase pathways which increase gene expression of
uncoupling protein 1 (UCP1) [26–28]. Several regions of
the spinal cord, brainstem, midbrain, and forebrain have
been found to innervate pre-autonomic neurons that control
ANS afferents in BAT.
Viruses such as pseudorabies and herpes simplex virus-
1, which spread in a directed manner via synaptically
connected neurons [40], have been used to trace CNS
neuronal connectivity with BAT. By the injection of a
transneuronal viral tract tracer in the interscapular BAT of
Siberian hamsters, Bamshad et al. were able to infect
neurons in the medial preoptic area (MPOA), paraven-
tricular (PVH), ventromedial (VMH), and suprachiasmatic
(SCN) nuclei of the hypothalamus, as well as the lateral
hypothalamic area (LHA), suggesting a neuronal connec-
tion between BAT and these hypothalamic areas [41].
Oldfield et al. obtained comparable results in rats using the
same technique. They found cocaine- and amphetamine-
regulated transcript (CART)- and proopiomelanocortin
(POMC)-expressing neurons in the lateral arcuate nucleus
(ARC), and melanin-concentrating hormone (MCH)- and
orexin-expressing neurons in the LHA to be infected [42].
Thus, several hypothalamic nuclei are associated with the
regulation of BAT NST, as will now be discussed.
The VMH was the first hypothalamic site to be identified
as important in thermoregulation by BAT. Electrical
stimulation of VMH increased interscapular BAT temper-
ature, an effect that was abolished by b-adrenergic block-
ade [43–45]. VMH neurons are known to exert some of
their functions through SNS activation, with steroidogenic
factor 1 (SF1)-expressing neurons projecting from the
VMH to autonomic centers, e.g., the parabrachial nucleus,
locus ceruleus (LC), and retrotrapezoid nucleus, as well as
the C1 catecholamine cell group of the rostral ventrolateral
medulla (RVLM) and the nucleus of the solitary tract
(NTS). These neuronal fibers also reach other hypothala-
mic regions involved in sympathetic outflow, including the
ARC and PVH [46]. In this context, a VMH-specific
knockdown of SF1 reduced EE and BAT UCP1 expression
in mice [47]. The VMH is also connected to other brain-
stem regions linked to the regulation of BAT NST, such as
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123
the raphe pallidus (RPa) and inferior olive (IO) [28, 29, 48,
49]. Activation of BAT NST can be modulated in the VMH
by glutamate, hydroxybutyrate, NA, serotonin and trypto-
phan [50–52], and by peripheral hormones. Recent evi-
dence from our group has revealed molecular mechanisms
by which the VMH controls BAT NST. These data point
toward a key role for AMP-activated protein kinase
(AMPK) in the VMH, as a negative regulator of BAT
activation via the SNS, integrating diverse peripheral sig-
nals such as thyroid hormones (THs), estradiol (E2), leptin,
and bone morphogenetic protein 8B (BMP8B), and drugs
such as nicotine and liraglutide [53–58]. We have therefore
named this canonical mechanism the AMPK (VMH)–
SNS–BAT axis. It is not yet known whether other
peripheral hormones, such as fibroblast growth factor 21
(FGF21) [59] or amylin [60, 61], act in the same axis. In
this context, alterations in hypothalamic lipid composition,
in particular ceramides, have been shown to induce endo-
plasmic reticulum (ER) stress, leading to a reduction in
SNS firing and NST, and thus to weight gain [62].
The RPa and IO are also important players in the regu-
lation of NST and are under the control of the dorsomedial
nucleus of the hypothalamus (DMH). The DMH is known
as a key site in the control of feeding and metabolic regu-
lation, as well as body temperature through NST [63, 64].
However, neurons of the DMH do not project directly to
sympathetic pre-ganglionic neurons in the spinal cord, but
instead send monosynaptic projections to the RPa, which
mediates the effects of DMH neurons on BAT activity [65].
Thus, the disinhibition of neurons in the DMH activates
glutamate receptors in the RPa, triggering BAT sympathetic
activation and NST [65]. Parallel evidence suggests that the
IO also has a role in SNS control of BAT and that this
nucleus is also involved in the functional interactions
between the motor and thermoregulatory systems via the
DMH [27, 49]. Recent studies have shown another possible
mechanism, in which BAT NST is modulated via leptin
receptors [66, 67] or neuropeptide Y (NPY) [68] in the
DMH. Thus, leptin receptors in the DMH mediate the
thermogenic response to hyperleptinemia in obese animals
by increasing sympathetic nerve activity, which leads to
increased EE by BAT [66]. In addition, activation of leptin
receptor-expressing neurons in the DMH is sufficient to
increase EE and regulate body weight [69]. Recently, it was
found that knocking down NPY in the DMH leads to an
increase in interscapular BAT and inguinal WAT (iWAT)
UCP1 levels and stimulates the formation of brown adipo-
cytes in iWAT, promoting a rise in NST and EE [68]. Leptin
is probably involved in this process by modulating DMH
NPY neuronal activation [70].
