Bimodal control of stimulated food intake by theendocannabinoid system

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Cells

Via activation of the cannabinoid type-1 (CB1) receptor, endogenous and exogenous cannabinoids modulate important biochemical and cellular processes in adipocytes. Several pieces of evidence suggest that alterations of mitochondrial physiology might be a possible mechanism underlying cannabinoids’ effects on adipocyte biology. Many reports suggest the presence of CB1 receptor mRNA in both white and brown adipose tissue, but the detailed subcellular localization of CB1 protein in adipose cells has so far been scarcely addressed. In this study, we show the presence of the functional CB1 receptor at different subcellular locations of adipocytes from epididymal white adipose tissue (eWAT) depots. We observed that CB1 is located at different subcellular levels, including the plasma membrane and in close association with mitochondria (mtCB1). Functional analysis in tissue homogenates and isolated mitochondria allowed us to reveal that cannabinoids negatively regulate complex-I-dependent oxygen consumption in eWAT. This effect requires mtCB1 activation and consequent regulation of the intramitochondrial cAMP-PKA pathway. Thus, CB1 receptors are functionally present at the mitochondrial level in eWAT adipocytes, adding another possible mechanism for peripheral regulation of energy metabolism. © 2022 by the authors.Role du recepteur CB1 mitocondriel du tissue adipeux dans la regulation de la balance energetiqueVieillissement et démence: un rôle hormonal?Development of pregnenolone derivatives as allosteric inhibitors of CB1 cannabinoid receptors for thetreatment of schizophrenia and psychotic syndrome

Functional heterogeneity of POMC neurons relies on mTORC1 signaling.

Hypothalamic pro-opiomelanocortin (POMC) neurons are known to trigger satiety. However, these neuronal cells encompass heterogeneous subpopulations that release γ-aminobutyric acid (GABA), glutamate, or both neurotransmitters, whose functions are poorly defined. Using conditional mutagenesis and chemogenetics, we show that blockade of the energy sensor mechanistic target of rapamycin complex 1 (mTORC1) in POMC neurons causes hyperphagia by mimicking a cellular negative energy state. This is associated with decreased POMC-derived anorexigenic α-melanocyte-stimulating hormone and recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Electrophysiology and optogenetic studies further reveal that pharmacological blockade of mTORC1 simultaneously activates POMC/GABAergic neurons and inhibits POMC/glutamatergic ones, implying that the functional specificity of these subpopulations relies on mTORC1 activity. Finally, POMC neurons with different neurotransmitter profiles possess specific molecular signatures and spatial distribution. Altogether, these findings suggest that mTORC1 orchestrates the activity of distinct POMC neurons subpopulations to regulate feeding behavior

Cannabinoid-induced motor dysfunction via autophagy inhibition

The recreational and medical use of cannabis is largely increasing worldwide. Cannabis use, however, can cause adverse side effects, so conducting innovative studies aimed to understand and potentially reduce cannabis-evoked harms is important. Previous research conducted on cultured neural cells had supported that CNR1/CB1R (cannabinoid receptor 1), the main molecular target of cannabis, affects macroautophagy/autophagy. However, it was not known whether CNR1 controls autophagy in the brain in vivo, and, eventually, what the functional consequences of a potential CNR1-autophagy connection could be. We have now found that Δ9-tetrahydrocannabinol (THC), the major intoxicating constituent of cannabis, impairs autophagy in the mouse striatum. Administration of autophagy activators (specifically, the rapalog temsirolimus and the disaccharide trehalose) rescues THC-induced autophagy inhibition and motor dyscoordination. The combination of various genetic strategies in vivo supports the idea that CNR1 molecules located on neurons belonging to the direct (striatonigral) pathway are required for the autophagy- and motor-impairing activity of THC. By identifying autophagy as a mechanistic link between THC and motor performance, our findings may open a new conceptual view on how cannabis acts in the brain

The endocannabinoid system controls food intake via olfactory processes

Comment in Sensory systems: the hungry sense. [Nat Rev Neurosci. 2014] Inhaling: endocannabinoids and food intake. [Nat Neurosci. 2014]; International audience; Hunger arouses sensory perception, eventually leading to an increase in food intake, but the underlying mechanisms remain poorly understood. We found that cannabinoid type-1 (CB1) receptors promote food intake in fasted mice by increasing odor detection. CB1 receptors were abundantly expressed on axon terminals of centrifugal cortical glutamatergic neurons that project to inhibitory granule cells of the main olfactory bulb (MOB). Local pharmacological and genetic manipulations revealed that endocannabinoids and exogenous cannabinoids increased odor detection and food intake in fasted mice by decreasing excitatory drive from olfactory cortex areas to the MOB. Consistently, cannabinoid agonists dampened in vivo optogenetically stimulated excitatory transmission in the same circuit. Our data indicate that cortical feedback projections to the MOB crucially regulate food intake via CB1 receptor signaling, linking the feeling of hunger to stronger odor processing. Thus, CB1 receptor-dependent control of cortical feedback projections in olfactory circuits couples internal states to perception and behavior

