Currently, pharmacological treatment for obesity is very limited and many drugs are often withdrawn because of serious side effects. Basically, the approach to mechanisms in the treatment of obesity focuses on two options: 1) central effect, (i.e., reducing food intake) 2) environmental effect, inhibition of lipid absorption etc. (Tseng et al. 2010). However, since there is inflammation in the adipose tissue and its function is impaired, there is no approved drug that is directly effective in obesity treatment. At the same time, impaired adipose tissue as an endocrine organ secretes several molecules that affect other organs and contribute to the development of abnormalities related to carbohydrate metabolism (Vargas-Castillo et al. 2017).
Taurine is an amino acid abundant in the human body. Taurine plays a variety of physiological roles in the body and has been investigated as a beneficial molecule for reducing metabolic dysfunctions such as dyslipidemia, insulin resistance, and hyperglycemia, which are mostly associated with obesity (Lambert et al. 2015; Kim et al. 2012). Therefore, the anti-obesity effect of taurine has attracted great interest by many researchers as a potentially safe agent for weight loss in the global age of obesity (Murakami 2017). It has been reported that obese people have lower amounts of taurine in their bodies (Rosa et al. 2014). Studies have shown the effects of taurine supplementation on adipose tissue. These effects can be listed as; reducing WAT storage (Tsuboyama-Kasaoka et al. 2006; Nardelli et al. 2011; Batista et al. 2013), increasing BAT (Cao et al. 2016), increasing PKA activity and β-adrenergic-induced lipolysis (Pina-Zentella et al. 2012), increasing PGC-1α (Tsuboyama-Kasaoka et al. 2006; Cao et al. 2016) and UCP1 expression (Guo et al. 2019), reducing proinflammatory molecules and increasing anti-inflammatory molecules (Caetano et al., 2017;). In particular, animal studies have shown that taurine effectively reduces or delays obesity in HFD-fed mice (Lin et al., 2013; Batista et al., 2013). Taurine along with exercise improved genes related to lipid metabolism (De Carvalho et al. 2021a) and improves inflammatory markers in plasma of obese women (De Carvalho et al. 2021b). A randomized clinical trial showed that taurine supplementation along with a weight-loss diet may be more effective in improving lipid profile and metabolic risk factors (Haidari et al 2020). These observations show that taurine deficiency in the body can indirectly cause metabolic dysfunctions such as obesity and dyslipidemia, and that taurine is a beneficial amino acid with very important effects. Therefore, it is even more important to clarify the molecular mechanism by which taurine inhibits metabolic dysfunction.
The primary aim of our study is to investigate whether taurine supplementation influences on reducing body mass in our experimental conditions. For this purpose, both HFD and HFD + T groups were fed for 20 weeks. The mean body weight of the HFD + T group was 36.32 ± 5.14 g, and the mean body weight of the mice in the HFD group was 41.95 ± 7.50 g. We examined whether these weight gains were related to food consumption, and we found the food consumption amounts of the HFD and HFD + T groups to be similar. Although their food consumption was similar, the increase in body weight was less in the HFD + T group compared to the HFD group. Although there was no difference in food consumption in taurine-supplemented groups, water consumption was higher in taurine-supplemented groups than in taurine-free groups. There are many studies that indicate that taurine supplementation increases renal excretory function. To maintain taurine homeostasis in the body, the renal taurine transporter co-transporter (Na+-Cl- taurine co-transporter) is tightly regulated. Excess taurine intake in the diet decreases the expression of the renal taurine transporter co-transporter, resulting in excess taurine in the urine. When renal co-transporter activity decreases, less taurine is taken up into tubule cells, followed by less sodium transport into tubule cells (Mozaffari and Schaffer 2002). Therefore, taurine supplementation is likely to lead to taurineuria by increasing natriuresis and diuresis. It can be thought that diuresis may have increased due to excessive consumption of taurine in the taurine supplemented groups in our study, and increased diuresis may also increase water consumption in the taurine supplemented groups.
Another aim of our study was to examine whether taurine supplementation has any effect on inducing the WAT browning program and the possible pathways of this effect. For this purpose, expression levels of AMPK, mTOR, S6K, PGC-1α, FLCN, TFE3, PGC-1β and UCP1 genes were determined in eWAT obtained from mice in each group. These studied genes are those reported to be involved in the browning pathways of WAT. Many studies have reported that the browning of WAT occurs through proteins encoded by the AMPK/mTORC1/S6K/PGC-1α genes. In a study published in 2016, it was reported that WAT browning can also occur via an alternative pathway other than this pathway. According to the afore mentioned study, it is stated that the interactions of the proteins encoded by the FLCN, mTORC1, TFE3 and PGC-1β genes can cause browning (Wada et al. 2016). In this study, we investigated the expression levels of genes that are effective in both pathways to determine both the effect of taurine on browning and through which pathway it exerts this effect.