In addition, recent studies have demonstrated that leptin
receptors in the ARC are necessary for leptin-induced
increases in BAT sympathetic discharge, with deletion of
leptin receptors in the ARC attenuating the response of
BAT to leptin [71]. It has also been demonstrated that ARC
orexigenic neurons inhibit BAT NST and that a partial loss
of agouti-related protein (AgRP)/NPY neurons leads to a
lean, hypophagic phenotype, also characterized by acti-
vated sympathetic innervation of BAT [72, 73]. Regulation
of NST by the ARC is closely linked to the central mela-
nocortin system. Melanocortins are a family of peptides
produced by post-translational processing of POMC. This
family of neuropeptides has an endogenous agonist, alpha-
melanocyte-stimulating hormone (a-MSH), and an antag-
onist, AgRP, both of which share common melanocortin
receptors (MCRs) [74, 75]. Loss of function in POMC and
its putative receptor melanocortin receptor 4 (MC4R)
induces an obese phenotype, both in humans and rodents
[76–79]. In this context, sympathetic cholinergic pre-gan-
glionic neurons, but not parasympathetic neurons, need
functional MC4R to regulate NST in response to cold
exposure and for browning of inguinal iWAT to occur [80].
Moreover, a lack of MC4R blocks the ability of leptin to
increase UCP1 expression in BAT and WAT [81]. Recent
evidence also suggests that correct protein folding in the
ER of POMC neurons is required to maintain EE [82] and
that POMC activation leads to browning of WAT which
counteracts diet-induced obesity (DIO) [83]. In line with
this, AgRP neurons in the ARC are also important in
attenuating browning of WAT [84]. Thus, fasting and
chemical-genetic activation of AgRP neurons suppress
browning in WAT through a mechanism involving O-
GlcNAc transferase (OGT) [84]. Hence, the ARC, previ-
ously known as the master control nucleus of feeding [85,
86], can now also be considered to have a role in the
modulation of BAT NST.
Finally, a recent study has revealed a rat insulin pro-
moter (Rip)-Cre neuronal population that intermingles with
POMC and AgRP neurons in the ARC, which is able to
increase EE without affecting food intake through the
synaptic release of GABA [87, 88]. In fact, mice lacking
synaptic GABA release from Rip-Cre neurons showed a
reduced potency of leptin in stimulating BAT NST, without
any effects on food consumption [87, 88]. The Rip-Cre
neurons project to the PVH and could be a source of the
GABAergic input to the PVH that triggers sympathetic
outflow and BAT NST [87, 88].
Autonomic control of body temperature
Maintenance of body temperature is achieved mainly by
the ability of BAT and skeletal muscle to generate heat and
secondarily by regulation of heat loss through the skin by
vasoconstriction and vasodilation, under SNS control and
accompanied by adrenergic cardiac stimulation [26–28]. In
response to cold, somatic motor nerves promote the
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123
generation of heat by skeletal muscle through shivering.
The thyroid and adrenal axes also participate in heat gen-
eration [28, 53, 89]. All these changes are coordinated
centrally, with a key region being the preoptic area (POA).
The POA contains cold-sensitive neurons and receives
input from thermosensitive areas in the abdominal viscera
where cold- and heat receptors send signals through the
vagus and splanchnic nerves [28, 29, 90]. Temperature
changes can also be sensed by thermoreceptors in the
spinal cord able to detect cold [91]. The POA also contains
heat-sensitive neurons whose tonic discharge is reduced by
skin cooling and whose thermosensitivity to preoptic
temperature is increased when the skin is cooled [92]. As a
result, skin cooling or direct cooling of POA neurons
modulates sympathetic stimulation of NST in BAT, as well
as shivering thermogenesis [92–94]. The POA is also
involved in the febrile response due to the integration of
pyrogenic signals, such as prostaglandin E2, that stimulate
the POA and activate BAT NST in a cAMP-dependent
manner [95].
BAT sympathetic sensory system feedback
BAT also has sensory innervation. Injection of an antero-
grade transneuronal virus into BAT has been used to trace
its sensory innervation to the PVH, periaqueductal gray,
parabrachial nuclei, raphe nuclei, and reticular area, all of
which are associated with sympathetic outflow to BAT,
suggesting the existence of BAT sensory system (SS)–SNS
NST feedback circuits [96]. In keeping with this, local
destruction of capsaicin-sensitive sensory neurons affects
the response of interscapular BAT (iBAT) to acute cold
exposure [96]. In this context, sympathetic stimulation of
iBAT directly activates dorsal root ganglia sensory neurons
associated with iBAT [97].
