The effect of Xuezhikang capsule on gene expression profile in brown adipose tissue of obese spontaneously hypertensive rats

The global pandemic of obesity and obesity-related comorbidities is increasing at an alarming rate. Currently, almost two billion adults in the world are overweight, and more than half of them are classified as obese (Hales et al., 2017). Obesity is a host risk factor for cardiovascular diseases and predisposes to the development of hyperlipidemia, hypertension, type 2 diabetes, and even certain cancers, placing a huge burden on the social healthcare system and the economy (Seravalle and Grassi, 2017; Vekic et al., 2019; Wiebe et al., 2019; Wu and Ballantyne, 2020). Despite this, the availability and efficacy of current interventions, particularly pharmacotherapy, are limited due to the difficulty in addressing the multifaceted causes and effects of obesity (Axelrod et al., 2020; Gadde et al., 2018). Hence, new methods of interventions are urgently needed to address obesity and related disorders.

A promising strategy for treating obesity and related metabolic disorders is the activation of brown adipose tissue (BAT) (Becher et al., 2021; Cheng et al., 2021). BAT is one type of adipose tissue that is distinguished from white adipose tissue (WAT) by origin, function, and morphology (Zwick et al., 2018). Since Cohade et al. first detected metabolically active BAT in adult humans, a series of researches on BAT have been conducted (Cohade et al., 2003). Studies have found that besides causing non-shivering thermogenesis, BAT also plays a key role in the regulation of systemic energy homeostasis (Singh et al., 2018; Tajima et al., 2020). Cold stimulation is the classical approach for activating BAT. Upon cold exposure, noradrenaline (NA) released from the sympathetic nervous system (SNS) activates the β3-adrenergic receptors (β3-AR), which trigger the thermogenic effect of BAT (Collins, 2011; Ikeda et al., 2018). Additionally, cold exposure activates BAT in rodents and healthy humans and accelerates the removal of circulating glucose and triglycerides, thus improving insulin resistance (Chondronikola et al., 2014; Nedergaard et al., 2011; Ouellet et al., 2012; Singh et al., 2018). Obese individuals exhibit a less pronounced response, and cold exposure presents a significant challenge for patients with cardiovascular diseases, which limits the widespread clinical application of cold stimulation for treating obesity (Orava et al., 2013). Many efforts have been devoted toward pharmacological therapeutic techniques for activating brown fat. β3-AR agonists have been extensively studied as an anti-obesity drug (Finlin et al., 2018; Schnabl et al., 2018). Mirabegron, a β3-AR agonist, is effective in activating BAT, increasing metabolic rate, and improving glucose tolerance in adult humans (Cypess et al., 2015; Finlin et al., 2020). A major obstacle to the application of Mirabegron for the treatment of obesity is that, besides poor bioavailability, effective pharmacological doses of Mirabegron increase blood pressure and heart rate (Cypess et al., 2015). Furthermore, recent studies have shown that BAT can be activated via the heat shock transcription factor 1 (HSF1)-hnrnpa2b1 (A2b1) transcriptional axis (Li et al., 2022). Hence, it is crucial to examine the gene expression profile of BAT, investigate other potential targets for brown fat activation, and develop a treatment strategy that can safely and effectively activate BAT.

Traditional Chinese medicine (TCM) plays an important role in the prevention and treatment of obesity (Fan et al., 2021; Li et al., 2020). Red yeast rice (RYR) is one of the representative TCMs, which is made by inoculating Monascus purpureus Went on rice (Oryza sativa L.) and cultured artificially. Many studies have shown that crude-extracted RYR and its isolated compounds have a broad range of pharmacological effects, possessing hypolipidemic, anti-atherosclerotic, anti-obesity, anti-diabetic, and anti-hypertensive effects (Yuan et al., 2022; Zhu et al., 2019). However, besides the difficulty in quality control, RYR sometimes requires very high doses to be effective, which severely limits its clinical application (Chen et al., 2008). Xuezhikang Capsule (XZK) is a purified product extracted from RYR under controlled pharmaceutical conditions. In China, it is a lipid-lowering medication approved for use in clinic by the China National Medical Products Administration (NMPA, Approval No. Z10950029) and is listed in Part 1 of the Chinese Pharmacopoeia (Ch.p.) 2020 (Chinese Pharmacopoeia, 2020). XZK contains a group of naturally occurring statins, as well as ergosterol, unsaturated fatty acids, amino acids, alkaloids, and a variety of other bioactive substances (Liu et al., 2011). XZK not only effectively modulates blood lipids but also significantly decreases the incidence of nonfatal myocardial infarction, coronary death, and all-cause mortality in patients with coronary artery disease (CAD) (Li et al., 2010; Lu et al., 2005; Moriarty et al., 2014; Zhao et al., 2004). According to a meta-analysis of randomized controlled trials (RCTs) of TCM conducted over the last three decades, XZK is the only one with hard endpoints in preventing arteriosclerotic cardiovascular diseases (ASCVDs) (Hao et al., 2017). The efficacy of XZK is associated with anti-inflammatory, anti-oxidative stress, and inhibition of vascular remodeling (Chu et al., 2016; Liang et al., 2019; Lin et al., 2015). Furthermore, XZK can prevent high-fat diet-induced weight gain in mice and improve the corresponding glucose and lipid metabolism (Feng et al., 2015; Wang et al., 2014). However, the mechanisms by which XZK reduces obesity and its associated metabolic diseases are elusive, and no study has determined the role of XZK in brown fat regulation.

Accordingly, the aim of this study was to investigate the protective mechanism of XZK in the obese spontaneously hypertensive rat (SHR) model by evaluating the regulatory effect of XZK on the BAT gene profile through transcriptome sequencing. These findings might elucidate new pharmacological strategies to treat obesity.

留言 (0)

沒有登入
gif