Cellular and molecular mechanisms of insulin resistance and inflammation in obese Wistar rats and lean Goto-Kakizaki rats: causes and associations with diet and physical exercise

• Grant number: 18/09868-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2018
• End date: September 30, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Rui Curi
• Grantee: Rui Curi
• Host Institution: Centro de Ciências Biológicas e da Saúde. Universidade Cruzeiro do Sul (UNICSUL). São Paulo , SP, Brazil
• Pesquisadores principais: Renata Gorjao ; Sandro Massao Hirabara ; Tania Cristina Pithon Curi
• Associated researchers: Adriana Cristina Levada-Pires ; Elaine Hatanaka Dermargos ; Maria Fernanda Cury Boaventura ; Mario Hiroyuki Hirata
• Associated research grant(s): 20/00707-0 - Involvement of inflammation in skeletal muscle hypertrophy and physical exercise performance, AP.R SPRINT; 20/06521-6 - Multi-user equipment approved in grant 18/09868-7: Varioskan LUX multimode reader+ EVOS FL Cell Imaging System, AP.EMU
• Associated scholarship(s): 23/03499-8 - Effect of resistance exercise on insulin resistance in skeletal muscle in non-obese type 2 diabetic animal model, BP.DR; 24/07646-8 - Regulation of insulin resistance in the soleus muscle of non-obese Goto-Kakizaki type2 diabetic rats by bone marrow transplantation, BP.IC; 24/05095-4 - Analysis of the inflammatory process and insulin resistance in the gastrocnemius muscle of non-obese Type 2 Diabetic Goto-kakizaki rats supplemented with omega-3, BP.IC; + associated scholarships 23/18436-1 - IMMUNOPHENOTYPING OF CELL CELLS BONE MARROW OF THE GOTO-KAKIZAKI MOUSE, BP.IC; 23/03741-3 - Effects of palmitoleic acid on wound healing in type 2 (Goto-Kakizaki) and 1 (Wistar injected with streptozotocin) diabetic rats, BP.DR; 23/11437-2 - Intestinal functions in Goto-Kakizaki (GK) rat, BP.IC; 23/02376-0 - SKELETAL MUSCLE ATROPHY IN GOTO-KAKIZAKI RATS BY SUSPENSION OF THE HIND LEGS, BP.IC; 22/12241-1 - Inflammatory status and satellite cells activity in muscular hypertrophy in goto-kakizaki rats, BP.DD; 22/11249-9 - Slow intestinal transit and intestinal microbiota composition in the genesis of insulin resistance in Goto-Kakizaki rats, BP.DD; 22/01256-8 - Effects of omega-3 rich fish oil supplementation on lymphocytes of the Goto-Kakizaki rats, BP.IC; 21/07063-4 - Epigenetic mechanisms involved in insulin resistance in skeletal muscle of obese Wistar rats and type 2 diabetic goto-kakizaki rats, BP.IC; 20/06641-1 - Evaluation of molecular markers involved with leukocyte function and activation in Goto-Kakizaki rats by flow cytometry., BP.TT; 20/06642-8 - Analysis of mRNA expression of inflammatory markers in skeletal muscle, white adipose tissue, macrophages and lymphocytes from Goto-Kakizaki rats., BP.TT; 19/20606-7 - Evaluation of protein expression involved with inflammation and insulin resistance in skeletal muscle, white adipose tissue and macrophages in Goto-Kakizaki rats, BP.TT; 19/10118-5 - Gene expression and cytokine secretion related to T lymphocyte differentiation during insulin resistance development in Goto-Kakizaki rats, BP.IC; 19/01942-6 - Neurochemical characterization of mioenteric plexus of Goto-Kakizaki rat intestine, BP.IC; 19/02175-9 - Evaluation of synthesis and degradation of proteins in the hypertrophic response of EDL and soil muscles in rats Goto Kakizaki, BP.IC - associated scholarships