Comparisons of both control and control + T, and HFD and HFD + T groups showed that there was no significant difference in expression levels of the genes we examined. In our experimental conditions, it was observed that taurine did not have any effect on the expression of these genes. In a study published in 2019, while our study in progress, Guo et al. (2019) administered taurine (daily 150 mg/kg for per mouse) intraperitoneally to C57BL/6 mice fed with HFD from the last 5 weeks of the feeding period (14 weeks) at + 4 ˚C. They observed that five weeks of taurine supplementation protected mice against weight gain. They observed that UCP1 and PGC-1α gene expressions were induced in BAT, iWAT and eWAT with taurine supplementation, mostly in iWAT. As a result, researchers reported that taurine has anti-obesity properties and induces WAT browning, especially in iWAT. After the study of Guo et al., in another study, Kim et al (2020) conducted a study with ICR mice. They fed the mice for 28 weeks. Although UCP-1 expression was found to be high in brown adipose tissue, they detected it at very low levels in inguinal WAT (iWAT). Taurine supplementation was done as 2% in drinking water. Kim et al. (2020) showed a decrease in fat mass similar to our study in mice fed HFD with taurine supplementation. However, they found at minimal level of UCP1 expression in iWAT. In addition, they found that UCP1 expression decreased in HFD + Taurine group compared to HFD group. This result is the opposite of the results of Guo et al. (2019). The authors attributed this difference, in part, to differences in the genetic background based on diet-induced obesity (DIO) between C57BL/6 and ICR mice. In our study, the mRNA level of the UCP1 gene, which is the most important browning marker, could not be analyzed eWAT since it was not detectable in any group. This shows that WAT browning did not occur at all or was at a minimal level that could not be detected in all groups.
In some previous studies, it was reported that UCP1 gene expression was not detected in WAT (García-Ruiz et al. 2015; Castrejón-Tellez et al. 2016). Various studies have shown that eWAT is less sensitive to browning agents compared to iWAT (Wang et al. 2015; Seale et al. 2011; Zhang et al. 2014; Guo et al. 2019). In study of Guo et al. (2020) the existence of UCP1 gene expression in both iWAT and eWAT may be because of they kept the mice at + 4 ˚C during the study. In their study, it is possible that cold-induced (adaptive) thermogenesis was induced by feeding at + 4 ˚C. Because it is known that cold exposure is the most powerful stimulus of UCP1 gene expression (Chouchani et al. 2019). In our study, mice were fed at approximately room temperature (22 ± 2 ˚C). The reason why we could not detect UCP1 gene expression in any group may be the ambient temperature in which the mice were fed. In addition, the studies of Guo et al. (2019) and our study differ from each other in terms of the way taurine was administered to mice. While they administered taurine intraperitoneally, we gave it dissolved in drinking water. Therefore, although taurine reached the tissue directly in their study, in our study, factors related to the absorption of taurine may have affected the amount of taurine reaching the tissue, since it was absorbed from the gastrointestinal tract and reached through the blood. Furthermore, Kim et al. (2020) used a different mouse model (ICR) than ours (C57BL/6). Therefore, as the authors point out, the genetic characteristics of the two mice are markedly different, and this may be the reason for the discrepancy between the results of the studies. In or study, although, we investigated the expression of the genes in eWAT, they did it in iWAT. In addition, they administered a different dose (2%) of taurine than we did (5%). Therefore, these effects may also be dose and adipose tissue type dependent.
In our study, when compared to the control group, PGC-1α mRNA level in the HFD group down-regulated 6.42 times compared to the control group. Similarly, there was a 2.16-fold decrease in PGC-1β mRNA level. No significant difference was found in other genes. It was determined that the expression of PGC-1α, PGC-1β and AMPK genes was significantly decreased in the HFD + T group compared to the control + T group. The expression decreased 3.77 times in the PGC-1α gene, 2.99 times in the PGC-1β gene, and 2.44 times in the AMPK gene. In previous studies, it was reported that the expression of PGC-lα and AMPK decreased in animals fed with HFD compared to animals fed with control food (Barroso et al. 2018; Lindholm et al. 2013). In our study, we observed that HFD decreased PGC-1α, PGC-1β and AMPK expressions in adipose tissue, and taurine supplementation had no effect on the expression of these genes. It is suggested that overfeeding and obesity reduce the expression of mitochondrial and metabolic genes through decreased PGC-lα expression, reducing the rate of oxidative phosphorylation and lipid oxidation, thus causing insulin resistance and type 2 diabetes (Liang and Ward 2006; Patti et al. 2003). On the other hand, Kim et al. (2020) found lower level of PGC-1α expression and found no different PGC-1α expression between HFD and HFD + T groups in iWAT. Furthermore, Guo et al. (2019) found increased PGC-1α expression both iWAT and eWAT in HFD + Taurine group to HFD. Therefore, further studies are needed to understand the reason for the differences in PGC-1α expressions in these studies.
In conclusion, we found that taurine supplementation had significant effects on reducing body mass. Therefore, we can say that taurine is an amino acid with anti-obesity properties. In our study, no effect of taurine on WAT browning was detected. More studies are needed in different experimental conditions to consider the effects of taurine on WAT browning.