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

Grant number: 18/09868-7
Support type:Research Projects - Thematic Grants
Duration: October 01, 2018 - September 30, 2023
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Rui Curi
Grantee:Rui Curi
Home Institution: Centro de Ciências Biológicas e da Saúde. Universidade Cruzeiro do Sul (UNICSUL). São Paulo , SP, Brazil
Co-Principal Investigators:Renata Gorjao ; Sandro Massao Hirabara ; Tania Cristina Pithon Curi
Assoc. researchers:Adriana Cristina Levada-Pires ; Elaine Hatanaka Dermargos ; Maria Fernanda Cury Boaventura ; Mario Hiroyuki Hirata
Associated scholarship(s):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


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)

Articles published in Agência FAPESP Newsletter about the research grant
Cellular alterations increase the vulnerability of obese and diabetic individuals to infections 

Scientific publications
(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. Web of Science Citations: 1.

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