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  • br Disclosure statement br Transparency document br Introduc


    Disclosure statement
    Transparency document
    Introduction Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that regulate lipid homeostasis [1] and PPAR isoforms regulate lipolysis, adipogenesis, and metabolism [2]. 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 [3]. 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 [6] 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 [7]. Previous research also shows that brown remodeling of white adipose tissue occurs by SiRT1-dependent deacetylation of PPARγ and inhibits lipid accumulation [5]. 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 [8], which takes part in nociception, thermosensation, and release of vasodilator neuropeptides such as Haloperidol gene-related peptide [9]. It was recently shown that TRPV1 channel activation prevents adipogenesis [10]. More significantly, the activation of TRPV1 by feeding capsaicin prevented high-fat diet-induced obesity [11], 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 [[22], [23], [24], [25]]. 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 [21]. 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 Haloperidol PPARγ [12]. The use of capsaicin or its non-pungent analogs in clinical trials has been shown to be beneficial [[29], [30], [31], [32], [33], [34], [35], [36], [37]]. 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.