Abstract

Peripheral Insulin Resistance (IR) and inflammation follow the development of Type 2 Diabetes Mellitus (DM2), with a high prevalence in obese patients. However, a significant percentage of non-obese individuals present DM2, especially in specific regions. For example, in Brazil, this percentage reaches 10 to 20%, while, in Japan, about 60% of type 2 diabetic patients have no Obesity. The causes associated with the development of T2DM, especially in lean individuals, remain to be completelly elucidated, as well as the association of this condition with different hypercaloric diets, fish oil administration and regular practice of physical activity. Goto-Kakizaki (GK) rats were genetically selected and develop a well-characterized condition of IR and inflammation, with further DM2 development without obesity. This experimental model will be used in the present project in comparison to the classical model of diet-induced RI (obese Wistar rats). As possible causes of IR and inflammation in conditions with and without obesity, we will investigate: chronic and subclinical inflammation and IR in various tissues, gastrointestinal tract morphology, intestinal microbiota composition, leukocyte metabolism and function, muscle tissue, white and brown tissue adipose, as well as the interaction between these factors. Thus, it will be possible to determine if the IR observed spontaneously in GK animals occurs by similar mechanisms to that observed in obese animals. The effects of fish oil supplementation and physical exercise, two interventions that improve IR and inflammation in different human and animal models, will be also determined. IR and inflammation of obese Wistar and lean GK rats will also be investigated using different hipercaloric diets, high-fat and/or high-carbohydrate diets. This proposal involves the following subprojects associated with the establishment of IR in obese Wistar and lean GK rats: 1) glutamine and glutamine metabolism and inflammassome activity in macrophages;2) lymphocyte metabolism and differentiation; 3) inflammatory process in skeletal muscle and white adipose tissue; 4) temporal evolution of the subclinical inflammatory condition and glucose metabolism in liver; 5) interaction between metabolism and inflammation in brown adipose tissue; 6) morphophysiology of the gastrointestinal tract and composition of intestinal microbiota in the establishment of IR; 7) effect of the administration of different diets rich in fat, carbohydrates, or both, in the establishment of IR; 8) identification of circulating microRNAs as biomarkers of the development of IR; 9) effect of treatment with fish oil rich in EPA or DHA in the development of IR; 10) attenuation of the IR by physical training. Therefore, we intend to map the cellular and molecular mechanisms involved in the development of inflammation and insulin resistance in two animal models (obese Wistar rats and lean Goto-Kakizaki type 2 diabetic rats), as well as to identify potential therapeutic targets for polyunsaturated fatty acid n-3 and physical exercise. (AU)

Scientific publications

(29)

(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)

TATAGIBA KUWABARA, WILSON MITSUO; FUKUSAWA YOKOTA, CAROLINE NAOMI; CURI, RUI; ALBA-LOUREIRO, TATIANA CAROLINA. Obesity and Type 2 Diabetes mellitus induce lipopolysaccharide tolerance in rat neutrophils. SCIENTIFIC REPORTS, v. 8, DEC 3 2018. (16/15766-7, 18/09868-7, 15/03175-1)

HIRABARA, SANDRO M.; SERDAN, TAMIRES D. A.; GORJAO, RENATA; MASI, LAUREANE N.; PITHON-CURI, TANIA C.; COVAS, DIMAS T.; CURI, RUI; DURIGON, EDISON L.. ARS-COV-2 Variants: Differences and Potential of Immune Evasio. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, JAN 18 2022. (18/09868-7)

ANTUNES, MARINA MASETTO; GODOY, GUILHERME; FERNANDES, INGRID DE LIMA; MANIN, LUCIANA PELISSARI; ZAPPIELO, CAROLINE; MASI, LAUREANE NUNES; BARBOSA DE OLIVEIRA, VIVIAN ARAUJO; VISENTAINER, JESUI VERGILIO; CURI, RUI; BAZOTTE, ROBERTO BARBOSA. The Dietary Replacement of Soybean Oil by Canola Oil Does Not Prevent Liver Fatty Acid Accumulation and Liver Inflammation in Mice. NUTRIENTS, v. 12, n. 12, DEC 2020. (18/09868-7)

