The atypical cannabinoid O-1602 stimulates food intake and adiposity in rats

Aims: Cannabinoids are known to control energy homeostasis. Atypical cannabinoids produce pharmacological effects via unidentified targets. We sought to investigate whether the atypical cannabinoid O‐1602 controls food intake and body weight. Methods: The rats were injected acutely or subchronically with O‐1602, and the expression of several factors involved in adipocyte metabolism was assessed by real‐time polymerase chain reaction. In vivo findings were corroborated with in vitro studies incubating 3T3‐L1 adipocytes with O‐1602, and measuring intracellular calcium and lipid accumulation. Finally, as some reports suggest that O‐1602 is an agonist of the putative cannabinoid receptor GPR55, we tested it in mice lacking GPR55. Results: Central and peripheral administration of O‐1602 acutely stimulates food intake, and chronically increases adiposity. The hyperphagic action of O‐1602 is mediated by the downregulation of mRNA and protein levels of the anorexigenic neuropeptide cocaine‐ and amphetamine‐regulated transcript. The effects on fat mass are independent of food intake, and involve a decrease in the expression of lipolytic enzymes such as hormone sensitive lipase and adipose triglyceride lipase in white adipose tissue. Consistently, in vitro data showed that O‐1602 increased the levels of intracellular calcium and lipid accumulation in adipocytes. Finally, we injected O‐1602 in GPR55 −/− mice and found that O‐1602 was able to induce feeding behaviour in GPR55‐deficient mice. Conclusions: These findings show that O‐1602 modulates food intake and adiposity independently of GPR55 receptor. Thus atypical cannabinoids may represent a novel class of molecules involved in energy balance.