Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats

Abstract

OBJECTIVE-Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats.RESEARCH DESIGN AND METHODS-Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies.RESULTS-Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonistelicited reduction of food intake.CONCLUSIONS-Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight. Diabetes 57:2977-2991, 2008 T he incidence of obesity and the metabolic syndrome have grown to epidemic proportions, making increased research efforts toward discovery of novel anti-obesity therapies increasingly important. Endocannabinoids are key modulators of feeding behavior through the activation of the CB1 receptor (1,2), which is localized in the periphery as well as in many brain areas involved in the regulation of energy homeostasis and reward processes (3,4). Recent studies (5-11) have demonstrated that blocking the activity of the endogenous cannabinoid system may be a successful strategy for the treatment of obesity and the metabolic syndrome.It is well known that CB1 receptors in the hypothalamus might regulate food intake through the disinhibition of the release of melanin-concentrating hormone from lateral hypothalamic neurons (12) and the inhibition of the release and/or expression of corticotrophin-releasing hormone in the paraventricular nucleus (13). Both these effects are under the negative control of leptin, which is known to negatively control endocannabinoid tone in the hypothalamus (2). On the other hand, the effects of CB1 activation on ␣-melanocyte-stimulating hormone are controversial, since both inhibition and stimulation were reported in the study by Hentges et al. (14), and no downstream effects of ␣-melanocyte-stimulating hormone on endocannabinoi...

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

“…Plasma insulin levels were reduced in diet-induced obese mice treated with a specific CB1R antagonist SR141716 [13,40]. In rats after chronic treatment with a CB1R antagonist, insulin sensitivity and skeletal muscle glucose uptake were also enhanced, whereas hepatic glucose production was diminished [20]. Chronic, peripheral CB1R antagonism decreases hepatic glucose production, promotes lipid mobilisation independently of food intake and increases glucose utilisation in rats [20].…”

“…Chronic antagonism of CB1R leads to weight loss and improved insulin sensitivity in animal models of obesity and in humans [2,4,[19][20][21]. However, it is still not clear whether the beneficial effects on insulin sensitivity and metabolic profiles are secondary to reduction in food intake with consequent weight loss or caused by other unrelated mechanisms.…”

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

“…In the studies by Nogueiras et al, 34 it was reported that differential effects were observed with icv or i.p. administration of rimonabant.…”

“…31 In contrast, it has been shown in independent studies that direct injection of agonists into brain can stimulate food intake, 32,33 and icv administration of rimonabant does reduce food intake and body weight. 34 Based on the totality of these reports, it seems to be that the negative result of Gomez et al 31 may represent a special limitation of the study.…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…increased energy expenditure) mechanisms (Cota et al ., 2003; Jbilo et al ., 2005; Herling et al ., 2008; Nogueiras et al ., 2008). Whilst this present study did not permit us to discriminate between these two different modes of action directly, our findings indicate that rimonabant is unlikely to convey its metabolic improvements in aged mice by increasing energy expenditure.…”