Autonomic modulation of WAT lipolysis
Until 20 years ago, WAT was considered only in terms of
its function in energy storage. However, since the seminal
discovery of leptin by Jeffrey Friedman [24] and the
identification of additional adipose hormones [98–100],
WAT has been regarded as a true endocrine organ [25,
101]. The CNS regulates metabolic and secretory functions
of WAT via the ANS. Abundant anatomical evidence
indicates that the regulation of WAT by the CNS is
mediated mainly by the SNS (for extensive reviews see
[39, 102, 103] ), whereas PSNS innervation of WAT is still
controversial [19, 20]. Using a viral retrograde transneu-
ronal tracer in WAT, labeled neurons have been found in
the brainstem (noradrenergic neurons of the LC), in
hypothalamic nuclei (ARC, DMH, LHA, and VMH), and
in some forebrain regions [104, 105]. The precise
connections from the hypothalamus to the autonomic
neurons have not been identified and might include addi-
tional projections between different hypothalamic nuclei.
Some of the most important functions of WAT to be
regulated by the SNS are mediated mainly by NA,
including lipolysis, the number of adipocytes, and secretion
of WAT proteins [102]. Adipocytes express several
adrenergic receptor subtypes, b1, b2, and b3-adrenergic
receptors that promote lipolysis, and the a2-adrenergic
receptor that inhibits it. In rodents, SNS stimulation of the
b3-adrenergic receptor triggers lipolysis in WAT through
increased cAMP production by adenylyl cyclase and
stimulation of the PKA pathway. In obesity, sensitivity of
white adipocytes to adrenergic stimulation is decreased
[106], whereas stimulation of the a2-adrenergic receptor
inhibits adenylyl cyclase, preventing PKA activation and
decreasing lipolysis [107].
Several hypothalamic–SNS–WAT axes regulate WAT
lipolysis. These include nuclei with key roles in energy
metabolism, such as the LHA, ARC, and VMH, as will
now be discussed. The LHA contains orexin-A (OX-A)
neurons that project to the brainstem and spinal cord and
are able to regulate WAT lipolysis [108]. Results from
intracerebroventricular (ICV) injection of high doses of
OX-A suggest that it can modulate WAT lipolysis through
activation of the SNS. This effect is also driven by his-
tamine neurons through the H1 receptor. However, low
doses of OX-A can decrease lipolysis by suppression of
sympathetic nerve activity and modulation of H3-receptor
activity [108]. MCH is a neuropeptide expressed in the
LHA that can mediate white adipocyte metabolism via the
SNS. Central infusion of MCH and activation of the MCH
receptor in the ARC stimulate lipid storage and decreases
lipid mobilization in WAT [109]. Several studies have
shown that central administration of MC3/4R agonists in
the CNS reduces fat mass in rodents, independent of food
intake [110–113]. Central melanocortins regulate turnover
of NA, a key initiator of lipolysis in mammals, in the
sympathetic neurons innervating WAT. Thus, central
injection of an MC3/4R agonist increases NA turnover in
specific fat depots [114], whereas blockade of the CNS
melanocortin system stimulates lipid storage and de novo
fatty acid synthesis in WAT [115]. Consistent with these
data, decreased secretion of a-MSH leads to an increase in
adiposity and impaired lipolysis, an effect that can be
reversed by treatment with isoproterenol, a b-adrenergic
agonist [116]. ARC NPY, moreover, regulates adiposity in
rats by promoting energy storage in WAT and inhibiting
BAT activity [28, 115]. NPY is also expressed in the SNS
neurons that innervate WAT and can act both directly on
white adipocytes and by increasing hypothalamic levels of
NPY, which in turn inhibit SNS outflow and suppress
catecholamine release and subsequent lipolysis [116].
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123
Another hypothalamic nucleus involved in WAT lipol-
ysis is the VMH. Electrical stimulation of the VMH in rats
leads to a lipolytic response in WAT [117]. Pretreatment
with cholinergic or b-adrenergic blockers blunts this effect,
while treatment with a-adrenoreceptor blockers has no
additional effect on the stimulation. These data suggest that
the effect of VMH stimulation on WAT lipolysis is mainly
via the SNS and b-adrenergic receptors within WAT [117,
118]. Recent findings show that VMH neurons can switch
the manner in which WAT responds to different diets.
Thus, on a chow diet, mice lacking the cannabinoid
receptor type 1 (CB1) in the VMH show decreased adi-
posity due to increased sympathetic activity and lipolysis;
on a high-fat diet (HFD), lack of CB1 in VMH neurons
leads to leptin resistance, attenuating lipolysis and
increasing adiposity [119].
WAT sympathetic sensory system feedback
Recent data show the existence of WAT SS–SNS feedback
loops in WAT. SNS and SS share central sites of regula-
tion, as well as some circuitries that may be involved in
crosstalk between the brain and WAT. It has been found
that some individual neurons participate in both central
SNS outflow from the brain to subcutaneous WAT and in
SS inflow from subcutaneous WAT to the brain [120].
Although the function of these SS–SNS circuits is still
unclear, two roles have been proposed: (1) informing the
brain of fat depot status and/or (2) interacting with SNS
activation of WAT in the regulation of lipolysis [13]. In
keeping with these potential functions, increases in SNS
signaling to WAT in response to glucose deprivation are
accompanied by increased sensory nerve electrophysio-
logical activity in WAT [121].
