RESUMO
OBJECTIVES: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. METHODS: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. KEY FINDINGS: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. CONCLUSIONS: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.
Assuntos
Ácidos e Sais Biliares , Iridoides , Fígado , Obesidade , Ratos Sprague-Dawley , Animais , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Iridoides/farmacologia , Ácidos e Sais Biliares/metabolismo , Masculino , Ratos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Bile/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismoRESUMO
Doxorubicin (DOX) is widely used to treat solid tumors, but its use is limited by its severe cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity. Metabolomic studies on DOX-induced toxicity are mainly focused on alterations in the heart and kidney, but systematic research on multiple matrices (serum, heart, liver, brain, and kidney) is rare. Thus, in our study, gas chromatography-mass spectrometry analysis of main targeted tissues (serum, heart, liver, brain, and kidney) was used to systemically evaluate the toxicity of DOX. Multivariate analyses, including orthogonal projections to the latent structure and t-test, revealed 21 metabolites in the serum, including cholesterol, d-glucose, d-lactic acid, glycine, l-alanine, l-glutamic acid, l-isoleucine, l-leucine, l-proline, l-serine, l-tryptophan, l-tyrosine, l-valine, MG (0:0/18:0/0:0), MG (16:0/0:0/0:0), N-methylphenylethanolamine, oleamide, palmitic acid, pyroglutamic acid, stearic acid, and urea. In the heart, perturbed metabolites included 3-methyl-1-pentanol, cholesterol, d-glucose, d-lactic acid, glycerol, glycine, l-alanine, l-valine, MG (16:0/0:0/0:0), palmitic acid, phenol, propanoic acid, and stearic acid. For the liver, DOX exposure caused alterations of acetamide, acetic acid, d-glucose, glycerol, l-threonine, palmitic acid, palmitoleic acid, stearic acid, and urea. In the brain, metabolic changes involved 2-butanol, carbamic acid, cholesterol, desmosterol, d-lactic acid, l-valine, MG (16:0/0:0/0:0), palmitic acid, and stearic acid. In the kidney, disturbed metabolites were involved in cholesterol, glycerol, glycine, l-alanine, MG (0:0/18:0/0:0), MG (16:0/0:0/0:0), and squalene. Complementary evidence by multiple matrices revealed disturbed pathways concerning amino acid metabolism, energy metabolism, and lipid metabolism. Our results may help to systematically elucidate the metabolic changes of DOX-induced toxicity and clarify the underlying mechanisms.