Involvement of the nutrient sensor mTOR in the development of obesity associated chronic metabolic diseases

• Grant number: 15/19530-5
• Support type: Research Projects - Thematic Grants
• Duration: November 01, 2015 - December 31, 2020
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: William Tadeu Lara Festuccia
• Grantee: William Tadeu Lara Festuccia
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Assoc. researchers: Alex Shimura Yamashita ; Fernanda Janku Cabral ; Patricia Chimin
• Associated grant(s): 19/00726-8 - Mechanisms underlying the antiinflammatory and thermogenic effects of fish oil in obesity and associated metabolic diseases, AP.R SPRINT
• Associated scholarship(s): 19/17660-0 - Discovery of new transcription factors involved in the development of steatosis, steatopatite and hepatocarcinome, BP.PD; 19/04271-5 - UCP1-independent mechanisms involved in the increased energy expenditure and protection against Obesity induced by fish oil in mice, BP.DR; 18/11156-5 - Effects of obesity and severe lipodystrophy on oxidation and peroxidation of lipids: involvement of these molecules on inflammation and insulin resistance, BP.PD; + associated scholarships 18/05387-4 - Training in the maintenance and genotyping of genetically modified mice, BP.TT; 17/23040-9 - Characterization of mTORC2 role in the hepatic steatosis, steatohepatitis and hepatocellular carcinoma progression induced by PTEN deletion in hepatocytes, BP.DR; 17/17403-1 - Characterization of the molecular mechanisms by which TSC1 deletion in adipocytes increases oxidative metabolism and UCP1 content in white adipose tissue, BP.IC; 17/17582-3 - Characterization of the involvement of nutrient sensor mTORC1 in the hepatic steatosis, steatohepatitis, and hepatocarcinoma induced by PTEN deletion into hepatocytes, BP.PD; 17/12260-8 - Autophagy involvment in the metabolic and inflammatory alterations in adipose tissue associated with Obesity induced by high fat diet, BP.DD; 16/23169-9 - Involvement of mTORC1 and 2 and PPARgamma in the regulation of leukocyte profile, recruitment and activation of brown adipose tissue and beige adipocytes induced by cold exposure, BP.DD; 15/13508-8 - Involvement of adipocytes mTOR complexes 1 and 2 in the morphological, metabolic and secretory changes induced by pharmacological PPARgamma activation, BP.DR; 16/05406-3 - Involvement of autophagy in the metabolic and inflammatory changes induced by mTORC1 inactivation in adipocytes, BP.MS; 16/07062-0 - Characterization of the mechanisms underlying omega-3 fatty acids effects on energy balance, BP.MS; 15/22983-1 - Discovery of new transcription factors involved in the development of steatosis, steatohepatitis, and liver cancer, BP.PD - associated scholarships

Abstract

The exponential growth of obesity worldwide is increasing the prevalence of several chronic diseases commonly associated to excessive adiposity such as type 2 diabetes, hepatic steatosis and some types of cancer. Despite of its major impact worldwide, little is known about the mechanisms that link obesity to the development of its associated chronic diseases. Being obesity a condition characterized by excess of nutrients, our laboratory has investigated over the years the involvement of nutrient and growth factor sensors as linking factors between obesity and associated chronic diseases. Thus the present research proposal aims to investigate the involvement of nutrient and growth factor sensors mTOR complexes 1 and 2 in the: 1 - regulation of adiposity and adipose tissue metabolism; 2 - development of obesity associated chronic low grade inflammation; 3 - development of obesity associated hepatic insulin resistance, steatosis and cancer; 4 - recruitment (hyperplasia and hypertrophy), activation and metabolism of brown adipose tissue and beige adipocytes. (AU)

Scientific publications

(13)

(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)

MOREIRA, RAFAEL J.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; BELCHIOR, THIAGO; PEIXOTO, ALBERT S.; CHAVES-FILHO, ADRIANO B.; MORENO, MAYARA F.; LIMA, JANAYNA D.; YOSHINAGA, MARCOS; MIYAMOTO, SAYURI; MORAIS, MYCHEL R. P. T.; ZORN, TELMA M. T.; COGLIATI, BRUNO; IWAI, LEO K.; PALMISANO, GIUSEPPE; CABRAL, FERNANDA J.; FESTUCCIA, WILLIAM. Lipoatrophy-Associated Insulin Resistance and Hepatic Steatosis are Attenuated by Intake of Diet Rich in Omega 3 Fatty Acids. MOLECULAR NUTRITION & FOOD RESEARCH, v. 64, n. 7 FEB 2020. Web of Science Citations: 0.

GUERRA, BEATRIZ A.; BRANDAO, BRUNA B.; PINTO, SILAS S.; SALGUEIRO, WILLIAN G.; DE-SOUZA, EVANDRO A.; REIS, FELIPE C. G.; BATISTA, THIAGO M.; CAVALCANTE-SILVA, VANESSA; D'ALMEIDA, VANIA; CASTILHO, BEATRIZ A.; CARNEIRO, EVERARDO M.; ANTEBI, ADAM; FESTUCCIA, WILLIAM T.; MORI, MARCELO A. Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects. MOLECULAR METABOLISM, v. 29, p. 124-135, NOV 2019. Web of Science Citations: 0.

