Abstract
We have previously demonstrated in dogs that following exposure to a high fat diet for 16 weeks, the brain and peripheral penetrating CB1R antagonist Rimonabant (RIM) promoted adipose tissue beiging and decreased adipocyte cell size. It is hoped that peripherally restricted CB1R antagonists, such as AM6545, will allow for the substantial beneficial metabolic effects of CB1R antagonism without the possible negative consequences associated with brain penetrance. Studies demonstrated beneficial metabolic effects of AM6545 in adipose tissue including increased energy expenditure and decreased adipocytes cell size. We thus compared the effects of RIM versus AM6545 on oxygen consumption and beiging in the well-characterized 3T3-L1 cell line model. Mature 3T3-L1s were treated for 4 or 48 hours with RIM, AM6545, vehicle or isoproterenol (ISO) (positive control). Baseline oxygen consumption and the proportional contribution of proton leak to maximal respiratory capacity was greater for cells exposed to RIM, ISO, and, in lesser extent, AM6545 after 48 hours, demonstrating greater mitochondrial uncoupling. Further, markers of adipose tissue beiging (UCP1, Prdm16, PGC1α) were also unregulated by approximately 2-fold (P<0.05) at 48 hours with RIM treatment and, in lesser extent, with AM6545. Hence, peripheral and central CB1R antagonists act directly on 3T3-L1 to increase mitochondrial function and adopt features of beige adipocytes. Thus, a direct role for CB1R antagonism on adipocytes does not require brain penetrance, supporting the importance of peripheral CB1R antagonism pharmacology for reducing the incidence of obesity and type 2 diabetes. Disclosure R.K. Paszkiewicz: None. R.N. Bergman: Consultant; Self; Zafgen, Inc. A. Frank: None. O.O. Woolcott: None. R. de Souza Santos: None. M.S. Iyer: None. D. Clegg: None. M. Kabir: None.
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