Orexin deficiency and cardiometabolic risk in narcolepsy: mechanistic pathways and therapeutic implications.

Orexin deficiency and cardiometabolic risk in narcolepsy: mechanistic
pathways and therapeutic implications

Keywords: cardiometabolic risk, insulin resistance, narcolepsy type 1, orexin, orexin receptor agonist

Abstract

Narcolepsy type 1 (NT1) results from autoimmune destruction of orexin-producing
neurons in the lateral hypothalamus. While traditionally viewed as a sleep
disorder, accumulating evidence indicates that orexin deficiency produces
widespread cardiometabolic consequences—including obesity, insulin
resistance, dyslipidemia, metabolic-associated steatotic liver disease, and
major adverse cardiovascular events—that cannot be fully explained by
weight gain or medication effects alone. This review examines four overlapping
mechanisms through which orexin deficiency drives cardiometabolic risk. First,
loss of orexin disrupts the coupling of hunger drive with arousal and energy
expenditure. Orexin neurons interact with neuropeptide Y (NPY)/agouti-related
peptide (AgRP) and pro-opiomelanocortin (POMC) circuits and project to reward
and cognitive control pathways; their absence impairs satiety signaling, blunts
hedonic reward processing, and uncouples food intake from physical activity.
Second, orexin has direct peripheral metabolic effects—enhancing
beta-cell function, promoting adipocyte insulin sensitivity, and suppressing
hepatic gluconeogenesis. Loss of these actions promotes insulin resistance,
atherogenic dyslipidemia, and hepatic steatosis. Third, disrupted sleep
architecture and autonomic dysfunction compound metabolic risk. Orexin loss
produces state-dependent dysautonomia—reduced resting sympathetic drive
with inadequate parasympathetic compensation during sleep—contributing to
nondipping blood pressure and elevated cardiovascular risk. Disease-specific
barriers, including cataplexy avoidance, further limit physical activity.
Fourth, the autoimmune inflammatory process may contribute to systemic metabolic
inflammation, though the extent of ongoing inflammation after neuronal loss
remains uncertain. These mechanisms are interdependent and mutually reinforcing.
Selective orexin receptor 2 agonists such as oveporexton offer the first
opportunity to restore lost orexin signaling. Whether this translates into
cardiometabolic improvements warrants systematic evaluation in future
trials.

INTRODUCTION

Orexin deficiency in narcolepsy type 1 contributes to cardiometabolic risk through
multiple interacting pathways—including dysregulated satiety signaling,
insulin resistance, sleep disruption, and autoimmune inflammation. These mechanisms
overlap and reinforce each other over time rather than acting independently. This
review examines the physiological basis for this increased risk and considers the
therapeutic implications of emerging orexin-based therapies.

Orexin-A and orexin-B (also referred to as hypocretin-1 and -2, respectively) are
hypothalamic neuropeptides originally identified in the late 1990s in the context of
feeding behavior and arousal (1, 2). Their discovery, by two independent groups
approaching the problem from different directions, ended up reshaping how sleep
regulation was understood (1, 2).

These peptides are produced by a small group of neurons in the lateral hypothalamus,
estimated at roughly 70,000 cells. Despite that, their projections extend widely
across the central nervous system. Through these connections, the orexin system
influences sleep-wake regulation, energy balance, reward pathways, autonomic
control, and neuroendocrine signaling (3). In
practical terms, the orexin system behaves less like a discrete circuit and more
like a coordinating network that links behavioral state with metabolic demand.

Orexins act via two G-protein-coupled receptors, orexin-1 receptor (OX1R) and orexin
receptor 2 (OX2R), which have overlapping but not identical patterns of expression
in both central and peripheral tissues (4).
OX1R shows higher affinity for orexin-A, whereas OX2R binds both peptides with
similar affinity (4). Functionally, OX2R
appears to play the dominant role in maintaining wakefulness, whereas OX1R is more
closely tied to reward and feeding-related behaviors (5).

Importantly, orexin receptors are present in peripheral tissues such as pancreatic
islets, adipose tissue, adrenal glands, and parts of the gastrointestinal tract
(4). Orexin signaling is thus not confined
to the brain and contributes to systemic metabolic regulation.

