Investigating mechanisms that link angiotensins to Obesity and Diabetes

• Grant number: 20/03175-0
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2020 - October 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Joilson de Oliveira Martins
• Grantee: Joilson de Oliveira Martins
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Obesity is a chronic metabolic disease that may be associated with physiological disorders, such as diabetes mellitus (DM) and hypertension (HTN). Some studies have shown common pathways linking obesity and diabetes to insulin resistance and the renin-angiotensin system (RAS), a leading regulator of blood pressure. Angiotensinogen (Agt) is the main precursor of RAS. Activation of Agt in adipose tissue exerts pro-inflammatory effects, often linked to dysfunctions in cellular processes, such as autophagy. In obesity, the pro-inflammatory profile in adipose tissue leads to the production of adipokines and cytokines that promote glucose intolerance and insulin resistance. The same happens in diabetes. Several studies have shown that the lipid mediator Leukotriene B4 (LTB4) plays a central role in the establishment of insulin resistance and in the development of DM in animal models. In macrophages, activation of the LTB4 receptor potentiates the proinflammatory phenotype. In the adipose tissue of hyperlipidemic diet-induced T2D mice, monocyte recruitment, macrophage polarization into the M1 profile, proinflammatory cytokine production and insulin resistance have been shown to be dependent on LTB4 production. In liver and muscle LTB4 promotes inflammation and insulin resistance. It is believed that dysregulated autophagy is linked to diabetes through the development of inflammation and insulin resistance. Therefore, we hypothesized that leukotrienes are involved with RAS contributing to inflammation associated with metabolic diseases through dysregulation of autophagy. We intend to investigate the involvement of leukotrienes in RAS in mice with T1D and obesity, with specific emphasis on the role of inflammation (systemic and local), autophagy and signaling of the insulin receptor in metabolically active organs/tissues. We will induce T1D chemically with streptozotocin and to inhibit RAS we will treat the diabetic mice with captopril. After the treatments, liver, adipose tissue and muscle will be removed for analysis. We will evaluate (1) expression of RAS gene markers, autophagy, inflammation, macrophages phenotype and insulin receptor profile by real-time PCR, (2) protein expression of RAS components, autophagy and insulin receptor via Western blotting, (3) production of pro and anti-inflammatory cytokines in these tissues by the ELISA method, to answer our hypothesis. Understanding the molecular mechanisms involved in these diseases can bring a direct benefit to the patient, improving their quality of life, as well as reducing the public expenses resulting from the complications of these metabolic syndromes. (AU)

Scientific publications

(6)

(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)

SERCUNDES, MICHELLE K.; ORTOLAN, LUANA S.; JULIO, VIVIANE DA SILVA; BELLA, LEONARDO M.; QUIRINO, THATYANE DE CASTRO; DEBONE, DANIELA; CARNEIRO-RAMOS, MARCELA S.; CHRISTOFFOLETE, MARCELO A.; MARTINS, JOILSON O.; D'IMPERIO LIMA, MARIA REGINA; et al. lockade of caspase cascade overcomes malaria-associated acute respiratory distress syndrome in mic. CELL DEATH & DISEASE, v. 13, n. 2, FEB 10 2022. (20/03163-1, 13/20718-3, 15/06106-0, 20/06747-4, 20/03175-0)

LARA, PRISCILA G.; ESTEVES, ELIANE; SALES-CAMPOS, HELIOSWILTON; ASSIS, JOSIANE B.; HENRIQUE, MARESSA O.; BARROS, MICHELE S.; NETO, LEILA S.; SILVA, PEDRO, I; MARTINS, JOILSON O.; CARDOSO, CRISTINA R. B.; et al. AeMOPE-1, a Novel Salivary Peptide From Aedes aegypti, Selectively Modulates Activation of Murine Macrophages and Ameliorates Experimental Colitis. FRONTIERS IN IMMUNOLOGY, v. 12, p. 15-pg., 2021-07-19. (20/03175-0, 13/00740-4, 09/09892-6, 15/22934-0, 13/07467-1)

GUIMARAES, JOAO PEDRO TORRES; MENIKDIWELA, KALHARA R.; RAMALHO, THERESA; QUEIROZ, LUIZ A. D.; KALUPAHANA, NISHAN S.; JANCAR, SONIA; RAMALINGAM, LATHA; MARTINS, JOILSON O.; MOUSTAID-MOUSSA, NAIMA. Effects of captopril on glucose metabolism and autophagy in liver and muscle from mice with type 1 diabetes and diet-induced obesity. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1868, n. 10, p. 13-pg., 2022-07-11. (18/50004-6, 20/03175-0, 17/11540-7, 19/09983-3, 18/23266-0)

QUEIROZ, LUIZ A. D.; ASSIS, JOSIANE B.; GUIMARAES, JOAO P. T.; SOUSA, EMANUELLA S. A.; MILHOMEM, ANALIA C.; SUNAHARA, KAREN K. S.; SA-NUNES, ANDERSON; MARTINS, JOILSON O.. ndangered Lymphocytes: The Effects of Alloxan and Streptozotocin on Immune Cells in Type 1 Induced Diabete. Mediators of Inflammation, v. 2021, OCT 19 2021. (20/03175-0, 17/11540-7)

ARORA, AASTHA; TRIPODI, GUSTAVO LUIS; KAREINEN, ILONA; BERG, MARTIN; FORTEZA, MARIA JOSEFA; GISTERA, ANTON; GRIEPKE, SILKE; CASAGRANDE, FELIPE BECCARIA; MARTINS, JOILSON O.; ABDALLA, DULCINEIA SAES PARRA; et al. Genetic Deficiency of Indoleamine 2,3-dioxygenase Aggravates Vascular but Not Liver Disease in a Nonalcoholic Steatohepatitis and Atherosclerosis Comorbidity Model. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 9, p. 17-pg., 2022-05-01. (19/13598-8, 20/03175-0)

RODRIGUES, STEPHEN F.; STOKES, KAREN Y.; FESTUCCIA, WILLIAM T.; MARTINS, JOILSON O.. Editorial: Interplay Between Autophagy and Metabolic Syndrome: Causes, Consequences and Therapeutic Challenges. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, p. 3-pg., 2021-10-06. (20/07212-7, 19/01763-4, 14/05146-6, 20/03175-0, 20/04159-8, 15/19530-5)