br Disclosure statement br Transparency document br Introduc
Introduction Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that regulate lipid homeostasis  and PPAR isoforms regulate lipolysis, adipogenesis, and metabolism . Interestingly, posttranslational modifications of PPARγ, especially its deacetylation, have been recognized as a marker for browning of white adipose tissue (WAT). Direct acetylation of PPARγ by histone acetyltransferases is involved in its adipocyte differentiation function . PPARγ acetylation enhances lipid synthesis, and the deacetylation of PPARγ is tightly regulated by NAD-dependent deacetylase sirtuin 1 [SiRT1; [4,5]]. It is well known that WAT functions as the main depot for fuel storage whereas brown fat dissipates this energy as heat  and increases energy expenditure, thus preventing from obesity. The third kind of fat shown recently is inducible brown fat in white fat also called as beige/brite (brown in white) cells . Previous research also shows that brown remodeling of white adipose tissue occurs by SiRT1-dependent deacetylation of PPARγ and inhibits lipid accumulation . Recent research has intensified the identification of various mechanisms that trigger the browning of WAT as a countermeasure for obesity. Transient receptor potential vanilloid subfamily 1 (TRPV1) is a nonselective cation channel , which takes part in nociception, thermosensation, and release of vasodilator neuropeptides such as Haloperidol gene-related peptide . It was recently shown that TRPV1 channel activation prevents adipogenesis . More significantly, the activation of TRPV1 by feeding capsaicin prevented high-fat diet-induced obesity , promoted weight loss and induced the conversion of white to brown fat in mice. Also, capsaicin enhanced the expression and thermogenic program in the brown fat of wild-type but not in TRPV1−/− mice. TRPV1 activation caused the deacetylation of PPARγ via SiRT-1 in white and brown adipose tissues [11,12]. In this study, we evaluated the crosstalk between TRPV1 and PPARγ by evaluating the effect of Troglitazone (Trog), a PPARγ activator. Our data suggest a novel TRPV1-dependent effect of Trog on the deacetylation of PPARγ in 3T3-L1 cells.
Materials and methods
Discussion Strategies to stimulate the conversion of energy-storing white fat to energy expending brown fat-like phenotype (also referred to as beige fat) have received significant attention in recent years [, , , ]. Predominately, the activation of SiRT-1, an NAD+-dependent deacetylase, and its subsequent deacetylation of PPARγ, PRDM-16, and their stabilization to promote thermogenic program have been regarded as mechanisms underlying the browning of WAT [5,11,20,26]. Consistently, several studies have demonstrated that the deacetylation of PPARγ is a marker for browning of WAT [5,11,27]. Specifically, research work demonstrating the novel role of thiazolidinedione (TZD) derivatives in SiRT-1-dependent deacetylation of PPARγ presents a new mechanism for the benefits of these molecules despite any adverse reactions associated with their use . Recently, TRPV1 has been identified as a novel partner in this browning phenomenon [11,28]. Published data suggest that activation of TRPV1 prevents diet-induced obesity by causing the browning of WAT via SiRT-1-dependent deacetylation of PPARγ . The use of capsaicin or its non-pungent analogs in clinical trials has been shown to be beneficial [, , , , , , , , ]. However, the precise mechanism(s) by which TRPV1 activation enhances energy expenditure and combats nutrient overload-induced metabolic dysfunction remains unclear. Pertinent to the role of TRPV1 in the browning of WAT, the results presented in this work suggest a cross-talk between PPARγ and TRPV1 signaling since TRPV1 activation enhanced the expression and deacetylation of PPARγ in epididymal fat (in vivo) as well as 3T3-L1TRPV1 cells in vitro. Moreover, our results illustrating the enhancement of adipogenic and thermogenic protein expression in TRPV1 overexpressing 3T3-L1 cells indicates a critical role of TRPV1 in adipogenic and thermogenic processes. These results validate that TRPV1 is a potential candidate for inducing browning of WAT.