CO M M E N TA RY The Journal of Clinical Investigation  

Coordination of metabolism, arousal, and reward

by orexin/hypocretin neurons
Natalie J. Michael1 and Joel K. Elmquist2
Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada. 2Center for Hypothalamic Research, Department of Internal Medicine and Department of Pharmacology,
1

UT Southwestern Medical Center, Dallas, Texas, USA.

Effects of obesity on the orexin

Orexin/hypocretin neurons located in the lateral hypothalamus play a
system
In this issue of the JCI, Tan and Hang et
critical role in the maintenance of arousal and contribute to the regulation of
al. (14) provide exciting results related to
multiple homeostatic and behavioral processes. In this issue of the JCI, Tan
the impact of diet-induced obesity (DIO)
and Hang et al. report that feeding a high-fat diet to mice compromised the
on orexin neuronal functions and the
function of the orexin system, leading to impairments in reward-seeking and behavioral responses they regulate. The
active coping mechanisms. The researchers observed changes at the cellular researchers report that mice fed a high-fat
and circuit levels suggesting that reduced excitability of orexin neurons diet developed impairment of glutamater-
affects behavior through induction of a hypoarousal state. gic neurotransmission to orexin neurons,
including decreased probability of neuro-
peptide release, decreased synaptic poten-
tiation, and decreased dopamine-mediat-
CNS circuits are altered Central administration of orexin was ed excitation (Figure 1). In addition to the
in obesity shown to stimulate feeding, and fast- altered excitatory inputs to orexin neu-
Obesity represents a growing global pub- ing results in upregulation of the orexin rons, intra- and extrahypothalamic circuit
lic health crisis. In addition to increasing precursor peptide (prepro-orexin) (5). In functions were altered. Electrophysiolog-
the risk of mortality and the likelihood of addition, functional loss of the orexin ical recordings showed increased sponta-
suffering other serious diseases, obesity is (Hcrt) gene or receptors in mice and dogs neous γ oscillations in the lateral hypothal-
associated with alterations in several CNS results in severe deficits in wakefulness, amus and decreased evoked hippocampal
functions. Initial research efforts focused mirroring the sleep disorder known as θ power; both neuroanatomical regions
on the consequences of high-fat feeding narcolepsy (7, 8). Moreover, postmortem represent direct targets of the orexin neu-
(HFF) on the neural circuits regulating studies in human subjects indicate that rons. Furthermore, these changes were
feeding, metabolism, and cardiovascular narcolepsy associates with loss of orexin accompanied by decreased reward seek-
functions (1). More recently, interest has neurons (10). ing, demonstrated by reduced cocaine-­
shifted to the impact of obesity on cognitive Subsequent studies linking the orexin induced conditioned place preference
and behavioral processes. Obesity nega- system with both feeding and wakefulness (CPP) and decreased coping responses to
tively disrupts reward behavior, mood, and suggest that orexin neurons are import- a stressor (forced swim test).
arousal (2, 3). However, the mechanisms by ant for driving increases in arousal and Given the previously recognized role
which obesity perturbs the CNS circuits reg- locomotor activity required for food-seek- of the orexin neurons in regulating moti-
ulating complex behaviors remain unclear. ing behaviors (11). This concept further vationally driven behaviors via increases
An example of a neuronal population extends to include other motivationally in arousal (11, 12), these results suggest
that is ideally positioned to link metabolism, driven behaviors. With connections to the that the diet-induced decrease in excit-
arousal, and reward processing is the orexin emotion and reward centers in the brain, atory tone to the orexin neurons may
population, located in the lateral hypothal- orexin neurons have since been implicated reduce arousal and underlie the observed
amus (4–6). Initial reports describing the in reward processing and addictive behav- behavioral modifications. To test this the-
discreet neuroanatomical location of orexin iors (12, 13). Therefore, orexin neurons’ ory, Tan and Hang et al. (14) exploited
neurons and their diffuse projections sug- extensive innervation of the CNS, role in pharmacological and chemogenetic tech-
gested they may regulate multiple physiolog- arousal, and ability to act as sensors of the niques to increase orexin neuron activity
ical processes. Indeed, orexin neurons were metabolic state make these neurons prime and arousal. The researchers selectively
quickly recognized for their importance in candidates for linking overnutrition and activated orexin neurons with excitatory
metabolic regulation and arousal (5, 7–9). obesity with altered behavior. designer receptors exclusively activated
by designer drugs (DREADDs). Notably,
Related Article: p. 4985 the DREADDs reversed the downstream
neural circuit changes and corrected the
Conflict of interest: The authors have declared that no conflict of interest exists.
decrease in reward seeking and compro-
Copyright: © 2020, American Society for Clinical Investigation. mised stress coping that occurred with
Reference information: J Clin Invest. 2020;130(9):4540–4542. https://doi.org/10.1172/JCI140585. HFF. When the authors treated the mice

