The endocannabinoid system plays an important role in the regulation of metabolism, growth and regeneration of peripheral tissues, including liver, adipose and muscle tissue. Studies in cells, rodents and humans showed that cannabinoid receptor 1 (CB₁) antagonist treatment is an effective strategy to improve features of metabolic health such as substrate metabolism, at least in models of metabolic dysregulation. However, acute signaling events that might induce these metabolic adaptations are not understood. It is not clear whether, and to which extent, a single treatment with a CB₁ antagonist induces acute effects in peripheral, metabolic tissues. Therefore, the present study compared the phosphorylation status of signaling pathways and metabolic markers in liver, adipose and muscle tissue of mice treated with the peripherally restricted CB₁ antagonist AM6545 and vehicle-treated mice. Protein kinase A phosphorylation was downregulated in white and brown adipose tissue, whereas the mitogen-activated protein kinase, phospho-extracellular signal-regulated kinase, was higher in liver, white adipose and muscle tissue of AM6545-treated mice. Additionally, Akt-mammalian target of rapamycin activation was higher in all tissues of AM6545-treated mice, whereas the phosphorylation status of metabolic markers remained unaffected. These data indicate that acute CB₁ antagonism is effective to induce phosphorylation events of signaling cascades and metabolic markers in metabolic tissues of healthy, lean mice within a 90-min time window. The observed adaptations to AM6545 treatment do not fully align with earlier in vitro and in vivo findings, which could be ascribed to differences in cell type, exposure intensity (dose and time), health status and species.

15 May 2024·The Journal of Neuroscience

Cholinergic Neurotransmission Controls Orexigenic Endocannabinoid Signaling in the Gut in Diet-Induced Obesity

Article

Author: DiPatrizio, Nicholas V ; Wood, Courtney P ; Alvarez, Camila

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut–brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

01 Jan 2024·Gastro Hep Advances

Cannabinoids Block Fat-induced Incretin Release via CB1-dependent and CB1-independent Pathways in Intestinal Epithelium

Article

Author: Makriyannis, Alexandros ; Perez, Pedro Antonio ; DiPatrizio, Nicholas Vincent ; Wiley, Mark Benjamin

Background and AimsGlucose homeostasis is regulated by a dynamic interplay between hormones along the gastro-insular axis. For example, enteroendocrine L- and K- cells that line the intestine produce the incretins glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), respectively, which are secreted following a meal. Broadly, incretin signaling enhances insulin release from the endocrine pancreas and participates in the control of food intake, and therapeutics that mimic their activity have recently been developed for the treatment of type-2 diabetes and obesity. Notably, genes for cannabinoid subtype-1 receptor (CB₁R) are expressed in these cell subpopulations; however, roles for CB₁Rs in controlling fat-induced incretin release are unclear. To address this gap in our understanding, we tested the hypothesis that intestinal epithelial CB₁Rs control fat-induced incretin secretion.MethodsWe treated mice with conditional deletion of CB₁Rs in the intestinal epithelium (IntCB₁-/-) or controls (IntCB₁+/+) with oil gavage to stimulate incretin release in the presence of the cannabinoid receptor agonists, WIN55,212-2 or Δ⁹ tetrahydrocannabinol (THC), and the peripherally-restricted CB₁R antagonist AM6545. Circulating incretin levels were measured in plasma.ResultsOral gavage of corn oil increased levels of bioactive GLP1 and GIP in IntCB₁+/+ mouse plasma. Pretreatment with the WIN55,212-2 or THC blocked this response, which was largely reversed by coadministration with AM6545. WIN55,212-2 failed to inhibit fat-induced GIP release, but not GLP1, in IntCB₁-/- mice. In contrast, THC inhibited the secretion of incretins irrespective of CB₁R expression in intestinal epithelial cells.ConclusionThese results indicate that cannabinoid receptor agonists can differentially inhibit incretin release via mechanisms that include intestinal epithelial CB₁R-dependent and CB₁R-independent mechanisms.

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Indication	Highest Phase	Country/Location	Organization	Date
Liver Diseases	Preclinical	US	MAKScientific LLC	-
Metabolic Diseases	Preclinical	US	MAKScientific LLC	-

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