Over the past four decades, the prevalence of obesity has continued to escalate at an alarming rate [1,2]. Over half of the global population is expected to be overweight or obese by 2030 [3]. Obesity has become one of the most daunting public health challenges [4,5]. In particular, the growing incidence of overweight and obesity in children is a major health concern not only in developed countries but also in the developing world [6,7]. Besides overall obesity, the anatomical location of fat is recognized as a key factor in disease development. Studies have shown that intra-abdominal visceral fat is strongly positively correlated with type 2 diabetes, coronary heart disease, stroke, obstructive sleep apnea, and several types of cancer [8,9]. Obesity and its associated comorbidities markedly increase healthcare costs and decrease life expectancy [10]. Thus, it is important to develop effective interventions for the treatment of obesity.

Obesity is the accumulation of excess fat in the body and white adipose tissue (WAT) is a complex organ with primary roles in controlling energy homeostasis [11]. The unhealthy expansion of WAT has been associated with numerous deleterious effects, including inflammation, hypoxia, oxidative stress, and mitochondrial dysfunction, each of which could represent a new therapeutic target in the treatment of obesity [[12], [13], [14]]. Adipose tissue expands through a combination of an increase in adipocyte size (hypertrophy) and number (hyperplasia). It is proved that such size expansion of adipocytes can lead to adipose tissue hypoxia, promoting the secretion of reactive oxygen species (ROS) [15]. Despite tremendous efforts invested in the past decades, effective strategies against obesity remain elusive. Therefore, there is an urgent need to explore effective and safe treatments to prevent the over-accumulation of WATs.

Transient receptor potential vanilloid (TRPV) ion channels are involved in multiple critical cellular behaviors by regulating the levels of intracellular Ca2+ [16,17]. In recent years, numerous studies have shown that TRPV ion channels are highly expressed in metabolic organs such as the liver, adipose tissue, skeletal muscle, pancreas, and central nervous system. These channels have been implicated in various metabolic diseases, including obesity and diabetes mellitus [18]. TRPV channels contain several subtypes based on ion selectivity, with TRPV1-4 channels serving as crucial regulators of ion homeostasis in adipocytes and playing a significant role in adipose tissue differentiation [18]. Among these channels, the role of TRPV1 in the regulation of metabolism and energy homeostasis is the most widely studied to date [19]. Ohnuki et al. indicated that chronic treatment of mice with capsaicin, a TRPV1 agonist, markedly suppressed body fat accumulation and promoted energy metabolism [20]. It showed that capsaicin treatment prevented adipogenesis of 3T3-L1 preadipocytes in vitro, with increased intracellular calcium levels [21]. Hsu et al. also demonstrated that capsaicin inhibited the expression of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and leptin, while inducing up-regulation of adiponectin at the protein level [22]. Hence, these studies support the notion that capsaicin, a TRPV1 agonist, can decrease adipogenensis, regulate genes function related to lipid metabolism, and potentially contribute to weight lose. TRPV2 and TRPV4 have been reported to promote thermogenesis, with TRPV2 knockout reducing Ca2+ influx in brown adipose tissue and attenuating β-adrenergic receptor-stimulated thermogenesis [23,24]. TRPV3, another member of the TRP family of channels, is involved in various physiological functions. Modulating TRPV3 activity can impact ion channel function, leading to neurodegenerative diseases, chronic pain and skin disorders [25]. However, evidence about the role of TRPV3 in obesity and excess fat accumulation is limited. Cheung et al. indicated that the expression of TRPV3 was reduced in the visceral adipose tissue from high-fat diet-fed, db/db, and ob/ob mice. In vivo, the antiadipogenic role of TRPV3 was further confirmed by the fact that chronic treatment with epicatechin or an established TRPV3 agonist, diphenylborinic anhydride, prevented adipogenesis in mice fed a high-fat diet [26]. However, the mechanisms through which TRPV3 influences adipose tissue homeostasis and responds to nutrient availability remain largely unknown.

We previously generated a TRPV3 gain-of-function mutation mouse model, allowing us to investigate the functional role and mechanism of TRPV3 channels in vivo. In this study, we focused on understanding how TRPV3 gain-of-function promotes visceral fat lipolysis and inhibits high-fat diet-induced obesity. Our findings demonstrated that TRPV3 gain-of-function mitigated high-fat diet-induced obesity, specifically by enhancing lipolysis in visceral fat through upregulation of the major lipolytic enzyme, ATGL. Additionally, we revealed that TRPV3 gain-of-function could target the nuclear factor erythroid 2-related factor 2 (NRF2)-ferroptosis suppressor protein 1 (FSP1) axis to enhance lipolysis by inhibiting lipid peroxidation. These results highlight a crucial role for TRPV3 in the regulation of lipolysis and suggest the unique potential of targeting TRPV3 as a strategy to combat obesity.