Capsaicin and the plasma of mice
Over the past decades, abundant evidence supporting the beneficial role of capsaicin in weight management[37–39]. In the present study, the body weight of Cap was significantly lower compared to Con at the end of the 6-week intervention(P < 0.05). That means capsaicin slowed weight gain in mice, similar to the previous view that capsaicin has a weight-reducing effect. Capsaicin has been demonstrated to have anti-obesity properties by affecting energy and lipid metabolism. In our study, there are indeed some differential metabolites and metabolic pathways in plasma associated with energy metabolisms, such as DL-lactate(D-lactate and L-lactate), L-Malate, ABC transporters, and Pyruvate metabolism. Both D-lactate and L-lactate can contribute to energy metabolism; L-Malate is an intermediate metabolite of three shuttle acid cycle, directly involved in mitochondrial energy metabolism; In addition, DL-lactate and L-malate are involved in the pathway of Pyruvate metabolism, which plays a pivotal role in cellular bioenergetics and energy production[43, 44]. Previous studies have reported that ABC transporters play an important role in the development of energy metabolism. In short, these changes suggest that the energy metabolism of mice may be altered following capsaicin intake, with consequent effects on their body weight. Similarly, 11 lipids and lipid-like molecules account for a large proportion of differential plasma metabolites, also suggesting altered lipid metabolism in Cap compared with Con. Dysregulated lipid metabolism has been reported to affect body fat mass, adiposity, fatty acid metabolism, and basal metabolic rate. Combined with the results of our study where Cap's weight was lower, we speculate that capsaicin may also inhibit weight gain in mice by modulating changes in lipid metabolism. Furthermore, among the lipids and lipid-like molecules, elevated Diacylglycerol may play an important physiological role which has been demonstrated to have the potential in decreasing body weight gain and body fat accumulation.
Capsaicin has been experimentally shown to control cellular oxidative stress due to its antioxidant properties[48–50]. In the current study, many differential metabolites associated with oxidative stress are also present in plasma, such as Cholic acid, Deoxycholic acid, Pipecolic acid, Carnosine, Taurine, Pyroglutamic acid, Gamma-Glutamylcysteines, and 3-Indolepropionic acid. Pipecolic acid, a metabolite of lysine, is known to induce oxidative stress in vitro in the cerebral cortex of experimental rats. Carnosine and Taurine have antioxidant activities[52–54], whose deficiencies might not be conducive to the recovery of oxidative stress damage in the disease. Gamma-glutamylcysteine, Pyroglutamic acid and taurine also play a role in regulating oxidative stress due to their connection with glutathione[55–58]. Our results suggest that capsaicin can exert some physiological effects by modulating oxidative stress through changes in these metabolites. However, among these metabolites, there are both those that cause and those that reduce oxidative stress; it is difficult to determine whether capsaicin attenuated or enhanced oxidative stress overall; in any case, oxidative stress was altered in mice after capsaicin gavage.
The anticancer activity of capsaicin has been extensively studied for a variety of cancer types. In contrast, there is conflicting evidence that capsaicin may also serve as carcinogenic or co-carcinogenic, thus, capsaicin may play a role in either preventing or causing cancer. In the present study, in addition to the alteration of energy metabolism, lipid metabolism, and oxidative stress impacted by capsaicin, KEGG pathway enrichment analysis also showed that metabolic pathways associated with cancer were significantly enriched in the plasma of Cap, such as Central carbon metabolism in cancer, Choline metabolism in cancer and Renal cell carcinoma. The central carbon metabolism, namely energy metabolism, is the main source of energy for living organisms. Due to the increased demand for cellular biomass in cancer, Central carbon metabolism has been studied for years for monitoring cancer progression and therapy response. The imbalance in the regulation of carbon metabolism will lead to carcinogenesis. The tumor-associated choline metabolism plays a key role in cell malignant transformation, tumor migration and metastasis[62, 63]. Previous study has reported that treatment of capsaicin reduced proliferation of renal carcinoma cells. In short, our results suggest that capsaicin may have an effect on cancer through changes in these pathways. Furthermore, the cAMP signaling pathway and HIF-1 signaling pathway were also enriched in the plasma of Cap. The cAMP signaling pathway is one of the oldest signaling able to regulate substantial biological behaviors containing cellular growth and differentiation, gene expression and neuronal function. It is now recognized that aberrant activation of cAMP signaling may activate multiple effector proteins at distinct intracellular regions and then contribute to tumorigenesis. HIF-1 is an important signaling pathway that modulates cancer dormancy and metabolism, increases stemness activity, and leads to cancer initiation and progression. All these results demonstrated the metabolic pathways associated with cancer might be disturbed in the mice after being gavaged with capsaicin. However, the specific effects of capsaicin on cancer still need to be further explored.
Capsaicin has also been found to play a crucial part in controlling anxiety and other emotional responses. Studies have also found that oral administration of CAP alleviated depressive behavior in mice. However, its mechanism of antidepressant effects is not yet fully understood. In our study, the elevation of the differential metabolite Sarcosine in plasma following oral gavage of capsaicin in mice may have a role in the alleviation of depression. Sarcosine, an N-methyl-d-aspartate receptor enhancer, can improve depression-like behavior in rodent models and depression in humans. Our results, therefore, suggest that the antidepressant effect of capsaicin may be related to Sarcosine.
Capsaicin and the skin of mice
There were also some differences in metabolites in the skin of Cap and Con, although the differential results were less. Including the rise of Sphingosine, Hypoxanthine, Creatinine, Thioetheramide-PC and the decline of Erucamide, N-Docosanoyl-4-sphingenyl-1-O-phosphorylcholine, Glyceryl monolinoleate. KEGG pathway enrichment analysis shows Sphingolipid metabolism, Sphingolipid signaling pathway, Apoptosis, and Necroptosis significantly enriched in Cap. Sphingosine, one of the metabolites of sphingolipids, is involved in these four enriched pathways. Sphingosine with one fatty acid attached is called ceramide. Ceramides based on phytosphingosine, Sphingosine and dihydrosphingosine are essential constituents of the skin lipid barrier that protects the body from excessive water loss. The rise in Sphingosine in the skin of Cap suggests that capsaicin may have an effect on skin lipid barrier function in mice; Of course, this requires further research to confirm. Moreover, Sphingolipids and their metabolites are also involved in signal transduction, such as cell growth, differentiation, senescence, and programmed cell death. In short, capsaicin might affect skin physiological functions in mice through changes in these metabolites and metabolic pathways.