Autonomic modulation of glucose metabolism
Glucose homeostasis is regulated by circulating hormones,
autonomic innervation, and the secretory activity of the
endocrine pancreas, through the coordinated modulation of
hepatic glucose production (HGP) and its release into the
circulation and regulation of glucose utilization by
peripheral tissues including liver, muscle, BAT, and WAT
[122, 123].
Autonomic modulation of hepatic glucose
homeostasis
The liver is a key organ in the regulation of whole-body
metabolic homeostasis. It is involved in amino acid and
lipid metabolism, acts as an exocrine gland responsible for
the production of bile acids [124, 125], and controls
glucose homeostasis. Besides being the principal site of
glucose storage, the liver responds to increases in circu-
lating glucose and insulin levels by reducing HGP. As a
regulatory mechanism, glucose output from the liver is
increased during hypoglycemia [126]. The CNS innervates
the liver through sympathetic and parasympathetic nerves
which contain afferent as well as efferent fibers [14, 22].
Transneuronal virus tracing after injection of pseudorabies
virus in the liver has detected first-order labeled neurons
that correspond to sympathetic and parasympathetic neu-
rons, while second- and third-order labeling has been found
in the brainstem, hypothalamus, and in limbic structures
[127]. Thus, sympathetic efferent pathways from the liver
reach the intermediolateral cell column (IML) in the spinal
cord. Pre-ganglionic neurons innervate the celiac and
mesenteric ganglia that ultimately innervate the liver.
Sympathetic nerves can modulate hepatocyte function
directly via a1- and b-adrenergic receptors [128, 129] or
indirectly through the release of neuropeptides such as
NPY and galanin [130, 131]. Parasympathetic efferent
pathways project to the dorsal motor nucleus of the vagus
(DMV) and from there send afferent pre-ganglionic nerves
to the liver [22].
Several hypothalamic sites send autonomic signals to the
liver. The LHA is involved in its parasympathetic inner-
vation [132], the VMH in its sympathetic innervation [133],
and the PVH integrates information from several areas
including the ARC, VMH, and SCN, as well as sending both
sympathetic and parasympathetic signals to the liver [14,
21]. Classical studies demonstrated that electrical stimula-
tion of the LHA induces hepatic glycogen synthesis as well
as a decrease in levels of the gluconeogenic enzyme phos-
phoenolpyruvate carboxykinase (PEPCK) [134]. Corre-
spondingly, activation of orexin-expressing neurons in the
LHA increases blood glucose levels through the stimulation
of endogenous glucose production; notably, an intact
autonomic outflow via the hepatic sympathetic innervation
is essential for this effect [135]. A recent study has shown
that knocking out orexin impairs daily rhythm in blood
glucose levels [136]. In addition, treatment with an adren-
ergic antagonist or parasympathectomy suppresses the day–
night oscillation of blood glucose levels induced by treat-
ment with OX-A in normal and db/db mice [136]. In
addition, the VMH has been shown to be involved in hepatic
glucose homeostasis. Electrical stimulation of the VMH
increased the activity of PEPCK and suppressed the gly-
colytic enzyme pyruvate kinase (PK) in rat liver [134].
Sympathetic stimulation of the liver increases hepatic glu-
cose output via rapid activation of glycogen phosphorylase,
resulting in hyperglycemia and a marked reduction of
glycogen within the liver [133]. These effects are not
blunted by adrenalectomy [137]. Within the past decade,
several studies have linked VMH AMPK to the regulation
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123
of hypoglycemia. Pharmacological activation of AMPK by
AICAR in rats leads to an increase in hormonal counter-
regulation, resulting in elevated endogenous glucose pro-
duction [138, 139]. In addition, downregulation of AMPK
in the VMH suppresses glucagon and adrenaline in response
to hypoglycemia [140]. Recent studies in murine models
have investigated the role of the VMH in glucose home-
ostasis, showing that SF1 neurons are involved in the reg-
ulation of glycaemia [141, 142]. Mice lacking vesicular
glutamate transporter 2 (VGLUT2) in VMH SF1 neurons
show hypoglycemia during fasting that is secondary to
impaired fasting-induced glucagon action and impaired
hepatic expression of PEPCK and glucose 6 phosphatase
(G6Pase) [141]. GABAergic inhibition in the VMH,
moreover, appears to modulate glucagon and sympathoad-
renal responses to hypoglycemia in non-diabetic and dia-
betic rat models [143, 144].
The ARC is sensitive to insulin, leptin, and glucose and
sends signals to the PVH and other nuclei of the
hypothalamus to modulate glucose homeostasis. It has been
shown that the ARC mediates the effect of leptin on glu-
cose homeostasis. Thus, restoration of the leptin signaling
pathway in mice lacking the leptin receptor is sufficient to
improve hyperinsulinemia and normalize blood glucose
levels [145]. In addition, re-expression of the long form of
the leptin receptor in POMC neurons is able to normalize
the hyperglycemia induced in leptin receptor-deficient
mice [146]. A recent study suggests that AgRP neurons are
sufficient and necessary to mediate leptin-induced reduc-
tion of circulating glucose levels, which is not the case for
VMH or POMC neurons [147]. In addition, ICV injection
of NPY increases endogenous glucose production in rats by
decreasing insulin sensitivity via sympathetic innervation
[148]. Accordingly, recent studies have shown that gluco-
corticoid signaling in the ARC induces hepatic insulin
resistance and prevention via NPY of the inhibition of HGP
during hyperglycemia and that this effect can be blocked
by sympathetic denervation [149].