Subcellular specificity of cannabinoid effects in striatonigral circuits

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior

Die humane Komplementfaktor H-Genfamilie

Im Rahmen der hier vorliegenden Arbeit über die Organisation und Regulation der Faktor HGenfamilie wurden folgende drei Themenkomplexe bearbeitet: Zur Aufklärung der genomischen Organisation der HF-Genfamilie wurden humane Mega YACund BAC-Klone mittels Restriktionsanalyse, Southernblothybridisierung, PCR und Sequenzierung analysiert. Alle Gene der Faktor H-Familie HF1- 5 konnten auf diesen Klonen lokalisiert werden, d.h. diese Genfamilie liegt zusammen auf einem DNS-Abschnitt von ca. 400 kb auf Chromosom 1q32. Weitere HF1-verwandte Genabschnitte wurde identifiziert, die in die Nähe von HF3, HF5 und F13B lokalisiert wurden. Flankierend zur Faktor H-Genfamilie wurden die Gene für F13B und PCP-2 kartiert. Die Gene können wie folgt von telomer nach zentromer angeordnet werden: PCP-2, HF1, HF4, HF2, HF5 gefolgt von HF3/HF6/F13B, deren Orientierung nicht eindeutig festgelegt werden konnte. Die Häufung der HF-Gene auf einem DNS-Abschnitt und deren Anordnung in Tandem- Orientierung läßt vermuten, daß diese Genfamilie ihren Ursprung in Genduplikation hat. In dieser chromosomalen Region werden Rekombinations-Hotspots vermutet, die eine erhöhte Rekombinationsfrequenz verursachen infolge derer Duplikationen entstehen können. Durch Fehler bei der Rekombination kann es jedoch auch zum Verlust von genetischem Material kommen. Vermutlich kann man die Deletion im Bereich des HF2- und HF4-Gens, die bei 4-5% der untersuchten Probanden gefunden werden kann, durch einen solchen Mechanismus erklären. Diese Deletion, ein genetischer Marker in dieser Region, kann nun mit einem einfachen PCR-basierenden Test, festgestellt werden. Die Isolierung und Kartierung des Faktor H-Genkomplexes erleichtert die Suche nach Kandidatengenen für das hämolytisch urämische Syndrom (HUS), da die Region als Kandidatenregion für dieses Syndrom identifiziert wurde. Es ist möglich, daß Faktor H oder die Faktor H-verwandten Proteine eine Rolle bei der Entstehung dieser Krankheit spielen. Ob die oben erwähnten HF2-Deletion eine Rolle bei der Pathogenese von entzündlichen Erkrankungen insbesondere rheumatischer Arthritis, spielt, wurde an einem großen Patientenkollektiv untersucht. Es wurde jedoch keine Korrelation zwischen Deletion und Erkrankung gefunden. Zur weiteren Untersuchung der Funktion der Faktor H-verwandten Proteine, wurde deren Expression auf Protein und mRNS-Ebene untersucht. Faktor H und die Faktor H verwandten Proteine 1 und 2 wurden im Liquor cerebralis entdeckt. Der Hauptsyntheseort im Gehirn für Faktor H scheint des Endothel des Plexus chorioideus und die Gliazellen zu sein. Die HFverwandten Transkripte sind nur auf geringem Niveau nachweisbar. Die Transkription von HF1 ist in den allen getesteten Gliomazellinien mit IFNg stimulierbar. Faktor H verhält sich also im Gehirn, ebenso wie in der Leber, als Akute-Phase-Protein und verhindert eine ungewünschte Komplementaktivierung im Zuge von Infektionen, Verletzungen und Erkrankungen des Gehirns. Durch die inflammatorischen Cytokine IL4 und IL6 wird die Transkription von HF1 nicht beeinflußt. Die HF1-verwandten Gene HF1- 5 sind in den Gliomazellinien nicht mit IFNg stimulierbar und auch IL4 und IL6 zeigen keinen Einfluß auf die Expression dieser Gene. Im Gegensatz zu Faktor H sind diese Proteine wahrscheinlich nicht an der Akute-Phase-Antwort des Gehirns beteiligt. Welche Aufgabe ihnen zufällt ist offen

Synaptic functions of type-1 cannabinoid receptors in inhibitory circuits of the anterior piriform cortex

In the olfactory system, the endocannabinoid system (ECS) regulates sensory perception and memory. A major structure involved in these processes is the anterior piriform cortex (aPC), but the impact of ECS signaling in aPC circuitry is still scantly characterized. Using ex vivo patch clamp experiments in mice and neuroanatomical approaches, we show that the two major forms of ECS-dependent synaptic plasticity, namely depolarization-dependent suppression of inhibition (DSI) and long-term depression of inhibitory transmission (iLTD) are present in the aPC. Interestingly, iLTD expression depends on layer localization of the inhibitory neurons associated with the expression of the neuropeptide cholecystokinin. Conversely, the decrease of inhibitory transmission induced by exogenous cannabinoid agonists or DSI do not seem to be impacted by these factors. Altogether, these results indicate that CB1 receptors exert an anatomically specific and differential control of inhibitory plasticity in the aPC, likely involved in spatiotemporal regulation of olfactory processes

CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity During Extinction of Conditioned Fear in Mice

Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activities in CB1-dependent extinction of conditioned fear behavior, conditioned CB1-deficient mice (CB1(-/-)) and wild-type littermates (CB1(+/+)) were sacrificed 30 min after recall of fear memory, and activation of ERKs, AKT, and calcineurin was examined by Western blot analysis in different brain regions. As compared with CB1(+/+), the nonreinforced tone presentation 24 h after auditory-cued fear conditioning led to lower levels of phosphorylated ERKs and/or calcineurin in the basolateral amygdala complex, ventromedial prefrontal cortex, dorsal hippocampus, and ventral hippocampus of CB1(-/-). In contrast, higher levels of phosphorylated p44 ERK and calcineurin were observed in the central nucleus of the amygdala of CB1(-/-). Phosphorylation of AKT was more pronounced in the basolateral amygdala complex and the dorsal hippocampus of CB1(-/-). We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner