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Both evolutionarily and functionally, wakefulness
requires, and is accompanied by, food search and
intake for survival. From the molecular perspective,
the neuropeptide orexin-A (OX-A) promotes
wakefulness, α–melanocyte-stimulating hormone (α-MSH)
promotes satiety, and the endocannabinoid
2-arachidonoylglycerol (2-AG) promotes appetite.
In the cerebrospinal fluid of obese mice and in the
plasma of human obese subjects, researchers found an
inverse correlation between OX-A and α-MSH levels,
which led us to uncover the role of OX-A in
promoting hyperphagia by enhancing 2-AG levels and
subsequently activating CB1 receptor-mediated
down-regulation of POMC synthesis and α-MSH release.
Pharmacological inhibition of OX-A receptor type 1
counteracted the impairment of α-MSH signaling and
the associated hyperphagia, obesity, and steatosis,
thus providing a potential therapy for these
pathological conditions.
In the hypothalamic arcuate nucleus (ARC),
proopiomelanocortin (POMC) neurons and the POMC-derived
peptide α–melanocyte-stimulating hormone (α-MSH)
promote satiety. POMC neurons receive orexin-A
(OX-A)-expressing inputs and express both OX-A
receptor type 1 (OX-1R) and cannabinoid receptor
type 1 (CB1R) on the plasma membrane.
OX-A is crucial for the control of wakefulness and
energy homeostasis and promotes, in OX-1R–expressing
cells, the biosynthesis of the endogenous
counterpart of marijuana's psychotropic and
appetite-inducing component Δ9-tetrahydrocannabinol,
i.e., the endocannabinoid 2-arachidonoylglycerol
(2-AG), which acts at CB1R.
Researchers report that OX-A/OX-1R signaling at POMC
neurons promotes 2-AG biosynthesis, hyperphagia, and
weight gain by blunting α-MSH production via
CB1R-induced and extracellular-signal-regulated
kinase 1/2 activation- and STAT3 inhibition-mediated
suppression of Pomc gene transcription.
Because the systemic pharmacological blockade of
OX-1R by SB334867 caused anorectic effects by
reducing food intake and body weight, our results
unravel a previously unsuspected role for OX-A in
endocannabinoid-mediated promotion of appetite by
combining OX-induced alertness with food seeking.
Notably, increased OX-A trafficking was found in the
fibers projecting to the ARC of obese mice (ob/ob
and high-fat diet fed) concurrently with elevation
of OX-A release in the cerebrospinal fluid and blood
of mice.
Furthermore, a negative correlation between OX-A and
α-MSH serum levels was found in obese mice as well
as in human obese subjects (body mass index > 40),
in combination with elevation of alanine
aminotransferase and γ-glutamyl transferase, two
markers of fatty liver disease.
These alterations were counteracted by antagonism of
OX-1R, thus providing the basis for a therapeutic
treatment of these diseases.
For more information
PNAS
Orexin-A represses satiety-inducing POMC neurons and
contributes to obesity via stimulation of
endocannabinoid signaling
doi:10.1073/pnas.1521304113
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