TANG, YUANJI; SERDAN, TAMIRES D. A.; MASI, LAUREANE N.; TANG, SHERRY; GORJAO, RENATA; HIRABARA, SANDRO M.. Epidemiology of COVID-19 in Brazil: using a mathematical model to estimate the outbreak peak and temporal evolution. EMERGING MICROBES & INFECTIONS, v. 9, n. 1, p. 1453-1456, JAN 1 2020. (18/09868-7)

HIRABARA, SANDRO MASSAO; GORJAO, RENATA; MARZUCA-NASSR, GABRIEL NASRI; VITZEL, KAIO FERNANDO; VINOLO, MARCO AURELIO RAMIREZ; MASI, LAUREANE NUNES. Editorial: Molecular and cellular mechanisms involved in inflammation, metabolism and oxidative stress induced by coronaviruses. FRONTIERS IN MICROBIOLOGY, v. 14, p. 3-pg., 2023-03-22. (18/15313-8, 18/09868-7)

LOBATO, TIAGO BERTOLA; GENNARI-FELIPE, MATHEUS; BARBOSA PAUFERRO, JANAINA RIBEIRO; CORREA, ILANA SOUZA; SANTOS, BEATRIZ FERREIRA; DIAS, BEATRIZ BELMIRO; DE OLIVEIRA BORGES, JOAO CARLOS; DOS SANTOS, CAMILA SOARES; DE SOUSA SANTOS, ELVIRAH SAMANTHA; LEITE DE ARAUJO, MARIA JANAINA; et al. Leukocyte metabolism in obese type 2 diabetic individuals associated with COVID-19 severity. FRONTIERS IN MICROBIOLOGY, v. 13, p. 18-pg., 2022-11-03. (18/09868-7, 18/07283-1)

RODRIGUES JR, CARLOS FLORES; MURATA, GILSON MASAHIRO; GERLINGER-ROMERO, FREDERICO; NACHBAR, RENATO TADEU; MARZUCA-NASSR, GABRIEL NASRI; GORJAO, RENATA; VITZEL, KAIO FERNANDO; HIRABARA, SANDRO MASSAO; PITHON-CURI, TANIA CRISTINA; CURI, RUI. Changes in Skeletal Muscle Protein Metabolism Signaling Induced by Glutamine Supplementation and Exercise. NUTRIENTS, v. 15, n. 22, p. 15-pg., 2023-11-01. (18/09868-7)

MARZUCA-NASSR, GABRIEL NASRI; PENAILILLO, LUIS; VALLADARES-IDE, DENISSE; MARTINEZ-HUENCHULLAN, SERGIO; CURI, RUI; HIRABARA, SANDRO MASSAO; VITZEL, KAIO FERNANDO. Editorial: Spotlight on aging: physiology, prevention, and management of skeletal muscle atrophy. FRONTIERS IN PHYSIOLOGY, v. 14, p. 3-pg., 2023-12-05. (18/09868-7, 22/09341-4)

DOS SANTOS, ALEF ARAGAO CARNEIRO; RODRIGUES, LUIZ EDUARDO; ALECRIM-ZEZA, AMANDA LINS; FERREIRA, LILIANE DE ARAUJO; TRETTEL, CAIO DOS SANTOS; GIMENES, GABRIELA MANDU; DA SILVA, ADELSON FERNANDES; SOUSA-FILHO, CELSO PEREIRA BATISTA; SERDAN, TAMIRES DUARTE AFONSO; LEVADA-PIRES, ADRIANA CRISTINA; et al. Molecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2. FRONTIERS IN MICROBIOLOGY, v. 13, p. 22-pg., 2022-11-10. (18/07283-1, 18/09868-7)

