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Evaluation of D-limonene effects on intermediate metabolism of mice: relationship between limonene metabolism and health effects

Grant number: 19/11324-8
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): September 01, 2019
Effective date (End): August 31, 2022
Field of knowledge:Agronomical Sciences - Food Science and Technology - Food Science
Principal Investigator:Eduardo Purgatto
Grantee:José Fernando Rinaldi de Alvarenga
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/07914-8 - FoRC - Food Research Center, AP.CEPID


The health effects of bioactive compounds found in fruits and vegetables have been studied for a long time and health-protective effects have been associated with different phytochemicals such as phytosterols, flavonoids, glucosinolates and many others. Despite their demonstrated bioactive effects in a variety of models, monoterpenoids are still overlooked when it comes to understanding their mechanism of action and efficacy in humans. The monoterpene d-limonene, found in high concentrations in the peel of citrus fruits is known for its anti-inflammatory, antinociceptive and hypolipemic effects. It is possible that due to its antimicrobial activity, this compound can modulate the composition of intestinal microbiota, which among other actions is responsible for converting primary bile acids into secondary ones with different physico-chemical properties and biological effects. Bile acids are agonists of receptors expressed in several tissues and are able to modulate fatty acid oxidation, gluconeogenesis, hormone secretion and other physiological processes related to intermediate metabolism. It has never been demonstrated, but we believe that changes in intestinal microbiota composition induced by d-limonene could affect bile acid metabolism and different physiological processes regulated by these molecules. The main goal of this study is to evaluate the effects of limonene on bile acid and intermediate metabolism. Male C57/Bl6-J mice will be distributed in 4 groups: 2 groups will receive a high fat-diet and the other 2 will be fed a control diet for 4 weeks. From the 5th week on, one group from each diet will be daily supplemented with 100 mg/Kg of d-limonene. The response to an oral glucose challenge will be evaluated at weeks 4 and 8. Hepatic lipid and glycogen content as well as other markers of lipid metabolism, including plasma triglyceride and cholesterol concentrations will be evaluated. Targeted metabolomics analysis (LC-QqQ) will be employed to analyse the concentration and composition of bile acids and markers of fatty acid/ amino acid oxidation (acylcarnitines) in plasma. Untargeted metabolomics (LC-qToF) will be used to determine the production of limonene metabolites and to assess whole-metabolome changes induced by limonene. The results obtained in this study will contribute to the elucidation of dietary monoterpenes mechanism of action and help assessing the potential use of d-limonene for the prevention/ treatment of metabolic diseases. (AU)

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Scientific publications (11)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
JULIANO, FERNANDA FRANCETTO; MASSARIOLI, ADNA PRADO; LAMUELA-RAVENTOS, ROSA MARIA; DE ALVARENGA, JOSE FERNANDO RINALDI; DE LIMA, LIZIANE MARIA; DOS SANTOS, ROSEANE CAVALCANTI; DA SILVA, CAMILA FURTUNATO; DE ALENCAR, SEVERINO MATIAS. Do drought-adapted peanut genotypes have different bioactive compounds and ROS-scavenging activity?. EUROPEAN FOOD RESEARCH AND TECHNOLOGY, v. 247, n. 6, . (15/02986-6, 16/16193-0, 19/11324-8, 16/06514-4, 13/07914-8)
MARHUENDA-MUNOZ, MARIA; RINALDI DE ALVARENGA, JOSE FERNANDO; HERNAEZ, ALVARO; TRESSERRA-RIMBAU, ANNA; MARTINEZ-GONZALEZ, MIGUEL ANGEL; SALAS-SALVADO, JORDI; CORELLA, DOLORES; MALCAMPO, MIREIA; MARTINEZ, JOSE ALFREDO; ALONSO-GOMEZ, ANGEL M.; et al. High Fruit and Vegetable Consumption and Moderate Fat Intake Are Associated with Higher Carotenoid Concentration in Human Plasma. ANTIOXIDANTS, v. 10, n. 3, . (13/07914-8, 19/11324-8)
LOZANO-CASTELLON, JULIAN; DE ALVARENGA, JOSE FERNANDO RINALDI; VALLVERDU-QUERALT, ANNA; LAMUELA-RAVENTOS, ROSA M.. Cooking with extra-virgin olive oil: A mixture of food components to prevent oxidation and degradation. TRENDS IN FOOD SCIENCE & TECHNOLOGY, v. 123, p. 9-pg., . (13/07914-8, 19/11324-8)
RINALDI DE ALVARENGA, JOSE FERNANDO; QUIFER-RADA, PAOLA; HURTADO-BARROSO, SARA; ILLAN, MONTSERRAT; TORRADO-PRAT, XAVIER; LAMUELA-RAVENTOS, ROSA M.. Cuisinomics: MS-based untargeted approach reveals chemical modulation by a recipe during home cooking. Food Research International, v. 138, n. B, . (19/11324-8, 13/07914-8)
LEVY, JESSICA; SILVA, ALEXSANDRO MACEDO; DE CARLI, EDUARDO; CACAU, LEANDRO TEIXEIRA; DE ALVARENGA, JOSE FERNANDO RINALDI; FIAMONCINI, JARLEI; BENSENOR, ISABELA MARTINS; LOTUFO, PAULO ANDRADE; MARCHIONI, DIRCE MARIA. Biomarkers of Fruit Intake Using a Targeted Metabolomics Approach: an Observational Cross-Sectional Analysis of the ELSA-Brasil Study. Journal of Nutrition, v. 152, n. 9, p. 8-pg., . (16/20054-6, 18/08319-0, 19/13424-0, 19/11324-8)
SILVA, VICTORIA; FARIA, HECTOR ORELIANA FERNANDES; SOUSA-FILHO, CELSO PEREIRA BATISTA; DE ALVARENGA, JOSE FERNANDO RINALDI; FIAMONCINI, JARLEI; OTTON, ROSEMARI. Thermoneutrality or standard temperature: is there an ideal housing temperature to study the antisteatotic effects of green tea in obese mice?. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 120, p. 15-pg., . (18/19189-0, 13/07914-8, 19/10616-5, 19/11324-8)
RINALDI DE ALVARENGA, JOSE FERNANDO; QUIFER-RADA, PAOLA; HURTADO-BARROSO, SARA; ILLAN, MONTSERRAT; TORRADO-PRAT, XAVIER; LAMUELA-RAVENTOS, ROSA M.. Cuisinomics: MS-based untargeted approach reveals chemical modulation by a recipe during home cooking. Food Research International, v. 138, p. 9-pg., . (13/07914-8, 19/11324-8)
RINALDI DE ALVARENGA, JOSE FERNANDO; GENARO, BRUNNA; COSTA, BRUNA LAMESA; PURGATTO, EDUARDO; MANACH, CLAUDINE; FIAMONCINI, JARLEI. Monoterpenes: current knowledge on food source, metabolism, and health effects. CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION, . (19/11324-8, 19/24267-2, 18/19189-0, 13/07914-8)
BARROSO, WERMERSON ASSUNCAO; SERRA, MARIANA BARRETO; ABREU, IRACELLE CARVALHO; BARBEIRO, HERMES VIEIRA; FIAMONCINI, JARLEI; RINALDI DE ALVARENGA, JOSE FERNANDO; DE SOUZA, HERALDO POSSOLO; DE LIMA, THAIS MARTINS. anana green peels extract protects against nonalcoholic fatty liver disease in high-fat-fed mice through modulation of lipid metabolism and inflammatio. Phytotherapy Research, v. 36, n. 2, . (17/12843-3, 13/07914-8, 19/11324-8)
RINALDI DE ALVARENGA, JOSE FERNANDO; GARCIA-ALOY, MAR; ULASZEWSKA, MARYNKA; ZAGMUTT, SEBASTIAN; PEREZ-MONTERO, MARTA; VRHOVSEK, URSKA; LAMUELA-RAVENTOS, ROSA M.; RODRIGUEZ-RODRIGUEZ, ROSALIA. Integrated Metabolomics, Lipidomics, and Genomics Reveal the Presence of a New Biomarker, Butanediol Glucuronide, Associated with the Activation of Liver Ketogenesis and Lipid Oxidation by Tomato-Based Sofrito in Obese Rats. ANTIOXIDANTS, v. 11, n. 11, p. 29-pg., . (19/11324-8, 13/07914-8)

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