The orexin system has a context-dependent role in glucose regulation. During
hypoglycemia, it helps maintain euglycemia by promoting glucose mobilization,
epinephrine release, and feeding behavior. Under hyperglycemic conditions, it
enhances insulin sensitivity via increased GLUT 4 expression (6). This kind of bidirectional behavior suggests that orexin
helps maintain metabolic balance rather than driving metabolism in one direction.
Thus, when orexin is deficient, what is disrupted may be state-dependent metabolic
coordination rather than just sleep itself.

The clinical data broadly support this idea. Meta-analyses show increased prevalence
of obesity, diabetes, hypertension, and dyslipidemia in patients with narcolepsy
compared with matched controls (7). Metabolic
syndrome has been reported in ∼30% of narcolepsy patients overall, and up to
59% of those with NT1. Prediabetes and nondipping blood pressure patterns, which are
both associated with adverse cardiovascular outcomes, frequently cooccur (8).

Large retrospective cohort studies reinforce this pattern. In one study including
over 22,000 patients with narcolepsy, higher rates of hypertension, hyperlipidemia,
diabetes, metabolic-associated steatotic liver disease (MASLD), and major adverse
cardiovascular events were observed compared with matched controls (9). These associations held even after adjusting
for treatment effects and were present in younger patients, suggesting that
cardiometabolic dysfunction starts relatively early in the disease course (9).

Taken together, narcolepsy can be viewed as a multisystem disorder rather than a
purely sleep-related condition. The following sections look at four overlapping
mechanisms—dysregulated hunger and satiety signaling, insulin resistance,
sleep disruption, and autoimmune inflammation—that may help explain this
increased cardiometabolic risk. Figure 1
provides a schematic overview of these interconnected mechanisms, and Table 1 summarizes the supporting evidence for
each.

Table 1.Summary of key evidence supporting the four mechanistic pathways linking
orexin deficiency to cardiometabolic risk in NT1

Mechanism Key Finding Population/Model References

Dysregulated appetite and satiety

 Impaired sensory-specific satiety NT1 patients failed to shift food preference after satiation;
consumed more calories ad libitum Human (NT1 vs. controls) van Holst 2016 (10)

 Blunted hedonic reward signaling VTA and nucleus accumbens responses blunted during reward tasks on
fMRI Human (unmedicated NT1) Ponz 2010 (11)

 Enhanced cognitive food-cue responses Increased vmPFC activation to food cues predicted snack intake; not
seen in idiopathic hypersomnia Human (NT1 vs. IH) van Holst 2018 (12)

 Weight gain despite reduced intake Orexin-KO mice gained weight with increased fat mass and hepatic
steatosis despite eating less Mouse (orexin-KO) Devère 2025 (13)

Insulin resistance and adipocyte dysfunction

 Elevated HOMA-IR independent of BMI Insulin resistance present early in pediatric narcolepsy, not
explained by body weight Human (pediatric NT1) Zhang 2023 (14)

 Orexin supports beta-cell function Orexin-A enhances glucose-stimulated insulin secretion via
PI3K/Akt/ERK and mTOR pathways In vitro (INS-1E, rat insulinoma) Skrzypski 2016 (15); Chang
2019 (16)

 Orexin deficiency → MASH and HCC Orexin-deficient mice on high-fat diet developed MASH with fibrosis;
orexin supplementation attenuated changes Mouse (orexin-deficient) Tsuneki 2022 (17)

 Impaired BAT thermogenesis Orexin-null mice show lower energy expenditure despite similar
caloric intake Mouse (orexin-null) Milbank 2019 (18); Sellayah
2011 (19)

Disrupted sleep and cardiovascular

 Sleep fragmentation Reduced slow-wave sleep, more frequent awakenings, and sleep
instability Human (NT1) Zhang 2021 (20); Maski 2022
(21)

 No difference in energy expenditure Calorimetry and doubly labeled water showed similar energy
expenditure in NT1 vs. controls Human (NT1 vs. controls) Donjacour 2025 (22)

 Loss of nocturnal BP dipping Non-dipping blood pressure in a substantial proportion of NT1
patients Human (NT1) Zhang 2026 (8); Jennum 2021
(23)

 Autonomic dysfunction Increased sympathovagal imbalance during sleep; blunted
cardiovascular reflexes Human (NT1) Grimaldi 2014 (24); Donadio
2014 (25); Aslan 2019 (26)

Autoimmune inflammation

 HLA-DQB1*06:02 association Strong genetic association with NT1 across populations Human (genetic studies) Liblau 2024 (3); Luo 2018
(27)

 Cross-reactive T cells T cells recognizing both influenza antigens and hypocretin peptides
identified Human/in vitro Luo 2018 (27)

 Autoreactive T cells in blood and CSF CD4+ and CD8+ T cells targeting hypocretin
antigens detected in peripheral blood and CSF Human (NT1) Latorre 2018 (28)

References are given as first author, year, and reference-list number;
additional supporting citations are provided in the corresponding
sections of the text. BAT, brown adipose tissue; BMI, body mass index;
BP, blood pressure; CSF, cerebrospinal fluid; fMRI, functional magnetic
resonance imaging; HCC, hepatocellular carcinoma; HOMA-IR, homeostatic
model assessment for insulin resistance; IH, idiopathic hypersomnia;
MASH, metabolic associated steatohepatitis; NT1, narcolepsy type 1;
vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmental area.

Mechanism 1: Dysregulated Appetite and Satiety Signaling

Orexin deficiency may also contribute to cardiometabolic risk by altering
appetite, satiety, and food-related decision-making. This mechanism is distinct
from insulin resistance, sleep disruption, and autoimmune inflammation because
it focuses on how the brain regulates food intake itself, including hunger
signaling, satiety perception, and reward-based eating.

Hypothalamic Appetite Signaling

Orexin neurons reside in the lateral hypothalamus, anatomically distinct from the
melanocortin system, which is organized around the arcuate nucleus and
paraventricular nucleus of the hypothalamus. Nonetheless, orexin interacts
directly with both components of this circuit. In the arcuate nucleus, orexin-A
preferentially activates NPY/AgRP neurons through OX1R-coupled calcium signaling
while suppressing POMC neuron activity through mechanisms involving both OX1R
and OX2R, producing effects that are largely reciprocal to leptin (29–33). Synaptic
connections between orexin neurons and NPY cells in the arcuate nucleus have
been demonstrated in both rodent and primate hypothalamus, suggesting this
interaction is conserved and functionally significant (34). Orexin-A signaling also reaches the paraventricular
nucleus, where it promotes food intake through the agouti-related peptide
(AgRP)/NPY pathway (35). Importantly,
orexin is an orexigenic neuropeptide that normally couples hunger drive with
arousal and energy expenditure, linking the motivation to eat with the
sympathetic activation needed to seek food and burn energy. When orexin neurons
are destroyed in NT1, hunger persists through intact orexigenic pathways
(NPY/AgRP, ghrelin), but the corresponding drive toward physical activity,
sympathetic tone, and thermogenesis is lost. This uncoupling of intake from
expenditure likely contributes to the positive energy balance and weight gain
observed in narcolepsy.

Satiety, Reward Processing, and Food Choice

Human studies provide important evidence that orexin deficiency affects satiety
and food-related behavior. van Holst et al. (10) showed that patients with NT1 have impaired sensory-specific
satiety. After eating a specific food to fullness, healthy controls naturally
shifted their preference toward different foods, whereas patients with NT1
continued selecting the same food and consumed substantially more calories
during ad libitum snacking. This suggests that abnormal orexin signaling can
disrupt the normal integration of satiety signals with reward-driven food
choice.

Orexin neurons in the lateral hypothalamus also project directly to the ventral
tegmental area (VTA), where they potentiate dopamine release in the nucleus
accumbens through OX1R signaling, forming the hedonic reward circuit for food
(36, 37). In NT1, this circuit appears functionally impaired. A
functional magnetic resonance imaging (fMRI) study in patients with unmedicated
NT1 found that VTA activity was not modulated during reward anticipation, and
nucleus accumbens responses were blunted during reward delivery (11). Clinically, patients with NT1 show
higher rates of binge eating and impulsivity, consistent with disrupted reward
processing (38).

