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The hardship of obesity: a soft-wired hypothalamus
Tamas L Horvath
Food intake and energy expenditure are determinants of
metabolic phenotype and are regulated by the CNS. Although
humans have a well-balanced homeostatic feedback loop,
obesity and metabolic disorders are spreading rapidly and
carry a heavy toll of morbidity and mortality. The past decade
has witnessed major advances in the understanding of basic
metabolic processes, the brain circuitry that determines
appropriate and, but, inappropriate behavioral and humoral
responses to changing metabolic cues remains largely ill
defined. This review summarizes current knowledge of
the brain anatomy that supports food intake and energy
expenditure and discusses cellular mechanisms such
as synaptic plasticity that may provide clues toward the
development of successful central therapies to combat
metabolic disorders, including obesity and diabetes.
on leptin-deficient obese ob/ob mice8–11. Subsequently, receptors for
leptin were cloned and localized to structures in the hypothalamus12,13,
some of which had been implicated in the regulation of metabolism by
lesion studies. However, leptin bound and its receptors accumulated
predominantly in a ventromedial hypothalamic structure, the arcuate nucleus14, which was not specifically suggested by the lesion studies. Further support for a role for this small hypothalamic nucleus in
energy homeostasis came when the melanocortin system was found to
be involved in obesity15,16. Because melanocortin is found in neurons
of the arcuate nucleus17, it was logical to test whether leptin affected
metabolism mediated by the arcuate nucleus melanocortin system—as
indeed was found to be the case18. An attractive model came from further analysis of components of the central melanocortin system19, which
today is considered to be the key component in the regulation of feeding
and energy expenditure.
Obesity is a metabolic state in which excess fat is accumulated in
peripheral tissues, including the white adipose tissue, muscle and
liver. Sustained obesity has profound consequences on one’s life, spanning from superficial psychological symptoms to serious co-morbidities that may markedly diminish both the quality and length of life.
Paradoxically, compelling evidence has been gathered during the last
100 years suggesting that the underlying cause of fat accumulation in
peripheral tissues arises, at least in part, from the CNS1–4.
Since the dawn of modern neurobiology at the end of the nineteenth
century, both intellectual and experimental attempts have been made to
identify and isolate the brain’s role in energy metabolism regulation. For
example, based on the emerging experimental observations on brainstem
regulation of respiration at the time, Sherrington suggested that a similar
blood link between the periphery and brain should exist for the regulation of food intake5. Others also concluded that there must be feeding
regulation signals from the periphery to the brain, implicating gut-born
humoral signals as responsible for appropriate brain responses to changing metabolic needs6,7. Of the various brain regions, the hypothalamus
emerged as one of the critical sites for the regulation of energy homeostasis during degeneration studies2 in the 1940s and 1950s. Destruction
of the hypothalamic ventromedial (VMH), paraventricular (PVH) and
dorsomedial (DMH) nuclei induced hyperphagia. In contrast, discrete
lesions placed in the lateral hypothalamus reduced food intake.
A fundamental breakthrough came in 1994 and 1995 when the gene
encoding the adipose signal leptin was discovered and its product tested
Hypothalamic regulators of feeding and energy expenditure
A simple and appealing model of the ‘heart’ of the central feeding
center followed from two discoveries: that the arcuate nucleus melanocortin system is critical in mediating leptin’s effect on metabolism
and that there are distinct local counterparts of the pro-opiomelanocortin (POMC) cells: agouti-related protein– and neuropeptide
Y–producing cells (NPY/AgRP cells) in the arcuate nucleus20. In this
model, activation of POMC neurons by leptin21,22 triggers the release
of α-melanocyte–stimulating hormone (α-MSH) from POMC axon
terminals, which in turn activates melanocortin receptor 4 (MC4R),
leading to suppressed food intake and increased energy expenditure.