LOBATO, TIAGO BERTOLA; MANOEL, RICHELIEAU; PEREIRA, ANA CAROLINA GOMES; CORREA, ILANA SOUZA; ISER-BEM, PATRICIA NANCY; SANTOS, ELVIRAH SAMANTHA DE SOUSA; PEREIRA, JOICE NAIARA BERTAGLIA; DE ARAUJO, MARIA JANAINA LEITE; BORGES, JOAO CARLOS DE OLIVEIRA; PAUFERRO, JANAINA RIBEIRO BARBOSA; et al. Insulin resistance in nonobese type 2 diabetic Goto Kakizaki rats is associated with a proinflammatory T lymphocyte profile. FEBS Letters, v. 598, n. 20, p. 15-pg., 2024-08-02. (18/09868-7)

GIMENES, GABRIELA MANDU; PEREIRA, JOICE NAIARA BERTAGLIA; DA SILVA, ELIANE BORGES; DOS SANTOS, ALEF ARAGAO CARNEIRO; RODRIGUES, THAIS MARTINS; SANTANA, GIOVANNA DE OLIVEIRA; SCERVINO, MARIA VITORIA MARTINS; PITHON-CURI, TANIA CRISTINA; HIRABARA, SANDRO MASSAO; GORJAO, RENATA; et al. Intestinal Motility Dysfunction in Goto-Kakizaki Rats: Role of the Myenteric Plexus. CELLS, v. 13, n. 19, p. 15-pg., 2024-10-01. (19/01942-6, 18/09868-7, 22/11249-9)

J.C.O. BORGES; V.A.B. OLIVEIRA; T.D.A. SERDAN; F.L.R. SILVA; C.S. SANTOS; J.R.B. PAUFERRO; A.S.F. RIBAS; R. MANOEL; A.C.G. PEREIRA; I.S. CORREA; et al. Brain glucose hypometabolism and hippocampal inflammation in Goto-Kakizaki rats. Brazilian Journal of Medical and Biological Research, v. 56, 2023-06-26. (18/09868-7, 21/02829-9)

G. GODOY; P.B. TRAVASSOS; M.M. ANTUNES; C.C. IWANAGA; A.B. SÁ-NAKANISHI; R. CURI; J.F. COMAR; R.B. BAZOTTE. Strenuous swimming raises blood non-enzymatic antioxidant capacity in rats. Brazilian Journal of Medical and Biological Research, v. 55, 2022-02-28. (18/09868-7)

R. GORJÃO; S.M. HIRABARA; L.N. MASI; T.D.A. SERDAN; R.B. GRITTE; E. HATANAKA; T. SOUZA-SIQUEIRA; A.C. PITHON-CURI; T.M. DE LIMA; T.C. PITHON-CURI; et al. Poor prognosis indicators of type-2 diabetic COVID-19 patients. Brazilian Journal of Medical and Biological Research, v. 55, 2022-06-22. (19/25892-8, 18/07283-1, 18/09868-7, 20/04738-8, 21/08624-0)

GORJAO, R.; HIRABARA, S. M.; MASI, L. N.; SERDAN, T. D. A.; GRITTE, R. B.; HATANAKA, E.; SOUZA-SIQUEIRA, T.; PITHON-CURI, A. C.; DE LIMA, T. M.; PITHON-CURI, T. C.; et al. Poor prognosis indicators of type-2 diabetic COVID-19 patients. Brazilian Journal of Medical and Biological Research, v. 55, n. 1, p. 11-pg., 2022-01-01. (18/09868-7, 20/04738-8, 21/08624-0, 19/25892-8, 18/07283-1)

