The Central Cannabinoid CB1 Receptor Is Required for Diet‐Induced Obesity and Rimonabant's Antiobesity Effects in Mice

Abstract

Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)–specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist‐induced hypothermia was attenuated in the mutant mice, but the agonist‐induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system‐mediated effect, was not. Compared to wild‐type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high‐fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions.

Mitochondria: a possible nexus for the regulation of energy homeostasis by the endocannabinoid system?

“…Similar anorectic responses are also observed following in vivo administration of pharmacological CB1R blockers such as SR141716 (65). These metabolic improvements can be partly explained by the ability of the ECS to regulate motivational aspects of feeding behavior (69,106,153).…”

Somatostatin receptor 5 and cannabinoid receptor 1 activation inhibit secretion of glucose-dependent insulinotropic polypeptide from intestinal K cells in rodents

“…Although most effects of rimonabant on feeding are mirrored in a mouse with CNS-restricted CB1 receptor knockout [33], there is still considerable interest in developing drugs targeting peripheral cannabinoid receptors for the treatment of obesity [27, 31]. Our results suggest that an additional effect of antagonising peripheral CB1 receptors may be to increase GIP secretion.…”

CNR1 Gene and Risk of the Metabolic Syndrome in Patients With Schizophrenia

“…40,41 Cannabinoid type 1 receptor is expressed widely in the central nervous system, being associated with reward, hunger, appetite, and satiety, and in peripheral tissues, including the adipocytes, liver, gastrointestinal tract, pancreas, and skeletal muscle, and exhibits a variety of actions implicated in vital functions (eg, behavioral, antinociceptive, neuroprotective, immunosuppressive, cardiovascular, and metabolic). 45,46 Moreover, studies have linked the CNR1 gene to obesity and various metabolic parameters 37,39,47Y51 ; however, some negative studies have also been reported. 41,44 The CB1 receptor is also important in regulating body mass; andrimonabant, a CB1 receptor antagonist/inverse agonist, has emerged as the first-in-class drug approved for weight control.…”