Separately, the cognitive control pathway also appears affected. Patients with
NT1 show enhanced ventromedial prefrontal cortex (vmPFC) responses to food cues,
with vmPFC activity predicting spontaneous snack intake—and this effect
was not seen in patients with idiopathic hypersomnia, suggesting it is specific
to orexin deficiency rather than sleepiness alone (12).

Together, these findings suggest that orexin loss disrupts both the reward
valuation of food and the executive control over food-seeking behavior.

Endocannabinoid-Mediated Satiety Suppression

Orexin may also influence appetite through endocannabinoid pathways. Morello et
al. (31) described a mechanism in which
orexin-A signaling in POMC neurons stimulates production of
2-arachidonoylglycerol, which then acts through cannabinoid-1 (CB1) receptors to
suppress POMC transcription and reduce alpha-melanocyte-stimulating hormone
(α-MSH) production. Since POMC and α-MSH are key satiety signals,
this provides a plausible molecular pathway by which orexin signaling can blunt
satiety. This pathway is important because it connects orexin biology directly
to appetite regulation at the cellular level, rather than relying only on
behavioral observations.

Weight Gain Despite Reduced Intake in Orexin Deficiency

A key observation in orexin biology is that orexin-deficient animal models may
eat less than controls but still gain weight. Devère et al. (13) showed that orexin-KO mice developed
increased body weight, greater fat mass, impaired glucose tolerance, reduced
insulin secretion, and hepatic steatosis despite reduced food intake in males.
Similarly, González et al. (39)
demonstrated that orexin neuron activity normally falls rapidly at the onset of
eating and remains suppressed during consumption, suggesting that orexin neurons
participate in the timing and control of feeding behavior. These findings imply
that weight gain in orexin deficiency cannot be explained by caloric intake
alone. Reduced energy expenditure, altered nutrient handling, impaired insulin
secretion, and abnormal satiety signaling may all contribute.

More explicitly, daytime sleepiness lowers habitual activity in NT1, which
promotes visceral adiposity and insulin resistance independent of caloric
intake; because orexin normally couples arousal with locomotor drive and energy
expenditure, its loss reduces the drive to move while orexigenic appetite
signaling remains intact, widening the mismatch between energy intake and
expenditure.

Appetite Hormones: Mixed Human Data

Human studies of appetite hormones in narcolepsy have been inconsistent. Kok et
al. (40) reported reduced plasma leptin
levels and loss of normal circadian leptin rhythmicity in hypocretin-deficient
patients. However, Donjacour et al. (41)
found no significant difference in 24-h ghrelin or leptin levels when patients
were carefully matched for body mass index (BMI), and a
meta-analysis (7) did not show a
consistent pooled leptin difference. Huda et al. (42) reported unchanged ghrelin but elevated obestatin,
which correlated with autonomic dysfunction.

These mixed results regarding NT1 and its influence on the hormonal modulation of
appetite are not surprising. Appetite hormones are influenced by body
composition, autonomic tone, sleep timing, medications, and disease duration.
Therefore, appetite dysregulation in NT1 is probably not explained by a single
hormone abnormality.

Taken together, the evidence from impaired sensory-specific satiety, altered
hormonal profiles, and disrupted orexin-mediated reward signaling suggests that
orexin deficiency may alter not only metabolism and sleep but also how the brain
registers satiety and responds to food cues. Appetite dysregulation therefore
represents one pathway linking narcolepsy to obesity and cardiometabolic
risk.

Mechanism 2: Insulin Resistance and Adipocyte Dysfunction

Orexin does not just act in the brain—it has direct effects on the
pancreas, adipose tissue, and liver. When that signaling is lost in NT1, the
metabolic consequences may go well beyond what weight gain alone can
explain.

Orexin Receptor Expression and Signaling in Metabolic Tissues

Orexin has direct metabolic effects on peripheral tissues that extend beyond its
central role. Orexin receptors are expressed in pancreatic islets, adipose
tissue, and hepatocytes, allowing orexin signaling to influence metabolism at
multiple levels (4).