The PVH is connected to the VMH, SCN, and ARC and
receives and integrates information from these or other
hypothalamic sites as well as from autonomic innervation
involved in liver glucose regulation. There is some evi-
dence to suggest a role for the PVH in mediating the effects
of the biological clock situated in the SCN. That interaction
regulates the daily rhythm of glucose plasma levels via
GABAergic and glutamatergic projections that control
sympathetic and parasympathetic pre-autonomic neurons
of the PVH [150]. In addition, recent findings have linked
the PVH to glucose intolerance induced by excess THs
levels. Thus, selective administration of T3 to the PVH of
euthyroid rats triggers an increased HGP and elevated
plasma glucose via the sympathetic projection to the liver
[14, 21].
Autonomic modulation of the pancreas on glucose
homeostasis
The islets of Langerhans that make up the endocrine pan-
creas regulate glucose homeostasis by secretion of insulin
and glucagon that control increases and decreases in blood
glucose [23]. a- and b-cells of the islets control the
secretion of glucagon and insulin, respectively. The
secretion of insulin by b-cells is a tightly regulated process.
Thus, b-cells respond to an increase in blood glucose by
correspondingly increasing secretion of insulin. Capacity
for insulin secretion is itself controlled by regulation of b-
cell mass [151–154]. Hormone secretion by the islets is
regulated by humoral factors and by the CNS via the ANS
[23], with the pancreas receiving both sympathetic and
parasympathetic innervation. Several studies have identi-
fied central regions that control pancreatic endocrine
function, showing overall that the following CNS sites
regulate output by both parts of the ANS to the pancreas:
PVH, perifornical hypothalamic region, A5 catecholamine
cell group, RVLM, and lateral paragigantocellular reticular
nucleus [155]. The sympathetic efferents are formed by
sympathetic neurons in the IML of the spinal cord that
innervate postganglionic neurons, mainly in the preverte-
bral ganglia, while parasympathetic efferents consist of
pre-ganglionic neurons in the DVM and peripheral post-
ganglionic neurons located within the pancreas [156, 157].
Pancreatic parasympathetic afferents originate in the
nodose ganglia and reach the NTS, while the sympathetic
afferents leave the dorsal root ganglia and synapse with
interneurons in spinal cord laminae I and IV [23].
Parasympathetic nerves innervate a- and b-cells, while
sympathetic nerves innervate mainly a-cells. A recent
study, in a noninvasive in vivo model, showed that the
stimulation of b-cells by their parasympathetic supply
increased insulin secretion and controlled glycaemia, while
the stimulation of their sympathetic supply decreased
plasma insulin concentration [158].
Central regulation of the ANS is by glucose-excited or
glucose-inhibited neurons, located mainly in the brainstem
and hypothalamus. Within the hypothalamus, the VMH
plays a key role in the glucose counterregulatory response.
The VMH has been shown to regulate glucagon secretion
by the pancreas in response to local levels of glucose. Thus,
low levels of glucose in the VMH lead to an increase in
glucagon secretion, whereas glucose infusion into the
VMH suppresses glucagon secretion in response to
decreased blood glucose [159, 160]. Thus the VMH is
implicated in sensing hypoglycemia and in generating a
counterregulatory response, with VMH AMPK playing an
important role [139–141]. Previous studies based on
lesions of the VMH showed that acute hyperinsulinemia
can be blunted by vagotomy [161]. In recent years, studies
Endocrine
123
in rats have shown that insulin acts on the VMH, sup-
pressing glucagon secretion in response to insulin-induced
hypoglycemia. This effect of insulin in the VMH might be
mediated by an increase in local GABAergic tone [162]. In
contrast, blockade of insulin in the VMH increases basal
glucagon levels. Moreover, chronic reduction of insulin
receptors in the VMH impairs glucose metabolism as well
as a- and b-cell function [163]. Suppression of GABAergic
neurotransmission in the VMH is crucial for normal glu-
cagon and sympathoadrenal responses to hypoglycemia
[144]. The VMH’s role in regulating endocrine pancreatic
function has also been demonstrated by studying propyl-
endopeptidase (PREP), an enzyme with endopeptidase
activity that might be involved in the regulation of neu-
ropeptide levels. PREP knockdown mice show glucose
intolerance, decreased fasting insulin levels, increased
fasting glucagon levels, and reduced glucose-induced
insulin secretion, as well as elevated sympathetic outflow
to and NA within the pancreas [164].