GALAN, B. S. M.; SERDAN, T. D. A.; RODRIGUES, L. E.; MANOEL, R.; GORJAO, R.; MASI, L. N.; PITHON-CURI, T. C.; CURI, R.; HIRABARA, S. M.. Reviewing physical exercise in non-obese diabetic Goto-Kakizaki rats. Brazilian Journal of Medical and Biological Research, v. 55, n. 1, p. 14-pg., 2022-01-01. (18/09868-7, 20/06641-1, 20/06642-8, 19/25892-8, 18/07283-1)

M.M. ANTUNES; G. GODOY; C.B. DE ALMEIDA-SOUZA; B.A. DA ROCHA; L.G. DA SILVA-SANTI; L.N. MASI; F. CARBONERA; J.V. VISENTAINER; R. CURI; R.B. BAZOTTE. A high-carbohydrate diet induces greater inflammation than a high-fat diet in mouse skeletal muscle. Brazilian Journal of Medical and Biological Research, v. 53, n. 3, 2020-02-14. (18/09868-7)

GODOY, G.; TRAVASSOS, P. B.; ANTUNES, M. M.; IWANAGA, C. C.; SA-NAKANISHI, A. B.; CURI, R.; COMAR, J. F.; BAZOTTE, R. B.. Strenuous swimming raises blood non-enzymatic antioxidant capacity in rats. Brazilian Journal of Medical and Biological Research, v. 55, n. 1, p. 9-pg., 2022-01-01. (18/09868-7)

ANTUNES, MARINA MASETTO; GODOY, GUILHERME; MASI, LAUREANE NUNES; CURI, RUI; BAZOTTE, ROBERTO BARBOSA. refrontal Cortex and Hippocampus Inflammation in Mice Fed High-Carbohydrate or High-Fat Diet. JOURNAL OF MEDICINAL FOOD, v. 25, n. 1, SEP 2021. (18/09868-7, 19/25892-8)

SERDAN, TAMIRES DUARTE AFONSO; MASI, LAUREANE NUNES; PEREIRA, JOICE NAIARA BERTAGLIA; RODRIGUES, LUIZ EDUARDO; ALECRIM, AMANDA LINS; SCERVINO, MARIA VITORIA MARTINS; DINIZ, VINICIUS LEONARDO SOUSA; DOS SANTOS, ALEF ARAGAO CARNEIRO; SOUSA FILHO, CELSO PEREIRA BATISTA; ALBA-LOUREIRO, TATIANA CAROLINA; et al. Impaired brown adipose tissue is differentially modulated in insulin-resistant obese wistar and type 2 diabetic Goto-Kakizaki rats. BIOMEDICINE & PHARMACOTHERAPY, v. 142, OCT 2021. (18/09868-7, 18/18815-4, 19/25936-5, 16/14529-1)

BERTAGLIA PEREIRA, JOICE NAIARA; MURATA, GILSON MASAHIRO; SATO, FABIO TAKEO; MAROSTI, ALINE ROSA; DE OLIVEIRA CARVALHO, CARLA ROBERTA; CURI, RUI. Small intestine remodeling in male Goto-Kakizaki rats. PHYSIOLOGICAL REPORTS, v. 9, n. 3, FEB 2021. (18/09868-7)

TANG, YUANJI; SERDAN, TAMIRES D. A.; ALECRIM, AMANDA L.; SOUZA, DIEGO R.; NACANO, BRUNO R. M.; SILVA, FLAVIANO L. R.; SILVA, ELIANE B.; POMA, SARAH O.; GENNARI-FELIPE, MATHEUS; ISER-BEM, PATRICIA N.; et al. simple mathematical model for the evaluation of the long first wave of the COVID-19 pandemic in Brazi. SCIENTIFIC REPORTS, v. 11, n. 1, AUG 12 2021. (18/09868-7)

GIMENES, G. M.; SANTANA, G. O.; SCERVINO, M. V. M.; CURI, R.; PEREIRA, J. N. B.. A short review on the features of the non-obese diabetic Goto-Kakizaki rat intestine. Brazilian Journal of Medical and Biological Research, v. 55, n. 1, p. 10-pg., 2022-01-01. (18/09868-7, 19/19097-0, 19/01942-6)