In pancreatic beta cells, orexin-A enhances beta-cell function and mass through
OX1R-mediated activation of phosphoinositide 3-kinase/protein kinase B
(PI3K/Akt) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling
pathways (6, 15). Notably, these effects are glucose-dependent, meaning
orexin potentiates the beta-cell response to ambient glucose rather than
independently driving insulin release (15). This pathway is clinically relevant beyond narcolepsy. In oncology,
drugs that inhibit the PI3K/Akt/mechanistic target of rapamycin (mTOR)
pathway—now a major class of targeted cancer therapies—commonly
cause insulin resistance and hyperglycemia. By analogy, loss of orexin-mediated
activation of this pathway in NT1 may contribute to insulin resistance and
downstream cardiometabolic dysfunction (6). Experimental work using INS-1E cells suggests that orexin-A
modulates insulin secretion through calcium-dependent signaling and transient
receptor potential channels (15). These
effects seem to depend on both receptor subtype and the surrounding metabolic
environment.

The insulinotropic effects of orexin-A are glucose-dependent. Orexin-A enhances
glucose-stimulated insulin secretion through intracellular calcium mobilization
involving adenylate cyclase and ryanodine receptor pathways, with exchange
protein directly activated by cyclic adenosine monophosphate 2 (Epac2) playing a
role (43). That detail is probably
important, since it implies that orexin is more involved in amplifying responses
when glucose is already elevated rather than driving insulin secretion at
baseline.

Time-course studies suggest that orexin participates in postprandial metabolic
regulation, with changes in insulin and leptin levels following glucose loading
(43). The effect appears relatively
transient, which again fits with a role in short-term metabolic adjustment.

Orexin-A has also been shown to activate the mTOR pathway in beta cells via OX1R,
which may support both beta-cell function (including glucose-responsive insulin
release) and cell maintenance through promotion of cell growth and survival
(16). How much this contributes to
long-term beta-cell function is still not entirely clear, but it is a plausible
link.

Adipose and Hepatic Effects

In adipose tissue, orexin-A promotes glucose transporter type 4 (GLUT4)
translocation and adiponectin secretion through orexin-1 receptor
(OX1R)-mediated activation of peroxisome proliferator-activated receptor
gamma/CCAAT/enhancer-binding protein alpha (PPARγ/CCAAT/(C/EBPα)
pathways while exerting anti-inflammatory effects via Sirtuin-1/NOD-, LRR-, and
pyrin domain-containing protein 3 [sirtuin-1 (SIRT1)/NOD-, LRR-, and pyrin
domain-containing protein 3 (NLRP3)] signaling (6). Orexin also enhances energy expenditure through browning of
white adipose tissue (44). When orexin
signaling is lost, insulin resistance develops at the level of the
adipocyte—insulin can no longer suppress hormone-sensitive lipase,
leading to increased lipolysis and excess free fatty acid release into the
circulation (45). This is the primary
driver of the atherogenic dyslipidemia seen in metabolic syndrome [elevated
triglycerides, low high-density lipoprotein (HDL), increased small dense
low-density lipoprotein (LDL)], and the excess free fatty acids also accumulate
ectopically in the liver and muscle, worsening systemic insulin resistance
(46).

In the liver, orexin suppresses gluconeogenesis via peroxisome
proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)
downregulation and maintains endoplasmic reticulum (ER) homeostasis through
daily bidirectional regulation of the autonomic nervous system (6, 47). Orexin-A further activates the hepatic OX1R/PI3K/Akt/mechanistic
target of rapamycin complex 1 (mTORC1) pathway, regulating forkhead box protein
O1 (FoxO1) phosphorylation and promoting hepatocyte survival (48). Without tonic orexin input, hepatic
insulin resistance develops, in which insulin fails to suppress gluconeogenesis
while simultaneously driving de novo lipogenesis via sterol regulatory
element-binding protein 1c (SREBP-1c), promoting hepatic steatosis. The
adipocyte-derived free fatty acid overflow compounds this by overwhelming
hepatic lipid disposal. Consistent with this, orexin-deficient mice on a
high-fat diet develop severe metabolic dysfunction–associated
steatohepatitis (MASH) with fibrosis and hepatocellular carcinoma, driven
by unchecked ER stress; daily orexin-A supplementation attenuated these changes
(17).