In addition to the role of the VMH in glucose home-
ostasis, recent evidence supports the involvement of AgRP
neurons in the ARC in regulating the balance between lipid
and carbohydrate metabolism. Ablation of these AgRP
neurons leads to a change in SNS output to liver, skeletal
muscle, and the pancreas [165]. On a chow diet, mice
lacking AgRP neurons become obese and hyperinsuline-
mic, whereas on a HFD these mice showed reduced body
weight and improved glucose tolerance [165].
Another key site of control of glucose homeostasis is the
dorsal vagal complex (DVC) which comprises the NTS,
DMV, and area postrema (AP) and presents glucosensing
neurons that react to changes in blood glucose levels by
modulating glucose homeostasis through vagal outflow to
the pancreas [166]. Many studies have shown that the
DMV, the main source of vagal innervation to the pan-
creas, has a role in pancreatic secretory function. Recently,
the DMV was demonstrated as one of the components of
the pancreatic vagovagal reflex that includes pancreatic
vagal afferents, the DMV, and pancreatic vagal efferents.
Electrical and chemical stimulation of the DMV activates
both endocrine and exocrine secretion via cholinergic
pathways which can be blunted by vagotomy or chemical
inhibition [167–169]. Activation of the DMV by bilateral
microinjection of a GABA antagonist results in a rapid
increase in glucose-induced insulin secretion, and this
effect can be inhibited by a muscarinic receptor antagonist
or significantly increased by inhibition of nitric oxide
synthesis [168]. Additionally, a population of DMV neu-
rons projects to the pancreas which can be depolarized by
exogenous GLP1. This suggests that GLP1 can increase
insulin secretion either by acting directly on pancreatic b-
cells or indirectly through the modulation of inhibitory or
excitatory DMV inputs to the pancreas [170, 171].
Autonomic modulation of muscle glucose uptake
Skeletal muscle is one of the main sites of insulin-stimu-
lated glucose uptake in the postprandial state [172]. After a
meal, hyperglycemia triggers insulin secretion, stimulating
glucose uptake in skeletal muscle. In insulin-resistant
states, such as type 2 diabetes (T2D) and obesity, insulin-
stimulated glucose uptake in skeletal muscle is markedly
impaired [172, 173]. Nevertheless, there is evidence of
non-insulin-mediated pathways of glucose utilization in
muscle induced by sympathetic nerve activity and muscle
contraction [18].
Recent studies in rodents have described labeling in
several areas of the brain, including the hypothalamus, fol-
lowing injection of pseudorabies virus in skeletal muscle
[174–176]. Correspondingly, several lines of evidence now
show that the hypothalamus plays an important role in the
modulation of glucose uptake by skeletal muscle via the SNS
[177]. First, VMH stimulation promotes glucose uptake
independently of insulin blood concentration [178, 179], an
effect that is blunted by blockade of sympathetic activity
[173, 180]. Second, the injection of leptin in the VMH
increases glucose uptake in peripheral tissues, including
skeletal muscle [181], in a manner that is apparently
dependent on b-adrenergic stimulation [177]. Third, injec-
tion of OX-A into the VMH of rodents enhances glucose
uptake and promotes insulin-induced glucose uptake and
glycogen synthesis in skeletal muscle through the activation
of SNS [182]. These effects of OX-A are abolished in mice
lackingb-adrenergic receptors but restored by the expression
of b2-adrenergic receptors in myocytes and other cell types
in skeletal muscle [182]. Thus, leptin and orexin each play an
important role in regulating glucose metabolism, increasing
skeletal muscle sympathetic activity via the hypothalamus.
Regulation of energy homeostasis by peripheralhormones acting on the CNS
Recent data have shown that signaling by peripheral hor-
mones is important in the control of energy homeostasis,
via their effects on the CNS and subsequent outflow by the
ANS. These hormones include adipokines (e.g., leptin),
classical hormones synthesized in peripheral glands (e.g.,
THs and estrogens), and gastrointestinal hormones (e.g.,
insulin and ghrelin). As an illustration of the mechanisms
by which these hormones exert their effects on energy
homeostasis, we will focus on leptin, THs, and insulin.
Leptin
Leptin is a hormone secreted by WAT in proportion to fat
mass which informs the hypothalamus of the status of
Endocrine
123
energy stores [24, 101, 183]. The leptin receptor is
expressed in several brain areas that mediate leptin’s cen-
tral effects. Leptin can exert its satiety effect by inhibiting
the orexigenic NPY/AgRP neuronal population and stim-
ulating activity of anorexigenic POMC neurons in the ARC
[101, 183, 184]. Leptin can also modulate peripheral lipid
[185] and glucose metabolism [186]. In this context,
infusion of leptin in the MBH of rats inhibits the synthesis
of lipids in adipose tissue [187]. The action of leptin on
adipocyte metabolism via the CNS requires intact auto-
nomic innervation since sympathetic denervation of adi-
pose tissue blunts leptin’s effects [187]. Moreover, leptin
can regulate NST by modulation of SNS activity in BAT
[55, 188]. The binding of leptin to its putative receptor
leads to an increase in POMC and a decrease in NPY/
AgRP levels that trigger SNS activation and a consequent
increase in UCP1 and NST in BAT [28, 55, 184]. Leptin is
also involved in the autonomic regulation of glucose
homeostasis [173]. At the central level, leptin infusion
decreases circulating insulin levels by acting on the b-cell
via the SNS [189], while interaction of leptin with its
receptor in the ARC improves hyperinsulinemia and blood
glucose levels [145]. In this context, expression of leptin
receptors in the ARC of leptin-receptor-deficient rats
decreases hepatic expression of gluconeogenic genes and
increases hepatic insulin signaling, an effect blunted by
hepatic denervation of the vagus nerve [190].