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The Journal of Clinical Investigation   CO M M E N TA RY

Figure 1. Obesity-induced cellular and circuit level changes in the orexin system are associated with maladaptive behavioral responses. Chronic HFF
alters glutamatergic inputs to orexin/hypocretin neurons (Ox/Hcrt), thereby increasing overall inhibitory tone and inducing a state of hypoarousal. Altered
cellular activity of orexin neurons influences the activity of downstream neural networks in the lateral hypothalamus and hippocampus and decreases
reward-seeking and coping behaviors. Chemogenetic activation of orexin neurons reverses changes in network activity and corrects the behavioral conse-
quences of HFF (14). GluR, glutamate receptor; D1R, dopamine 1 receptor; hM3Dq, chemogenic receptor.

with a therapeutic for narcolepsy (modaf- orexin neurons, which then reverses with this relationship is bidirectional (21), and
inil) to enhance alertness, the mice also longer-term consumption (17). Together, connections between orexin neurons
overcame the obesity-induced stress defi- these studies demonstrate that multiple and the energy-sensing arcuate nucleus
cit. Collectively, these findings suggest pre- and postsynaptic mechanisms serve neurons likely contribute to such circuit
that hypoarousal mediated by the orexin to dynamically regulate glutamatergic function changes. These data raise the
system may cause the neural circuit and inputs to orexin neurons, which parallel possibility that multiple signals reflective
behavioral changes observed with HFF. short- and long-term changes in the met- of metabolic status may influence orexin
abolic state. system function. While it is interesting
Physiological significance and The orexin system adaptation to HFF to speculate, further work is required to
future studies likely serves to regulate arousal and the determine the precise factors driving the
Glutamatergic synaptic activity contrib- motivation for reward relative to meta- synaptic changes with HFF.
utes to the basal electrical excitability bolic status. However, the paper by Tan Additional remaining questions relate
of orexin neurons (15), and increasing and Hang et al. raises additional questions to the outputs driving the behavioral con-
evidence suggests that metabolic sta- about what is driving the effect. DIO asso- sequences. Although it is likely that orexin
tus is central in setting this tone. While ciates with multiple physiological chang- itself mediates the effects, orexin neurons
Tan and Hang et al. (14) demonstrate es, and orexin neurons are responsive to coexpress glutamate, and chemogenic acti-
that chronic HFF decreased signaling various signals reflective of energy status, vation of orexin neurons provides limited
at glutamatergic synapses onto orex- including circulating nutrients, endo- control over selective release of peptides or
in neurons, fasting has been shown to cannabinoids, and hormones (12, 18). A fast neurotransmitters (22). Furthermore,
have the opposite effect and rapidly large component of the diet-driven effect both orexin receptor (OxR) subtypes are
promotes excitatory neurotransmission appears to involve presynaptic mecha- expressed in regions of the brain implicat-
at orexin synapses (16). These synaptic nisms. Given that leptin administration can ed in arousal, motivation, and reward (12).
changes are likely crucial for orexin neu- prevent fasting-induced synaptic changes While the OxR1 may be more relevant for
rons’ ability to formulate the appropri- at orexin synapses (16), persistently elevat- reward and OxR2 for arousal (13), the con-
ate autonomic, endocrine, or behavioral ed leptin levels may also contribute to the tribution of each receptor to the observed
responses according to metabolic status; synaptic changes seen with HFF. effects is unknown. Moreover, the down-
they also raise questions about how the Notably, the central melanocor- stream target neurons mediating these
orexin system may change over time with tin system innervates orexin neurons, effects remain undetermined. Although
exposure to HFF. Conveniently, data including excitatory inputs from proop- orexin neurons directly project to the hip-
recently published demonstrates that iomelanocortin neurons (19). The mela- pocampus and reward systems, they also
HFF produces a time-dependent change nocortin system is crucial in detecting heavily innervate monoaminergic arous-
in orexin neuron synaptic plasticity (17). energy status and signals to other arous- al-promoting neurons (12). This includes
Short-term HFF (1 day to 1 week) is asso- al centers via perifornical lateral hypo- the histaminergic neurons of the tubero-
ciated with increased excitatory drive to thalamic neurons (20). Furthermore, mammillary nucleus, which are important

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CO M M E N TA RY The Journal of Clinical Investigation  

for mediating orexin effects on arousal Address correspondence to: Natalie J. tion: implications for obesity. Physiol Behav.
(23). Histaminergic neurons are also impli- Michael, IUCPQ, 2725 chemin Ste-Foy, 2010;100(5):419–428.
14. Tan Y, et al. Impaired hypocretin/orexin system
cated in motivation and goal-directed local Y3150, Québec, Canada, G1V 4G5.
alters responses to salient stimuli in obese male
behaviors and project to many important Phone: 418.656.8711, ext. 3341; Email: mice. J Clin Invest. 2020;130(9):4985–4998.
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