Simultaneously, leptin suppresses the activity of arcuate nucleus NPY/
AgRP neurons21,22, which otherwise would antagonize the effect of
α-MSH on MC4Rs through the release of AgRP19. Not only does the
NPY/AgRP system antagonize anorexigenic melanocortin cells at their
target sites, where MC4Rs are located, but it also very robustly and
directly inhibits POMC perikarya through both NPY and the inhibitory neurotransmitter GABA22, which acts through basket-like synaptic
innervation of POMC cells by NPY/AgRP cell terminals23. This apparent unidirectional anatomical interaction between the NPY/AgRP and
POMC perikarya23 is of potential significance, as it provides a tonic
inhibition of the melanocortin cells whenever the NPY/AgRP neurons
are active. Because there is no constitutive direct feedback mechanism
from the POMC cells to disengage the NPY/AgRP neurons, this simple
anatomical constellation (Fig. 1) may provide the easiest explanation of
why the baseline blueprint of feeding circuits is more likely to promote
feeding than satiety. Although this bias toward positive energy balance is
necessary from an evolutionary perspective, it is also likely to contribute
to the etiology of metabolic disorders, such as obesity.
The majority of both NPY/AgRP and POMC neurons are small cells
characterized by infolded nuclei with a 1:1 ratio of inhibitory to excitatory
Tamas L. Horvath is in the Department of Obstetrics, Gynecology &
Reproductive Sciences and the Department of Neurobiology, Yale University
School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
e-mail: [email protected]
Published online 6 April 2005; doi:10.1038/nn1453
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PERSPECTIVE
projections of AgRP and POMC fibers to the
nucleus of the solitary tract in the hindbrain26,27.
Another exception is a set of larger POMC perikarya that also express the anorexigenic peptide
cocaine and amphetamine–regulated transcript (CART) in the arcuate nucleus and retrochiasmatic area and that provide innervation of
the sympathetic ganglia at thoracic segments of
the spinal cord28. This projection, which does
not contact by NPY/AgRP fibers, is most likely
to be important in the activation of the sympathetic nervous system. An important common
target of NPY/AgRP and POMC projections is
the hypothalamic parvicellular paraventricular
nucleus (PVN). The interplay between AgRP
and α-MSH fibers on MC4R-expressing neurons in the PVN is suggested to be the most
critical interaction for metabolism regulation.
Signals from here may then travel in various
directions, including to brainstem nuclei, to
spinal cord, to cortex (through various routes),
to the thalamus and to portal vessels connecting
the hypothalamus to the anterior pituitary. It is
intriguing that in this case, once again, an interaction between the arcuate nucleus NPY and
POMC neurons in food intake regulation had
been proposed years before leptin was discovered or the significance of MC4Rs recognized
in metabolism regulation23.
The simplicity of the putative hypothalamic
feeding center is remarkable, and it suggests
Figure 1 Schematic of three hypothalamic peptidergic systems, which show rapid synaptic perikaryal
remodeling in response to peripheral metabolic changes. In the arcuate nucleus (ARC), the orexigenic
that manipulation of either component of the
NPY/AgRP neurons (yellow) have a greater ratio of excitatory (red) to inhibitory (green) input during
melanocortin system should shift energy balnegative energy balance (low leptin, high ghrelin in the circulation) than during satiety. Arrows
ance. More importantly, if this system is the
indicate the direction of synaptic movement after leptin levels increase and ghrelin levels diminish
primary regulator of energy homeostasis, then
as satiety emerges. In contrast, neighboring anorexigenic α-MSH cells (blue) have a higher ratio of
it should be possible to correct metabolic disinhibitory to excitatory input during negative energy balance than during satiety. These two systems
orders such as obesity by altering either the
have overlapping projections, targeting neurons that express melanocortin receptor 4 (MC4R) in
various regions, including the hypothalamic paraventricular nucleus (PVN). MC4Rs (brown membranes
NPY/AgRP or POMC circuit. Although genetic
in the PVN) may be localized postsynaptically or presynaptically in close proximity to AgRP- and αmanipulations of either component can lead
MSH–containing fibers. A substantial proportion of the inhibitory inputs on melanocortin perikarya
to an altered metabolic phenotype, it is reasonin the arcuate nucleus arise from local NPY/AgRP neurons. A large proportion of the excitatory
able to think that this arcuate nucleus system
inputs on NPY/AgRP neurons are from neurons expressing hypocretin/orexin originating in the lateral
does not stand alone as the backbone for the
hypothalamus (LH). These lateral hypothalamic cells are also orexigenic, and their perikarya are
adequate regulation of daily energy balance, as,
dominated by excitatory inputs both during negative energy balance and during satiety, although the
level of excitatory inputs is blunted during satiety. As shown by the electron micrographs, all three of
for example, no successful medical strategies
these cell types are frequently in close proximity to capillary vessels (v), indicating a likelihood that
have emerged that target this system for the
they are directly regulated by circulating leptin or ghrelin.