Thyroid hormones
THs are produced in the thyroid and play an important role
in energy and metabolic homeostasis by influencing food
intake and EE in metabolically active tissues, such as BAT,
WAT, liver, pancreas, and skeletal muscle [14, 89, 191,
192]. BAT expresses at least two TH receptors (TRs), TRaand TRb1, which make it a direct target of THs. Never-
theless, over the last few years, a large body of evidence
has suggested that the CNS is also a key player in ther-
mogenetic regulation and metabolic homeostasis, acting
via the ANS and THs. A strong relationship between TH
and thermoregulation is shown by the following: (1) direct
cooling of the POA leads to the activation of the
hypothalamic–pituitary–thyroid (HPT) axis; (2) THs play a
critical role in the maintenance of body temperature by
influencing NST; and (3) alteration in TH levels leads to
clear symptoms related to body temperature in both hypo-
and hyper-thyroidism. The precise mechanisms through
which these effects are mediated have started to be
uncovered [14, 89, 191, 192]. Thus, mice with a mutant
TRa1 that has a low affinity for T3 show hypermetabolism
with increased thermogenesis and EE, while this effect is
blunted after functional sympathetic denervation to BAT,
indicating that the effect of THs in these mice is mediated
by the CNS via the ANS [193]. Data generated by our
group support the evidence that the stimulation of BAT
NST by the SNS depends on T3-mediated activation of de
novo lipogenesis in the hypothalamus, due to inhibition of
VMH AMPK [53]. Notably, while these data were initially
obtained from THs, more recent experiments show that
endogenous hormones (estrogens, BMP8B, and probably
leptin) and drugs such as liraglutide and nicotine act in a
similar manner to THs to promote BAT NST and browning
[53–58].
THs can also modulate glucose production and insulin
sensitivity [14, 21, 194] through SNS projections from the
PVH. Accordingly, sympathectomy attenuates the increase
in HGP associated with thyrotoxicosis, whereas parasym-
pathectomy does not affect HGP but decreases hepatic
insulin sensitivity [194]. The ARC also expresses TRs [14,
89, 191, 192, 195, 196]. Given that the ARC also modulates
HGP [197, 198] and hepatic insulin sensitivity through
sympathetic output to the liver [149], it will also be
important to investigate the potential relevance of TH sig-
naling and glucose metabolism in this hypothalamic area.
Insulin
Insulin is secreted by pancreatic b-cells in response to
increases in circulating glucose and acts as an anabolic
hormone in peripheral tissues. BAT is one of the most
insulin-responsive tissues with respect to stimulation of
glucose uptake. Thus, under physiological conditions,
plasma insulin levels are elevated after feeding and glucose
uptake by BAT is increased [26, 28, 199, 200]. Under
starvation or fasting, on the other hand, insulin levels are
lowered and BAT shows reduced glucose uptake [26, 28,
200]. In keeping with this, in rodents insulin can trigger
sympathetic activation to BAT and lead to increased NST
through its action within the brain [201]. Besides its effect
on BAT, insulin also acts as one of the principal regulators
of WAT metabolism. Insulin stimulates glucose and fatty
acid uptake and inhibits hormone-sensitive lipase (HSL)
activity and thus lipolysis in WAT [202, 203]. Recent data
have shown that insulin can exert this effect by acting on
the MBH, with mice lacking the neuronal insulin receptor
exhibiting uncontrolled lipolysis and decreased de novo
lipogenesis in WAT [204]. Thus, insulin action within the
brain suppresses basal WAT HSL activation, a marker of
sympathetic outflow to WAT [13, 204, 205].
The most characterized role of insulin is its regulation of
blood glucose levels. Insulin suppression of HGP is regu-
lated by way of insulin receptors (IRs) in both the liver and
brain. Thus, genetic inactivation of IRs in either of these
organs abrogates the effect of insulin [206–208]. IRs have
been found in several hypothalamic sites involved in
sympathetic regulation of glucose homeostasis [209, 210].
Endocrine
123
Insulin signaling in the hypothalamus plays a key role in
the regulation of HGP and glucose disposal [173, 206].
ICV administration of insulin or an insulin mimetic in rats
suppresses HGP independently of changes in circulating
levels of insulin or glucose [206], while hepatic vagotomy
and sympathectomy independently blunt the inhibitory
effect of central insulin on HGP [148, 173].
