Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling.
Giovanna MorelloRoberta ImperatoreLetizia PalombaCarmine FinelliGiuseppe LabrunaFabrizio PasanisiLucia SacchettiLorena BuonoFabiana PiscitelliPierangelo OrlandoVincenzo Di MarzoLuigia CristinoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2016)
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 Δ(9)-tetrahydrocannabinol, i.e., the endocannabinoid 2-arachidonoylglycerol (2-AG), which acts at CB1R. We 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.
Keyphrases
- low density lipoprotein
- body mass index
- weight gain
- high fat diet
- body weight
- weight loss
- spinal cord
- physical activity
- insulin resistance
- cerebrospinal fluid
- transcription factor
- dna methylation
- cell proliferation
- gene expression
- mental health
- induced apoptosis
- spinal cord injury
- oxidative stress
- risk assessment
- climate change
- tyrosine kinase
- bariatric surgery
- skeletal muscle
- birth weight
- replacement therapy
- cell wall
- smoking cessation
- human health
- endoplasmic reticulum stress
- genome wide identification