Orexin also contributes to energy expenditure through activation of brown adipose
tissue thermogenesis (4, 18). This involves hypothalamic regulation
of sympathetic output. Part of this regulation occurs through the melanocortin
system—orexin neurons in the lateral hypothalamus project to
melanocortin-4 receptor (MC4R)-expressing neurons in the paraventricular
nucleus, which in turn drive sympathetic outflow to brown adipose tissue (49). In orexin-null and orexin/ataxin-3
transgenic mice, orexin deficiency is associated with lower energy expenditure,
largely due to impaired brown adipose tissue thermogenesis and reduced
spontaneous physical activity. As a result, these animals are more prone to
weight gain even when caloric intake is similar to, or lower than, that of
wild-type controls (18, 19). Loss of orexin thus removes a critical
input to the melanocortin-sympathetic-thermogenic axis, reducing energy
expenditure independent of food intake (19, 49).

Evidence of Insulin Resistance

Clinical data suggest that insulin resistance is a central feature of metabolic
dysfunction in narcolepsy. Pediatric studies report elevated homeostatic model
assessment for insulin resistance (HOMA-IR) in a large proportion of patients,
independent of BMI (14). This is notable
because it suggests that metabolic abnormalities may develop early and are not
simply secondary to changes in body weight.

Meta-analyses further support this, showing elevated insulin levels and increased
waist circumference in patients with narcolepsy (7). The magnitude varies across studies, but the overall pattern is
fairly consistent.

Mechanism 3: Autonomic Dysregulation and Disrupted Sleep Architecture

Orexin neurons project to central autonomic structures including the rostral
ventrolateral medulla (RVLM), NTS, and raphe pallidus, where they function as a
gain controller, modulating sympathetic and parasympathetic output based on
behavioral state rather than driving basal tone directly (50).

The clinical picture is nuanced. Microneurography in patients with untreated NT1
shows lower resting muscle sympathetic nerve activity, heart rate, and blood
pressure during wakefulness, with values tracking cerebrospinal fluid (CSF)
hypocretin-1 levels (24). Yet heart rate
variability studies find the opposite during sleep—medication-naïve
NT1 patients have consistently higher heart rates across all sleep stages
independent of fragmentation, and an elevated LF/HF ratio during non-rapid eye
movement (NREM) sleep suggests sympathovagal imbalance (25, 26). What seems
to be happening is not a simple shift in one direction but rather a loss of
autonomic flexibility—reduced tonic sympathetic drive at rest with
inadequate parasympathetic compensation when it matters most (51).

Cardiovascular reflex testing in treatment-naïve patients supports this.
Studies have found blunted Valsalva ratios, reduced respiratory sinus
arrhythmia, and impaired cold face responses—all pointing to
parasympathetic dysfunction that cannot be attributed to medications (24). During sleep, the dissociation is even
more striking: sleep-onset rapid eye movement periods (SOREMPs) in NT1 lack the
sympathetic surge that normally accompanies rapid eye movement (REM) sleep,
instead resembling light NREM (24). In
orexin-deficient mice, the nocturnal blood pressure fall is blunted, and
REM-associated pressure swings are exaggerated—effects abolished by
adrenergic blockade—offering a mechanistic basis for the nondipping
pattern seen clinically (50).

In short, orexin deficiency does not simply raise or lower sympathetic tone. It
disrupts the ability to appropriately adjust cardiovascular output across
changing states—and over time, that loss of flexibility likely adds to
cardiovascular risk in NT1 (51, 52).

Narcolepsy is associated with sleep instability. Beyond excessive daytime
sleepiness (EDS), patients often have reduced sleep efficiency, more frequent
awakenings, and less consolidated slow-wave sleep (20, 21). These
changes are generally thought to reflect the loss of orexin-mediated
stabilization of sleep-wake states. Without that stabilizing influence, the
system transitions easily between states rather than maintaining sustained
periods of sleep or wakefulness.

Sleep fragmentation and irregular sleep timing have both been linked to metabolic
dysfunction in several large cohort studies. Variability in sleep patterns, even
when total sleep time is similar, has been associated with a higher risk of
metabolic syndrome and related abnormalities (53, 54). The relationship is
not entirely straightforward, but it does seem that disrupted sleep continuity
itself—not just sleep duration—plays a role.

Beyond sleep fragmentation, circadian misalignment may further compound metabolic
risk. Resting energy expenditure varies with circadian phase, and in shift
workers—a well-studied model of circadian disruption—simulated
night-shift schedules reduce total daily energy expenditure while increasing
acylated ghrelin levels and appetite for energy-dense foods (55–57). Broader evidence
suggests that sleep disruption promotes weight gain primarily through increased
energy intake driven by alterations in appetite-regulating hormones rather than
through large changes in energy expenditure (58).

In narcolepsy specifically, Donjacour et al. measured energy expenditure in
patients with NT1 and matched controls using both respiration chamber
calorimetry and doubly labeled water and found no significant differences in
resting, 24-h, or activity-induced energy expenditure (22). These calorimetric findings suggest that reduced
energy expenditure is unlikely to be the primary driver of weight gain in this
population, and instead point toward alterations in satiety
signaling—consistent with orexin’s known role in appetite
regulation—as the more likely contributor to positive energy balance
(22, 58).

A related and clinically relevant finding is the loss of nocturnal blood pressure
dipping, which is seen in a substantial proportion of patients with NT1 (8). In the general population, nondipping
patterns are associated with higher cardiovascular risk, including increased
rates of stroke and cardiac events. In narcolepsy, this likely reflects a
combination of altered autonomic regulation and the effects of fragmented sleep.
Orexin neurons project to key autonomic centers, and their loss may interfere
with the normal nocturnal reduction in sympathetic tone (23).

At the same time, repeated arousals and sleep stage transitions may further
contribute to sympathetic activation. It is probably not a single mechanism but
rather an overlap of several processes that together shift the normal circadian
pattern of blood pressure regulation.

Mechanism 4: Autoimmune Inflammation

Narcolepsy type 1 is widely considered to be an autoimmune condition
characterized by selective destruction of hypocretin-producing neurons (3). The strength of the association with
human leukocyte antigen DQB1*06:02 (HLA-DQB1*06:02) is striking and has been one
of the more consistent findings across studies (3, 27). Additional genetic
associations involving T cell receptor loci and other immune-related genes
further support this model, although the exact sequence of events is still not
completely defined.

Environmental triggers appear to play a role as well. Epidemiological data
linking narcolepsy onset to influenza infection and
vaccination—particularly during the 2009 H1N1 pandemic—have been
difficult to ignore (3, 59). These observations led to the
hypothesis that molecular mimicry may be involved, where immune responses
directed at viral antigens cross react with hypocretin-related peptides.

Experimental work has provided some support for this idea. Cross-reactive T cell
populations recognizing both influenza antigens and hypocretin peptides have
been identified, suggesting at least a plausible mechanistic link (27). Animal models have also shown that
immune activation in genetically susceptible settings can lead to targeting of
orexinergic neurons, involving both CD4+ and CD8+ T cell
responses (59).

Direct evidence in humans comes from studies demonstrating autoreactive T cells
targeting hypocretin-associated antigens (28). These cells have been detected in both peripheral blood and
cerebrospinal fluid, indicating that they are capable of accessing the central
nervous system.

What remains less clear is how much ongoing inflammation persists after the
initial neuronal loss. Some postmortem studies show evidence of gliosis in the
hypothalamus, suggesting prior inflammatory activity, but whether there is
sustained low-grade inflammation contributing to systemic metabolic effects is
still somewhat uncertain.

That said, chronic inflammation is already known to be linked to insulin
resistance and endothelial dysfunction in other settings. So even if it is not
the primary driver, it could still contribute to the overall cardiometabolic
profile seen in narcolepsy.

Metabolomic Alterations and Cardiovascular Risk

The metabolic profile observed in narcolepsy seems to reflect the combined
effects of orexin deficiency, sleep disruption, and inflammation rather than any
single mechanism. Meta-analytic data show abnormalities in glucose metabolism,
lipid parameters, and inflammatory markers (7). These findings are broadly consistent with features of metabolic
syndrome, although the pattern is not always uniform across studies.

Large retrospective analyses add to this picture by showing increased risk of
hypertension, hyperlipidemia, diabetes, nonalcoholic fatty liver disease, and
major adverse cardiovascular events (9).
These associations persist even after adjusting for commonly used narcolepsy
medications, which suggests that the underlying disease process itself plays a
major role.

One of the more notable findings is that these risks are present even in younger
individuals, including those under 25 yr of age (9). That observation makes it less likely that these are purely
long-term complications and instead points toward early metabolic changes that
may accumulate over time.

From a clinical standpoint, this raises the question of whether screening for
metabolic abnormalities should be more routine in patients with narcolepsy, even
early in the disease course.

FUTURE DIRECTIONS

Limitations of Present Therapies

Current treatments for narcolepsy—specifically sodium oxybate,
modafinil/armodafanil, solriamfetol, and pitolisant—are effective for
symptom control but do not address the underlying orexin deficiency (5). These interventions improve wakefulness
or reduce cataplexy, but do not restore the signaling pathways that are
lost.

Overall, current therapies are not designed to modify the metabolic aspects of
the disease, and there is limited evidence that they do so in practice.

Orexin Receptor Agonists

The development of selective OX2R agonists represents a different therapeutic
approach—one that attempts to replace lost orexin signaling rather than
bypass it. The rationale comes from the observation that OX2R plays a dominant
role in wake regulation, whereas OX1R appears less critical in this context
(5).

TAK-994 was one of the first agents in this class to show strong clinical
efficacy. In trials, it led to substantial improvements in wakefulness and
reductions in cataplexy frequency (60).
However, its development was halted due to hepatotoxicity, and this drug never
came to market.

Oveporexton (TAK-861), which is a highly selective oral orexin receptor 2
agonist, is a structurally distinct compound that has shown similar efficacy
without the same liver toxicity concerns, at least in early studies (5). Improvements in both objective and
subjective measures of sleepiness have been reported, along with reductions in
cataplexy. The adverse effect profile—mainly insomnia and urinary
symptoms—appears manageable so far, although longer-term data are still
pending.

Potential Metabolic Effects

An open question is whether restoring orexin signaling will translate into
measurable improvements in cardiometabolic outcomes in patients with NT1. Given
what is known about orexin’s role in insulin sensitivity, adipocyte
function, and energy expenditure, it is biologically plausible. Most trials to
date have focused on sleep-related endpoints, and metabolic outcomes have not
been systematically evaluated; more investigation is needed to better answer
this important question.

CONCLUSIONS

Orexin deficiency in NT1 contributes to cardiometabolic risk through multiple,
interconnected pathways, including dysregulated satiety signaling, insulin
resistance, sleep disruption, and autoimmune inflammation. These mechanisms are
interdependent due to their overlap, thus reinforcing their sequelae and
effects.

ACKNOWLEDGMENTS

Present address of A. Shukla: Div. of Pulmonary, Critical Care, and Sleep Medicine,
Dept. of Medicine, University of California, San Francisco (UCSF Fresno), Fresno,
CA, United States; Inspire Health Medical Group, Fresno, CA, United States.

GRANTS

Dr. Nokes is supported by the Department of Veterans Affairs CSR&D CDA-2
IK2CX002524-01A2.

DISCLAIMERS

The contents do not represent the views of the U.S. Department of Veterans Affairs or
the United States Government.

DISCLOSURES

Dr. Nokes is a consultant for Takeda and has consulted for D.E. Shaw. Dr. Wojeck has
served on advisory boards for Corcept Therapeutics, and Amgen. Dr. Wojeck has done
consulting work for D.E. Shaw, Key Quest Health, Leerink, Partners, Medscape, Morgan
Stanley, Third Bridge, Fletcher Spaght Inc, Slingshot Insights, and Tegus. None of
the other authors has any conflicts of interest, financial or otherwise, to
disclose.

AUTHOR CONTRIBUTIONS

A.S.: Writing – original draft, Writing – review & editing,
Visualization; J.H.G.: Conceptualization, Writing – review & editing,
Visualization, Supervision, Project administration; B.N.: Funding acquisition,
Writing – original draft, Writing – review & editing,
Visualization, Supervision; B.S.W.: Conceptualization, Writing – review &
editing, Visualization, Supervision, Project Administration.

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