BAZOTTE, ROBERTO BARBOSA; HIRABARA, SANDRO MASSAO; DUARTE SERDAN, TAMIRES AFONSO; GRITTE, RAQUEL BRAGANTE; SOUZA-SIQUEIRA, TALITA; GORJAO, RENATA; MASI, LAUREANE NUNES; ANTUNES, MARINA MASETTO; CRUZAT, VINICIUS; PITHON-CURI, TANIA CRISTINA; et al. 4-Aminoquinoline compounds from the Spanish flu to COVID-19. BIOMEDICINE & PHARMACOTHERAPY, v. 135, MAR 2021. (19/25936-5, 18/09868-7)

ARTIGAS-ARIAS, MACARENA; CURI, RUI; MARZUCA-NASSR, GABRIEL NASRI. Myogenic microRNAs as Therapeutic Targets for Skeletal Muscle Mass Wasting in Breast Cancer Models. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 12, p. 16-pg., 2024-06-01. (18/09868-7, 22/09341-4)

HIRABARA, SANDRO MASSAO; GORJAO, RENATA; CURI, RUI; LEANDRO, CAROL GOIS; MARZUCA-NASSR, GABRIEL NASRI. Editorial: Nutritional modulation of inflammation and insulin resistance. FRONTIERS IN NUTRITION, v. 10, p. 3-pg., 2023-03-23. (18/09868-7, 15/12728-4)

BARQUILHA, GUSTAVO; DOS SANTOS, CESAR MIGUEL MOMESSO; CACULA, KIM GUIMARAES; SANTOS, VINICIUS CONEGLIAN; POLOTOW, TATIANA GERALDO; VASCONCELLOS, CRISTINA VARDARIS; GOMES-SANTOS, JOSE ALBERTO FERNANDES; RODRIGUES, LUIZ EDUARDO; LAMBERTUCCI, RAFAEL HERLING; SERDAN, TAMIRES DUARTE AFONSO; et al. Fish Oil Supplementation Improves the Repeated-Bout Effect and Redox Balance in 20-30-Year-Old Men Submitted to Strength Training. NUTRIENTS, v. 15, n. 7, p. 19-pg., 2023-04-01. (18/09868-7, 10/08147-2)

GRITTE, RAQUEL BRAGANTE; SOUZA-SIQUEIRA, TALITA; DA SILVA, ELIANE BORGES; DE OLIVEIRA, LAIANE CRISTINA DOS SANTOS; BORGES, RODRIGO CERQUEIRA; ALVES, HELOISA H. DE OLIVEIRA; MASI, LAUREANE NUNES; MURATA, GILSON MASAHIRO; GORJAO, RENATA; LEVADA-PIRES, ADRIANA CRISTINA; et al. Evidence for Monocyte Reprogramming in a Long-Term Postsepsis Study. CRITICAL CARE EXPLORATIONS, v. 4, n. 8, p. 12-pg., 2022-08-01. (17/13715-9, 18/09868-7, 21/08624-0)

SILVEIRA, AMANDA SANTOS DE ALMEIDA; ALVES, AMARA CASSANDRA DOS ANJOS; GIMENES, GABRIELA MANDU; QUESSADA, PATRICIA DA SILVA; LOBATO, TIAGO BERTOLA; DIAS, BEATRIZ BELMIRO; PEREIRA, ANA CAROLINA GOMES; ISER-BEM, PATRICIA NANCY; PEREIRA, JOICE NAIARA BERTAGLIA; HATANAKA, ELAINE; et al. Evidence for a Pro-Inflammatory State of Macrophages from Non-Obese Type-2 Diabetic Goto-Kakizaki Rats. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 25, n. 19, p. 13-pg., 2024-10-01. (18/09868-7)