α-Cedrene protects rodents from high-fat diet-induced adiposity via adenylyl cyclase 3

Objective: The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective strategies for the prevention of weight gain. Here, we investigated the potential of α-cedrene, a volatile sesquiterpene compound derived from cedarwood oil, in regulation of obesity and delineated the mechanisms involved. Methods: For the prevention of obesity, C57BL/6 N mice were fed a high-fat diet (HFD) and were orally administered either with vehicle or α-cedrene for 8 weeks. For the therapy of obesity, obese Sprague Dawley rats, induced by a HFD for 8 weeks, were orally treated either with vehicle or α-cedrene for 12 weeks. To determine whether the action of α-cedrene was Adcy3 dependent, Adcy3 heterozygous null mice (Adcy3 ^+/− ) and wild-type controls were fed either HFD or α-cedrene supplemented HFD for 17 weeks. Results: Oral α-cedrene administration prevented or reversed HFD-induced obesity and abnormal metabolic aberrations in rodents, without affecting their food intake. Downregulation of Adcy3 expression by small interfering RNA abrogated the beneficial effects of α-cedrene on the oxygen consumption rate and intracellular lipid accumulation in 3T3-L1 adipocytes. Similarly, in Adcy3 ^+/− mice, the α-cedrene-driven suppression of body weight gain observed in wild-type mice was substantially (~50%) attenuated. Expression of thermogenic and lipid oxidation genes was increased in adipose tissues of α-cedrene-treated mice, with concomitant downregulation of adipogenic gene expression. These beneficial molecular changes elicited by α-cedrene were blunted in adipose tissues of Adcy3 ^+/− mice. Conclusions: Our results highlight the potential of α-cedrene for antiobesity interventions and suggest that the antiobesity effect of α-cedrene is mediated by Adcy3 in adipose tissues.