In this study, the modulatory effect of capsaicin (CAP) on the circadian rhythm of glucose metabolism in the liver and pancreas of mice fed a high-fructose and high-fat diet (HFFD) was investigated. Our results indicated that CAP alleviated HFFD-induced insulin resistance and increased liver glycogen content in mice. In addition, it restored the rhythmic expressions of circadian clock genes and glucose metabolism-related genes in the liver and pancreas, alleviated pancreatic dysfunction and reprogrammed the fecal metabolic profile of HFFD-fed mice. These findings suggested that CAP might work as a functional food ingredient to improve the circadian rhythm of glucose metabolism, providing a more effective dietary intervention strategy for the prevention of metabolic disorders and circadian rhythm disturbances.

Obesity and metabolic disorders are significant global health challenges, contributing to the prevalence of numerous chronic diseases. Capsaicin (CAP) has demonstrated the ability to promote the browning of white adipose tissue (WAT) and enhance thermogenesis in brown adipose tissue (BAT), thereby maintaining energy homeostasis primarily through uncoupling protein 1 (UCP1)-mediated thermogenesis. The thermogenic function of BAT is regulated by circadian rhythms, and disruptions in these rhythms may contribute to metabolic dysfunctions and obesity. However, the effects of CAP on the circadian regulation of BAT thermogenesis remain unclear. This study investigates the effect of CAP on circadian thermogenesis in BAT and its potential to counteract obesity induced by a high-fat, high-fructose diet (HFFD) in murine and cell models. The results demonstrated that CAP significantly reduced weight gain and adiposity, preserved the thermogenic capacity of BAT, and restored the circadian rhythms of key thermogenic genes in BAT. CAP also promoted the differentiation of C3H10T1/2 mesenchymal stem cells into brown adipocytes and enhanced mitochondrial function by mitigating oxidative stress and improving mitochondrial membrane potential through a circadian involvement mechanism. These findings highlight CAP as a promising therapeutic agent for regulating energy expenditure and preventing obesity-related metabolic disorders.

In this study, an obese rat model induced by a high-fat diet (HFD) was used to investigate the modulating effect of 1-piperoylpiperidine (PIP) on circadian misalignment caused by metabolic dysregulation. The results showed that PIP attenuated HFD-induced liver injury, lowered blood lipid levels, alleviated circadian rhythm disruptionthe biological clock and lipid metabolism genes in the liver, and restored the changes in the expression of lysophosphatidic acid (16:0_18:1), bis-methyl phosphatidic acid (BisMePA, 38:8e), phosphatidyl ethanolamine (PE, 16:0p_22:6) and methylphosphocholine (MePC, 32:4e), which are closely associated with the biological clock. These findings may provide a theoretical basis for understanding the regulatory effect of PIP on the circadian rhythm of liver lipid metabolism.

As the body’s internal clock, the circadian rhythm regulates the energy expenditure, appetite, and sleep. There exists a close relationship between the host circadian rhythm and gut microbiota. In this work, a circadian disorder mouse model induced by constant darkness (CD) was constructed to investigate the regulating effects of capsaicin (CAP) on disturbances of metabolism homeostasis and gut microbiota in the respect of circadian rhythm-related mechanisms. Our results indicated that CAP reduced weight gain induced by circadian rhythm disorder in mice by inhibiting fat accumulation in liver and adipose tissue. The rhythmic expressions of circadian clock genes and lipid-metabolism related genes in liver were also recovered by CAP. Microbial study using 16S rRNA sequencing revealed that CAP modulated the gut microbiota richness, diversity and composition, and restored diurnal oscillations of gut microbes at the phylum and family level. These results indicated that CAP could alleviate CD-induced hepatic clock gene disruption and gut microbiota dysbiosis in mice, providing theoretical basis for CAP to be used as a muti-functional ingredient with great health-promoting effects.

The interplay between the host circadian clock and microbiota has significant influences on host metabolism processes, and circadian desynchrony triggered by high-fat diet (HFD) is closely related to metabolic disorders. In this study, the modulatory effects of piperine (PIP) on lipid metabolism homeostasis, gut microbiota community and circadian rhythm of hepatic clock gene expressions in obese rats were investigated. The Sprague-Dawley (SD) rats were fed with normal diet (ND), HFD and HFD supplemented with PIP, respectively. After 9 weeks, rats were sacrificed with tissue and fecal samples collected for circadian analysis. Results showed that chronic PIP administration ameliorated the obesity-induced alterations in lipid metabolism and dysregulation of hepatic clock gene expressions in obese rats. The gut microbial communities studied through 16S rRNA sequencing showed that PIP ameliorated the imbalanced microbiota and recovered the circadian rhythm of Lactobacillaceae, Desulfovibrionaceae, Paraprevotellaceae, and Lachnospiraceae. The fecal metabolic profiles indicated that 3-dehydroshikimate, cytidine and lithocholyltaurine were altered, which were involved in the amino acid and fatty acid metabolism process. These findings could provide theoretical basis for PIP to work as functional food to alleviate the lipid metabolism disorder, circadian rhythm misalignment, and gut microbiota dysbiosis with wide applications in the food and pharmaceutic industries.