Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

Abstract

Aims/hypothesis Modulation of central nervous system (CNS) and extra-CNS cannabinoid receptor type 1 (CB1R) affects metabolic conditions, independently of weight loss. Here we examined the relative contributions of acute CNS and extra-CNS CB1R modulation on insulin sensitivity using pharmacological gain-and loss-of-function of CB1R in mice. Methods We assessed the effects of acute modulation of CB1R on insulin sensitivity and tissue glucose uptake by administering a CB1R agonist (HU210) and antagonist (AM251) (vs vehicle) i.v. in wild-type mice. In addition, we administered a CB1R agonist (vs vehicle) systemically (i.v.) to Cb1r (also known as Cnr1) knockout (Cb1r −/− ) mice or intracerebroventricularly (i.c.v.) in wild-type mice to elucidate the peripheral vs CNS-mediated regulatory effect of CB1R on insulin sensitivity.Results HU210 induced significant insulin resistance in wild-type mice with a reduction of whole-body glucose disappearance rate and muscle Akt phosphorylation, as well as of glucose uptake by skeletal muscle, but not by adipose tissue, changes that were prevented by pretreatment with AM251. HU210 did not affect insulin sensitivity in Cb1r −/− mice, suggesting that the observed effects were mediated through CB1R. HU210 administered i.c.v. did not induce insulin resistance, suggesting that acute stimulation of CNS CB1R was not required for this effect. Conclusions/interpretation Skeletal muscle insulin sensitivity is affected by acute CB1R modulation. These changes are mediated by extra-CNS CB1R, probably by the receptors in skeletal muscle tissue.

Hepatic Cannabinoid Receptor-1 Mediates Diet-Induced Insulin Resistance via Inhibition of Insulin Signaling and Clearance in Mice

“…Although diet-induced glucose intolerance is predominantly attributable to hepatic insulin resistance, CB 1 can also inhibit glucose uptake into skeletal muscle 40,41 and adipose tissue 42,43 and inhibit insulin signaling in pancreatic beta cells. 44 The relative contributions of these targets to glycemic control by endocannabinoids may be different in rodents and humans and remain to be further explored.…”

Endocannabinoid signaling at the periphery: 50 years after THC

“…The latter have shown that systemic pharmacological CB 1 antagonism in obese humans or rodents results in increased energy expenditure/oxygen consumption, which in turn is due to elevated fatty acid oxidation [93-96], possibly subsequent to increased muscle mitochondrial biogenesis [97]. In addition, chronic treatment of ob/ob mice and lean or obese Zucker rats with rimonabant results in increased glucose uptake in the soleus muscle [96, 98], whereas administration of a single dose of the CB 1 /CB 2 agonist HU210 caused CB 1 -dependent reduction of whole body glucose clearance and glucose transport into muscle but not adipose tissue, and decreased insulin-dependent Akt phosphorylation in hind leg muscle [99]. It seems also noteworthy that in soleus muscle explant cultures from lean and insulin-resistant Zucker rats, AEA and rimonabant significantly decrease and increase, respectively, both basal and insulin-dependent glucose import [89].…”

The role of Endocannabinoid System in pathogenesis and therapy of obesity

“…Ekspresja receptorów CB1 oraz innych elementów układu endokanabinoidowego w mięśniach szkieletowych została dowiedziona zarówno na poziomie mRNA, jak i białek [12,31,32,41,42]. Mięśnie stanowią podstawowe miejsce utleniania kwasów tłuszczowych i wychwytu glukozy [32,43].…”

“…3-kinazy fosfatydyloinozytolu/kinazy białkowej B(PI 3-K/PKB) oraz Raf-MEK1/2-ERK1/2 [32,43]. W innym badaniu stymulacja CB1 w tkance mięśniowej przez podanie agonisty tego receptora -HU210 indukowała wytworzenie oporności na insulinę, podczas gdy zastosowanie selektywnego antagonisty CB1-AM251 przyczyniło się do zniesienia tego efektu u myszy doświadczalnych [42]. W tym samym badaniu u myszy Cb1r -/--pozbawionych tego receptora zarówno w CUN, jak i w tkankach obwodowych nie wykazano podobnych zmian.…”

“…Co więcej, Song i wsp. sugerują, iż zmiany wrażliwości komórek na insulinę pod wpływem HU210 są niezależne od centralnego układu nerwowego [42]. Wyniki te dają podstawy do stwierdzenia, iż nadekspresja układu ECS w tkankach obwodowych, takich jak mięśnie szkieletowe, jest odpowiedzialna za rozwój insulinooporności, skutkując zaburzeniem wychwytu glukozy przez komórki.…”