CB1 receptor antagonist AVE1625 affects primarily metabolic parameters independently of reduced food intake in Wistar rats

Abstract

objective of the present study was to investigate in fed Wistar rats whether the cannabinoid-1 (CB1) receptor antagonist AVE1625 causes primary effects on metabolic blood and tissue parameters as well as metabolic rate, which are independent of reduced caloric intake. After single administration to rats postprandially, AVE1625 caused a slight dose-dependent increase in basal lipolysis. Six hours after single administration, liver glycogen content was dose-dependently reduced to ϳ60% of that of untreated controls. These findings demonstrate a primary acute effect of AVE1625 on induction of 1) lipolysis from fat tissue (increased FFA) and 2) glycogenolysis from the liver (reduced hepatic glycogen). Measured by indirect calorimetry, AVE1625 caused an immediate increase in total energy expenditure, a long-lasting increase of fat oxidation, and a transient increase of glucose oxidation, which were consistent with the acute findings on metabolic blood and tissue parameters. We conclude that, in addition to the well-investigated effects of CB1 receptor antagonists to reduce caloric intake and subsequently body weight, this pharmacological approach is additionally linked to inherently increased lipid oxidation. This oxidation is driven by persistently increased lipolysis from fat tissues, independently of reduced caloric intake, and might significantly contribute to the weight-reducing effect. cannabinoid receptors; lipolysis; glycogenolysis; energy expenditure OBESITY COMBINED WITH ITS COMORBIDITIES has become one of the major health problems not only in industrialized but also in developing countries (16,17,37). Epidemiological and clinical experiences have demonstrated that dietary and behavioural treatments of obesity alone are of limited efficacy (41). Therefore, tremendous efforts in the pharmaceutical industry have been undertaken to investigate efficacious pharmacological mechanisms for the treatment of obesity. Recently, cannabinoid-1 (CB1) receptor antagonism has been intensively investigated for its potential to reduce food intake and subsequently to treat obesity (12,31,33). CB1 receptors are widely distributed in the central (14) and peripheral nervous systems (10) as identified for the enteric nervous system of the gut in pigs, guinea pigs, rats, and mice (23, 35), as well as in the nodose ganglion in humans, rabbits, and rats (8, 28). Furthermore, CB1 receptors are also present in several peripheral tissues (32). Recently, peripheral CB1 receptors were reported to be present on adipocytes in humans, rats, and mice (3, 9, 38), on hepatocytes (30), and on pancreatic ␤-cells in mice (21), and on thyroid cells in rats (36). CB1 receptors belong to the G protein-coupled receptor family and transmit their response via a G i/0 protein with subsequent decreases in cAMP (6, 19). Accordingly, CB1 receptor antagonism is connected to increased cellular cAMP levels (27). The localization of CB1 receptors in the hypothalamus, the center of regulation of food intake and energy balance, makes it very likely that the redu...

Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

“…Moreover, investigators frequently normalize EE and oxygen consumption to total body weight, thereby ignoring fat-free versus fat mass, which causes an overestimation of EE when fat mass is lost without changes in lean mass. 20,38 The effect of CB 1 -receptor antagonism to prevent weight gain and to ameliorate adiposity levels in the LF, HF as well as HF/FO-fed mice corresponds with other studies showing treatment effects irrespective of diet composition. [14][15][16]18,21 It is, however, rather surprising in light of the findings by others showing that HF diets given to mice cause dysregulation of the ECS, either via alterations in the expression of CB 1 receptors, via alterations in the levels of endogenous ligands, or both.…”

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

“…Food intake reduction and energy expenditure increase have also been shown in rodents for rimonabant or AVE1625. [26][27][28] Although the in vivo effects of CB1R inverse agonists are well replicated, the site of action for some of these drugs has been debated, specifically regarding whether peripherally located CB1R mediates the in vivo effects.…”

Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties

“…The preceding discussion is of relevance to the clinical utility of CB1 antagonists with inverse agonist activity, including SR141716A or other currently available antagonists such as AM251, CP-272871, or Ave1625 [21,22,9,3,23]. As described above for SR141716A, antagonist/ inverse agonists that have been thoroughly investigated in laboratory and/or clinical studies appear to produce direct physiological and behavioral effects that may limit their therapeutic application.…”