Summary and conclusions
The CNS regulates energy homeostasis by acting on
metabolic organs via the ANS [13–16] (Fig. 1). The SNS
and PSNS differentially innervate BAT, WAT, liver, and
the pancreas [39, 127, 158, 211], modulating the metabolic
and secretory function of these peripheral tissues as a result
of signals and drugs that act on homeostatic regulatory sites
in the CNS [21, 53, 54, 57, 58, 62, 119, 162]. Lipid
metabolism is regulated by modulation of NST in BAT
[26] and lipolysis in WAT [212]. The regulation of glucose
homeostasis is driven by the balance between glucose
production in the liver and secretion of glucagon and
insulin by the pancreas, in response to blood glucose levels
[126] and glucose uptake in peripheral tissues such as
skeletal muscle [18]. Regulation of glucose metabolism
occurs via splanchnic sympathetic and vagal parasympa-
thetic nerves and involves several hypothalamic sites and
the DVC [22, 23]. Overall, several lines of evidence
Muscle
Liver
PVH
LHA
DMH
VMH
ARC3V
PVH
LHA
DMH
VMH
ARC
Hypothalamus
Autonomic cell groups IML
DMV
SNS
PSNS
Pancreas
DMV
IML
PSNS
SNS
Preganglionicneurons
SNS
PVH
LHA
DMH
VMH
ARC3V
PVH
LHA
DMH
VMH
ARC
Hypothalamus
POA
BATRPaIO
SNSIML
SNS IML
Leptin, THs, Insulin, BMP8, E2, etc.
Foodintake
EnviromentTª
Physicalactivity
NTSAP
DVC
Possible projections
Projections
Fig. 1 Autonomic control of energy homeostasis. Energy balance is
controlled by the central nervous system (CNS) which receives and
integrates signals from peripheral tissues and the external environ-
ment, responding by modulating food intake and energy expenditure
(EE). The CNS controls autonomic innervation of peripheral tissues
through several key areas, such as the hypothalamus and dorsal vagal
complex (DVC). Specific projections from the hypothalamic nuclei to
pre-autonomic neurons are not known and might include additional
connections between different hypothalamic nuclei (dotted lines).
Sympathetic nervous system (SNS) output to peripheral tissues
involves the intermediolateral nucleus (IML), whereas the parasym-
pathetic nervous system (PSNS) relays in the dorsal nucleus of the
vagus nerve (DMV). Within the hypothalamus, the preoptic area
(POA) is responsible for temperature regulation and the febrile
response; it receives and integrates information pertaining to
thermosensitive areas and modulates sympathetically stimulated
thermogenesis in brown adipose tissue (BAT). Other hypothalamic
nuclei implicated in sympathetic non-shivering thermogenesis are the
ventromedial (VMH), dorsomedial (DMH), and paraventricular
nuclei (PVH), which send projections to the raphe pallidus (RPa) to
modulate the BAT thermogenic response via the SNS. The CNS also
modulates white adipose tissue (WAT) lipolysis and the secretory
activity of WAT through sympathetic innervation of different depots.
The hypothalamic–SNS axes that regulate WAT lipolysis involve the
lateral hypothalamic area (LHA), VMH, and ARC. Glucose home-
ostasis is regulated by the CNS through SNS and PSNS innervation of
the liver and pancreas. Several hypothalamic nuclei are involved in
the regulation of hepatic glucose metabolism: the LHA, VMH, ARC,
and PVH. The VMH, ARC, and DVC (which comprises the nucleus
of the solitary tract (NTS), DMV, and area postrema (AP)) modulate
pancreatic secretion of insulin and glucagon via the autonomic
nervous system. The CNS regulates glucose uptake by skeletal muscle
via the SNS. 3 V: third ventricle
Endocrine
123
demonstrate that the hypothalamic–ANS axis (afferent and
efferent pathways) plays a major role in the regulation of
energy metabolism. Further elucidation of the neural and
molecules involved, such as AMPK, extracellular signal-
regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)
[15, 213], and mammalian target of rapamycin (mTOR)
[53–58, 214], can be expected to provide specific novel
pharmacological targets for the treatment of obesity and
metabolic disorders, including T2D, hypertension, and
CVD [5, 215].
Acknowledgments The research leading to these results has
received funding from the European Community’s Seventh Frame-
work Programme (FP7/2007-2013) under Grant agreement No
281854—the ObERStress European Research Council Project (ML),
the Xunta de Galicia (ML: 2012-CP070; RN: EM 2012/039 and
2012-CP069), Instituto de Salud Carlos III (ISCIII) (ML: PI12/
01814), and MINECO co-funded by the European Union FEDER
Program (RN: BFU2012-35255; CD: BFU2011-29102). CIBER de
Fisiopatologıa de la Obesidad y Nutricion is an initiative of ISCIII.
The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript. The manuscript
was edited for English language by Dr. Pamela V Lear.
Conflict of interest The authors declare no conflict of interest.
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