treatment of either positive (obesity) or negative (cachexia) energy balance. Indeed, other
hypothalamic systems have also been closely
synaptic inputs24. Both neuronal systems are directly targeted by leptin tied to this regulatory mechanism (for review, see refs. 3,4). These
and can also be affected by other peripheral metabolic signals, such as include two distinct lateral hypothalamic orexigenic neuronal popughrelin, glucose, insulin and peptide YY, a putative satiety signal released lations producing either melanin-concentrating hormone (MCH)29
from the gastrointestinal tract postprandially in proportion to the calorie and hypocretin/orexin30. The interaction of the melanocortin system
content of a meal25. Their localization in ventromedial aspects of the arcu- with other hypothalamic and extrahypothalamic neuronal systems is
ate nucleus close to the median eminence, a region with no blood-brain redundant, so that alternative signaling modalities can be used once a
barrier between vessels and the parenchyma, means that these neurons pathway is blocked. In addition, the flexibility of the hypothalamic cenmight be reached by circulating metabolic signals in the most effective ter of metabolism may be due not only to redundant interconnectivity
manner. Indeed, NPY/AgRP or POMC perikarya or dendrites are often but also to the consequence of its soft wiring24.
seen in direct contact with capillaries (Fig. 1), thus increasing the likelihood that these neurons are direct targets of peripheral signals. The pro- Neuronal plasticity in the regulation of energy balance
jections of these two systems grossly overlap both within and outside the Underlying this connectivity and the integration of peripheral signals
hypothalamus26,27, although they are rarely very long. An exception is of brain circuits associated with feeding and energy expenditure is
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an intriguing redundancy. This is reflected by the ability of a feeding
circuit to rearrange itself to maintain its prior level of output even if
one of the components of the normal signaling modality is removed.
This indicates that the interactions of hypothalamic neuronal circuits
have substantial plasticity, some of which is retained in adulthood.
Synapses in the magnocellular system are rearranged during changes
in water homeostasis31, and they are rearranged in the arcuate nucleus
interneuronal system as a result of variations in the gonadal steroid
milieu32. Such synaptic plasticity has not previously been considered to
be a critical component in the regulation of daily energy homeostasis.
However, our observations24,33 now suggest34 that synaptic plasticity is
a key component in the physiological regulation of energy homeostasis,
and that under pathological conditions, the synaptic constellation and
its plasticity may be impaired.
Mice that lack the gene encoding circulating leptin (ob/ob mice) and
their wild-type littermates were used in these experiments. The phenotype of ob/ob mice resembles human morbid obesity. Replacement of
leptin in ob/ob mice rapidly decreases food intake and triggers weight
loss9–11. Thus, ob/ob mice and their wild-type littermates provide an
excellent model in which to determine the effects of leptin on the
wiring pattern of the hypothalamic peptidergic circuits. Two distinct
populations of neurons of the melanocortin system were analyzed: the
NPY/AgRP and POMC neurons. Although these studies focused on
the arcuate nucleus melanocortin system, it is important to emphasize
that regulation of energy metabolism by the brain is organized from
various sites that are not limited to the hypothalamus but include other
regions, most notably the brainstem35.
To more easily and precisely identify the two populations of cells
(NPY/AgRP and POMC), we used transgenic mice in which τ-sapphire
green fluorescence protein (GFP) is expressed under the transcriptional control of the NPY genomic sequence, or in which τ-topaz GFP
is expressed under the transcriptional control of the POMC genomic
sequence. We examined the afferent inputs to these neuronal populations of the arcuate nucleus using patch-clamp electrophysiological
recording in slice preparations together with stereology to quantify the
synaptic density onto these cells. The results showed that leptin-deficient ob/ob mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto NPY and
POMC neurons. When leptin was delivered systemically to ob/ob mice,
the synaptic density rapidly normalized24; this effect could be detected
within 6 h—several hours before leptin’s effect on food intake (Fig. 2).
These observations clearly indicate that rapid synaptic rearrangement
is induced by leptin, and most likely by other metabolic signals as well.
In support of the latter, we found that the orexigenic peripheral hormone ghrelin rapidly (within 2 h) shifts input organization of POMC
perikarya to support decreased cellular activity24. Because of these rapid
synaptic changes and because circulating ghrelin and leptin levels show
circadian rhythms in which the peak of one coincides with the nadir
of the other36, it is very plausible that the synaptic organization of
the melanocortin system undergoes circadian alterations in line with
circadian feeding and metabolic patterns.
An important question is whether these synaptic alterations influence
neuronal activity and, consequently, metabolic phenotype. Although
this remains to be proven, these changes occur both before and during the various behavioral and endocrine outputs24. Even if it does
not directly affect action potentials, the changing input organization
of NPY/AgRP and POMC perikarya should influence the setpoint of
these cells under various circumstances. For example, a trans-synaptic
excitatory signal is more likely to trigger an action potential if this input
is located proximally with few surrounding inhibitory connections than
if it is bordered by numerous inhibitory synapses. If the synaptic wiring
NATURE NEUROSCIENCE VOLUME 8 | NUMBER 5 | MAY 2005
Figure 2 Schematic showing relative changes in body weight and food
intake in wild-type (yellow), ob/ob PBS-replaced (red) and ob/ob leptinreplaced (purple) mice. Leptin replacement induced statistically significant
changes in food intake and adiposity within 2 d, and by 12 d, food intake
and adiposity of leptin-replaced mice were lower than those of PBS-treated
ob/ob mice and closely resembled values for wild-type controls. Synaptic
measurements were done 6 h, 48 h and 12 d into leptin or PBS replacement
(blue arrows). By 6 h, significant changes in the wiring of the melanocortin
system were detected preceding the behavioral and metabolic changes. By
48 h, synaptic organization of leptin-treated ob/ob mice resembled that
of wild-type mice, and food intake was already significantly decreased.
This close temporal relationship between synaptic and behavioral changes
establishes a correlation between synaptic changes and behavioral and
endocrine alterations induced by leptin.
indeed participates in determining the setpoint of the central feeding
circuit rather than acutely determining postsynaptic activity, then it is
possible that subjects who are sensitive to diet-induced obesity have a
wiring and plasticity of the melanocortin system different from those
who are resistant to obesity, even before obesity develops. If this is
the case, then one could argue that developmental programming of
hypothalamic circuits37 contributes not to obesity per se but to predisposing individuals to the development of obesity. There is a critical
developmental period during which the development of efferents from
the melanocortin system is affected by leptin37. This event may affect
the hardwiring of at least some parts of the feeding circuits, thereby
determining the set point of this system.
The melanocortin system is not the sole regulator of energy balance. Thus, it is important to determine whether synaptic plasticity is
characteristic of other systems in the adult brain that are associated
with metabolic regulation. The lateral hypothalamic hypocretin-orexin
system is important in establishing orexigenic drive associated with
arousal38,39. As mentioned above, our unpublished pilot studies found
that this system also seems to be softwired in nonhuman primates. To
further investigate this, we used a transgenic mouse model in which
neurons that express hypocretin/orexin are visualized using GFP40.
