Endocannabinoids Produced by White Adipose Tissue Modulate Lipolysis in Lean but Not in Obese Rodent and Human

Abstract

White adipose tissue (WAT) possesses the endocannabinoid system (ECS) machinery and produces the two major endocannabinoids (ECs), arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). Accumulating evidence indicates that WAT cannabinoid 1 receptors (CB1R) are involved in the regulation of fat storage, tissue remodeling and secretory functions but their role in controlling lipid mobilization is unclear. In the present study, we used different strategies to acutely increase ECS activity in WAT and tested the consequences on glycerol production as a marker of lipolysis. Treating lean mice or rat WAT explants with JLZ195, which inhibits ECs degrading enzymes, induced an increase in 2-AG tissue contents that was associated with a CB1R-dependent decrease in lipolysis. Direct treatment of rat WAT explants with AEA also inhibited glycerol production while mechanistic studies revealed it could result from the stimulation of Akt-signaling pathway. Interestingly, AEA treatment decreased lipolysis both in visceral and subcutaneous WAT collected on lean subjects suggesting that ECS also reduces fat store mobilization in Human. In obese mice, WAT content and secretion rate of ECs were higher than in control while glycerol production was reduced suggesting that over-produced ECs may inhibit lipolysis activating local CB1R. Strikingly, our data also reveal that acute CB1R blockade with Rimonabant did not modify lipolysis in vitro in obese mice and human explants nor in vivo in obese mice. Taken together, these data provide physiological evidence that activation of ECS in WAT, by limiting fat mobilization, may participate in the progressive tissue remodeling that could finally lead to organ dysfunction. The present findings also indicate that acute CB1R blockade is inefficient in regulating lipolysis in obese WAT and raise the possibility of an alteration of CB1R signaling in conditions of obesity.

Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist

“…Further, an increase in the endocannabinoid tone in adipose tissue is associated with a dysregulation of adipocyte metabolism, thus, promoting fat mass expansion and related disorders [52][53][54][55][56]. In line with this, we recently indicated that activation of ECS in adipose tissue decreased lipolysis [57,58]. Here, we interestingly observed that JM-00266 treatment potentiates ß3 adrenergic receptor-stimulated lipolysis in vivo suggesting this compound might improve fat mobilization targeting adipose tissue CB1R.…”

Effects of endocannabinoids on feed intake, stress response and whole-body energy metabolism in dairy cows

“…The endocannabinoid system (ECS) is a complex network ubiquitously expressed throughout the body. The best studied endocannabinoids (EC) N-arachidonylethanolamide (anandamide; AEA) and 2-arachidonoylglyerol (2-AG) are synthesized from membrane phospholipids, with fat depots providing an important source for plasma EC 1 . Due to their amphiphilic character, EC can modulate the activity of many membrane proteins and activate the G protein-coupled cannabinoid receptors 1 and 2 (CB 1 and CB 2 ) or the G protein-coupled receptor 55 (GPR55), all of them expressed at the cell surface 2 , 3 .…”

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity

“…CB 1 activation was found to stimulate lipogenesis (Matias et al, 2006; Osei‐Hyiaman et al, 2005). Accordingly, increased cannabinoid tone (induced by treatment with the dual inhibitor of the endocannabinoids degrading enzymes) decreased the fat mobilization and lipolysis via a CB 1 ‐ and Akt‐dependent mechanism in vitro (rat and lean human) and in vivo (lean mice) (Buch et al, 2021). CB 1 antagonism increased adipocyte lipolysis, adiponectin expression, and oxygen consumption, together with improved glucose handling (Dong et al, 2018; Gary‐bobo et al, 2006; Han et al, 2019; Hildebrandt et al, 2003; Irwin et al, 2008; Jorgačević et al, 2019; Lipina et al, 2016; Mehrpouya‐bahrami et al, 2019; Murumalla et al, 2011; Nam et al, 2012; Paszkiewicz et al, 2020).…”

“…This latter is a mitochondrial protein found in brown adipose tissue and is responsible for nonshivering thermogenesis. It should be noted that cannabinoid signaling might be differentially regulated in lean and obese adipose tissue, as it was shown that CB 1 antagonism decreased lipolysis in “lean” adipose tissue but not in “obese” adipose tissue, for example, due to CB 1 desensitization (Buch et al, 2021; Mølhøj et al, 2010).…”