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Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling (2016-04-17)

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.

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Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling