Investigation on the mechanisms underlying brown adipose tissue/liver crosstalk for the regulation of hepatic de novo lipogenesis and glucose production

• Grant number: 17/08264-8
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: April 01, 2018
• End date: March 31, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Osório Silveira Leiria
• Grantee: Luiz Osório Silveira Leiria
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Isis Do Carmo Kettelhut ; Ljubica Tasic ; Marcelo Alves da Silva Mori ; Pedro Manoel Mendes de Moraes Vieira
• Associated research grant(s): 20/05040-4 - Translational study on the role of specialised pro-resolving lipid mediators in the tolerance against CARS-CoV-2 infection, AP.R
• Associated scholarship(s): 22/12896-8 - ROLE OF 5-LIPOXYGENASE DERIVED LIPIDS FOR BROWN FAT FUNCTION, BP.IC; 21/03785-5 - Adipocyte-secreted lipids mediate adipose tissue and pancreas organ crosstalk, BP.PD; 21/01607-2 - Omega-3 lipid metabolites effects on histomorphological parameters of livers from mice with non-alcoholic fatty liver disease, BP.IC; + associated scholarships 21/01608-9 - Characterization of the signaling pathway triggered by Maresin-2 in hepatocytes, BP.IC; 21/01311-6 - 12-Lipoxygenase as a rate-limiting step to promote brown fat/liver cross talk and suppress hepatosteatosis in high-fat diet fed mice, BP.MS; 18/25053-3 - Study of the anti-lipogenic activity of lipids in the liver, BP.MS; 19/02766-7 - Identification and characterization of 12-hydroxypentaenoic acid receptor (12-HEPE), BP.DD; 18/05753-0 - Investigation on the mechanisms underlying brown adipose tissue/liver crosstalk for the regulation of hepatic de novo lipogenesis and glucose production, BP.JP - associated scholarships

Abstract

Due to the remarkable capacity of Brown Adipose Tissue (BAT) to combust glucose and fatty-acids and the presence of BAT in adult humans, this tissue has been considered as an attractive target for the treatment or prevention of Type-2 Diabetes (T2DM)/Obesity. Nonetheless, BAT activation results in improved insulin sensitivity and glucose utilization in other tissues, such as liver or muscle. These distal effects are a consequence of BAT capacity to act as a secretory organ, releasing factors that mediate its peripheral effects. While cold is known as an effective way to activate BAT and to provoke several beneficial metabolic effects, identification of the molecular mimetics of cold exposure will provide new avenues for the prevention and treatment of metabolic diseases such as Obesity, Diabetes, and Non-Alcoholic Fatty Liver Disease (NAFLD). The use of metabolomics technologies combined with genetic models has helped to identify several lipid mediators that serve as metabolic messengers to communicate the energy status and modulate substrate utilization among tissues. NAFLD takes place as a consequence of a high-fat and mainly high-carbohydrate diet and plays a pivotal role connecting Obesity with Type-2 Diabetes and cardiovascular diseases. BAT and liver communicates through the release of factors that can modulate each other functions. Based on our preliminary data, we hypothesized that brown adipose tissue is capable of biosynthesizing and secreting lipid metabolites that regulate hepatic function and gene expression profile. We therefore propose that the cold-induced omega-3 metabolites such as 12-HEPE, 14-HDHA and Maresin-2 are produced in BAT under cold through increased 12-lipoxygenase activity and then released into the circulation, thus suppressing liver lipogenesis, hepatic glucose production and triglycerides synthesis by stimulating G-coupled protein receptors in the liver. In the present project, we present a comprehensive and innovative approach in order to elucidate the BAT-liver cross talk and identify/characterize novel omega-3 lipid metabolites capable of ameliorating NAFLD and T2DM. (AU)

Scientific publications

(5)

(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)

SACCON, TATIANA DANDOLINI; MOUSOVICH-NETO, FELIPPE; LUDWIG, RAISSA GUIMARAES; CARREGARI, VICTOR CORASOLLA; DOS ANJOS SOUZA, ANA BEATRIZ; DOS PASSOS, AMANDA STEPHANE CRUZ; MARTINI, MATHEUS CAVALHEIRO; BARBOSA, PRISCILLA PASCHOAL; DE SOUZA, GABRIELA FABIANO; MURARO, STEFANIE PRIMON; et al. SARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner. NATURE COMMUNICATIONS, v. 13, n. 1, p. 15-pg., 2022-09-29. (20/08716-9, 20/04558-0, 19/05155-9, 21/10373-5, 13/07607-8, 20/04919-2, 20/04746-0, 17/01184-9, 17/23920-9, 16/24163-4, 16/00194-8, 18/21635-8, 19/00098-7, 20/05040-4, 17/08264-8, 20/04579-7, 19/26119-0, 19/04726-2, 20/04583-4, 20/15959-5)

BARRETO, ESTER A.; CRUZ, AMANDA S.; VERAS, FLAVIO P.; MARTINS, RONALDO; BERNARDELLI, RAFAELLA S.; PAIVA, ISADORA M.; LIMA, THAIS M.; SINGH, YOUVIKA; GUIMARAES, RAPHAEL C.; DAMASCENO, SAMARA; et al. COVID-19-related hyperglycemia is associated with infection of hepatocytes and stimulation of gluconeogenesis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 120, n. 21, p. 10-pg., 2023-05-15. (16/00194-8, 20/05040-4, 17/08264-8, 20/04558-0)

LEIRIA, LUIZ O.; TSENG, YU-HUA. Lipidomics of brown and white adipose tissue: Implications for energy metabolism. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1865, n. 10, OCT 2020. (17/08264-8)

GUIMARAES, RAPHAEL C.; GONCALVES, TIAGO T.; LEIRIA, LUIZ O.. Exploiting oxidized lipids and the lipid-binding GPCRs against cardiometabolic diseases. British Journal of Pharmacology, v. 178, n. 3, DEC 2020. (19/02766-7, 20/05040-4, 18/25053-3, 17/08264-8)

SPONTON, CARLOS H.; DE LIMA-JUNIOR, JOSE CARLOS; LEIRIA, LUIZ O.. What puts the heat on thermogenic fat: metabolism of fuel substrates. TRENDS IN ENDOCRINOLOGY AND METABOLISM, v. 33, n. 8, p. 13-pg., 2022-07-12. (20/05040-4, 17/08264-8, 19/26008-4, 19/15025-5)