Abstract 52: Capsaicin Activates the Trpv1-camkii-ampk-sirt-1-dependent Mechanism to Trigger Brown Remodeling of White Adipocytes to Antagonize Diet-induced Obesity

Abstract

Obesity is a leading cause of metabolic syndrome. The growing endemic of diet-induced obesity necessitates the development of novel strategies to counter obesity. Recent research suggests a regulatory role of transient receptor potential vanilloid 1 (TRPV1) in diet-induced obesity. Here, we evaluated the hypothesis that capsaicin (CAP), a TRPV1 agonist, inhibited high fat diet (HFD)-induced obesity by inducing browning of white adipose tissue (WAT). Dietary CAP (0.01% of HFD) significantly prevented obesity in wild type (WT) but not in TRPV1-/- mice without modifying the food/water intake in these mice. CAP increased the expression of the brown fat-specific thermogenes, peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1 alpha, uncoupling protein-1 and bone morphogenetic protein b8 in the subcutaneous and brown fat pads of WT mice in vivo. Furthermore, CAP increased the expression of sirtuin-1 (SiRT-1 deacetylase) and PR domain protein 16 (PRDM-16-gene responsible for the molecular switch of white to brown fat) in WAT. CAP-triggered deacetylation of PPARγ and PRDM-16 by activating SiRT-1 to facilitate the PPARγ-PRDM-16 interaction and initiate browning of WAT. This effect also corresponded with increased respiratory coefficient, heat production and locomotor activity in CAP-fed WT mice. Analysis of mechanism of action of CAP revealed that CAP activated TRPV1-dependent signaling cascade of Ca2+/calmodulin-dependent protein kinase II (CaMKII)- 5’ adenosine monophosphate-activated protein kinase (AMPK) and increased the phoshorylation of CaMKII, AMPK and SiRT-1 as well as SiRT-1 activation. Pharmacological inhibition of CaMKII by KN-62 (5 μM; 1 hr. preincubation), inhibition of TRPV1 by capsazepine (10 μM; 1 hr. preincubation) or chelation of intracellular Ca2+ by BAPTA-AM (10 μM; 1 hr preinbubation) prevented the effects of CAP (1μM; 30 min. treatment) on SiRT-1 phosphorylation. Collectively, our data unambiguously suggest that CAP prevents HFD- induced obesity by stimulating browning of WAT through TRPV1 activation and uncover a novel role of TRPV1-stimulated intracellular Ca2+-dependent CaMKII-AMPK-SiRT-1 signaling cascade in the browning of WAT.