Evidence of CB1-Receptor Antagonism in Fat-Fed Dogs Promoting Beiging of Adipose Tissue Mainly via Activation of Sarco/Endoplasmic Reticulum Ca2+ ATPase 2b and Ryanodine Receptor 2

Abstract

We have previously demonstrated that 16 weeks following exposure to a high fat diet (HFD), dogs treated with the CB1-receptor antagonist (Rimonabant (RIM)) upregulated β3-adrenergic receptors, PGC1α, Prdm16, and slight increase of UCP1 in the subcutaneous (SC) and visceral (VIS) depots when compared to control treated dogs. These data suggest an improvement in metabolic flux of adipose tissue consistent with beiging. The mechanism(s) by which RIM promotes adipose tissue beiging is unknown. We hypothesize that the beiging effect might be induced via UCP1-independent thermogenic mechanisms through upregulation of sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). To explore the mechanism by which RIM enhances adipose tissue function, dogs were fed a HFD (52% fat) for 6 weeks followed by a continued 16 weeks of fat feeding with either HFD + placebo (PL) (n=9) or HFD + RIM (1.25 mg/kg per day; n=11). Biopsies from SC and VIS depots were obtained for gene expression: before HFD (pre-fat) and 16 weeks of HFD +/- RIM. RIM increased SERCA2b expression in the SC depot by 8-fold (P<0.05) and in the VIS depot by 2-fold (P<0.05) compared to the PL+HFD groups. Also, RIM increased RyR2 3-fold in the SC (P<0.005) and 4-fold in the VIS depots (P<0.05). Our data suggest that a potential mechanism by which CB1-receptor antagonism increases beiging of adipose tissues may be through upregulation of the key genes involved in an UCP1-independent pathway. Importantly, for the first time we are beginning to identify mechanisms by which CB1-receptor antagonism enhances adipose tissue function and improves energy homeostasis in the presence of a HFD. Disclosure R.L. Paszkiewicz: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S. J.M. Richey: None. M.S. Iyer: None. O.O. Woolcott: None. C.M. Kolka: Research Support; Self; AstraZeneca. D. Clegg: None. M. Kabir: None.