Hypocretin neurons showed an unusual perikaryal synaptic input
organization, in which excitatory inputs dwarfed inhibitory contacts
by several orders of magnitude (Fig. 1), as seen in both ultrastructural and electrophysiological analyses33. This domination of excitatory inputs was further increased, in a leptin-dependent manner, by
fasting33. Normally, such long-projecting neurons have an excess of
inhibitory inputs on their perikarya to appropriately filter out noise41.
In the case of the hypocretin neurons, however, the proximal localization of stimulatory inputs suggests that these cells are easily excited
by various stimuli. From an evolutionary perspective, this paradoxical
input organization makes perfect sense in the case of the hypocretin
neurons, as subjects need to be easily aroused when in danger or in
need of food. Of course, there is another side to the coin: when incom-
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PERSPECTIVE
ing signals increase, perhaps because of emotional or physical stress,
easy activation of the hypocretin system will trigger insomnia and
an orexigenic drive. Thus, the unorthodox input organization and
plasticity of hypocretin perikarya may improve understanding of how
insomnia leads to obesity42–44.
To gain further insight into the role of synaptic plasticity in the
regulation of feeding and energy expenditure, it will be critical first to
determine regulatory elements and intracellular correlates of synaptic plasticity triggered by the changing metabolic state. Without these
basics, it will be almost impossible to answer the ultimate question:
what contribution does synaptic plasticity make to physiological and
pathological metabolic conditions? When this question is addressed, it
will be important to keep in mind the experience with the most studied
plasticity phenomena, long-term potentiation (LTP) and long-term
depression (LTD), in relation to learning and memory. LTP and LTD by
now are generally accepted as building blocks for learning and memory.
Notably, however, although both LTP and LTD and their morphological correlates are very closely associated with behavioral output, no
causal direct evidence exists that LTP is mandatory for learning and
memory in the mammalian brain45–47. This work suggests that a similar
approach to hypothalamic synaptic plasticity, with mechanistic and
correlative studies of its physiological role in energy metabolism, may
hold promise.
The lack of therapies for obesity: an apparent paradox
After the discovery of leptin in 1994 and 1995, the assumption that
medical approaches for metabolic disorders would soon follow seemed
to be well founded. These medical breakthroughs have yet to occur,
however, and this is unlikely to change in the immediate future, despite
the amount of intellectual talent and monetary resources being directed
at this issue. To emphasize the complexity of the peripheral tissue functions that are governed by the hypothalamus, it is logical to draw parallels between the regulation of food intake and energy expenditure
and that of the pituitary gonadal axis. The discovery of hypophyseotropic hormones in the 1960s rapidly helped uncover regulation by the
brain of various peripheral tissues, including the ovaries and testes,
and helped clarify how the feedback from these tissues influences the
brain. For example, the characterization and synthesis of luteinizing
hormone–releasing hormone (LHRH) and its influence on the pituitary had immediate academic as well as clinical implications for issues
associated with ovarian cycles and infertility48. This rapid translation
of newfound principles for clinical medicine occurred at a time when
genetics and molecular biology were not in common practice.
The argument can be made that, from an evolutionary perspective,
the regulation of energy balance is at least as important as reproduction. Thus, if the regulation of metabolism turns out to be redundant,
a method could be found to successfully shortcut its CNS component,
similar to what was done in reproductive medicine. It is worthwhile to
note that although the principal hypothalamic neurons in the regulation of ovarian and testicular function, the LHRH cells, have been
extensively studied49, the blueprint of gonadal feedback on the hypothalamus remains largely ill-defined. Whether or not it is reasonable to
anticipate similar breakthroughs in metabolism regulation (the dream
of patients and the pharmaceutical industry!) will largely depend upon
our ability to understand the fine points of the brain’s role in this regulatory process and how these brain processes couple with the activity
of peripheral tissues.
ACKNOWLEDGMENTS
The work of T.L.H. on the relationship between synaptic plasticity and energy
metabolism has been supported by National Institutes of Health grants DK-060711
and RR-014451.
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COMPETING INTERESTS STATEMENT
The author declares that he has no competing financial interests.
Received 12 January; accepted 11 March 2005
Published online at http://www.nature.com/natureneuroscience/
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