OLIVEIRA, TIAGO E.; CASTRO, ERIQUE; BELCHIOR, THIAGO; ANDRADE, MAYNARA L.; CHAVES-FILHO, ADRIANO B.; PEIXOTO, ALBERT S.; MORENO, MAYARA F.; ORTIZ-SILVA, MILENE; MOREIRA, RAFAEL J.; INAGUE, ALEX; YOSHINAGA, MARCOS Y.; MIYAMOTO, SAYURI; MOUSTAID-MOUSSA, NAIMA; FESTUCCIA, WILLIAM T. Fish Oil Protects Wild Type and Uncoupling Protein 1-Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure. MOLECULAR NUTRITION & FOOD RESEARCH, v. 63, n. 7 APR 2019. Web of Science Citations: 4.

PAHLAVANI, MANDANA; RAMALINGAM, LATHA; MILLER, EMILY K.; SCOGGIN, SHANE; MENIKDIWELA, KALHARA R.; KALUPAHANA, NISHAN S.; FESTUCCIA, WILLIAM T.; MOUSTAID-MOUSSA, NAIMA. Eicosapentaenoic Acid Reduces Adiposity, Glucose Intolerance and Increases Oxygen Consumption Independently of Uncoupling Protein 1. MOLECULAR NUTRITION & FOOD RESEARCH, v. 63, n. 7 APR 2019. Web of Science Citations: 3.

BLANCHARD, PIERRE-GILLES; MOREIRA, RAFAEL J.; CASTRO, ERIQUE; CARON, ALEXANDRE; COTE, MARIE; ANDRADE, MAYNARA L.; OLIVEIRA, TIAGO E.; ORTIZ-SILVA, MILENE; PEIXOTO, ALBERT S.; DIAS, FRANCE ANNE; GELINAS, YVES; GUERRA-SA, RENATA; DESHAIES, YVES; FESTUCCIA, WILLIAM T. PPAR gamma is a major regulator of branched-chain amino acid blood levels and catabolism in white and brown adipose tissues. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 89, p. 27-38, DEC 2018. Web of Science Citations: 5.

PASCHOAL, VIVIAN A.; BELCHIOR, THIAGO; AMANO, MARIANE T.; BURGOS-SILVA, MARINA; PEIXOTO, ALBERT S.; MAGDALON, JULIANA; VIEIRA, THAYNA S.; ANDRADE, MAYNARA L.; MORENO, MAYARA F.; CHIMIN, PATRICIA; CAMARA, NIELS O.; FESTUCCIA, WILLIAM T. Constitutive Activation of the Nutrient Sensor mTORC1 in Myeloid Cells Induced by Tsc1 Deletion Protects Mice from Diet-Induced Obesity. MOLECULAR NUTRITION & FOOD RESEARCH, v. 62, n. 17 SEP 2018. Web of Science Citations: 2.

YAMASHITA, ALEX S.; BELCHIOR, THIAGO; LIRA, FABIO S.; BISHOP, NICOLETTE C.; WESSNER, BARBARA; ROSA, JOSE C.; FESTUCCIA, WILLIAM T. Regulation of Metabolic Disease-Associated Inflammation by Nutrient Sensors. Mediators of Inflammation, 2018. Web of Science Citations: 7.

CHIMIN, PATRICIA; ANDRADE, MAYNARA L.; BELCHIOR, THIAGO; PASCHOAL, VIVIAN A.; MAGDALON, JULIANA; YAMASHITA, ALEX S.; CASTRO, ERIQUE; CASTOLDI, ANGELA; CHAVES-FILHO, ADRIANO B.; YOSHINAGA, MARCOS Y.; MIYAMOTO, SAYURI; CAMARA, NIELS O.; FESTUCCIA, WILLIAM T. Adipocyte mTORC1 deficiency promotes adipose tissue inflammation and NLRP3 inflammasome activation via oxidative stress and de novo ceramide synthesis. Journal of Lipid Research, v. 58, n. 9, p. 1797-1807, SEP 2017. Web of Science Citations: 11.

CASTRO, ERIQUE; SILVA, TIAGO E. OLIVEIRA; FESTUCCIA, WILLIAM T. Critical review of beige adipocyte thermogenic activation and contribution to whole-body energy expenditure. HORMONE MOLECULAR BIOLOGY AND CLINICAL INVESTIGATION, v. 31, n. 2, SI AUG 2017. Web of Science Citations: 7.

PASCHOAL, VIVIAN A.; AMANO, MARIANE T.; BELCHIOR, THIAGO; MAGDALON, JULIANA; CHIMIN, PATRICIA; ANDRADE, MAYNARA L.; ORTIZ-SILVA, MILENE; CASTRO, ERIQUE; YAMASHITA, ALEX S.; ROSA NETO, JOSE CESAR; CAMARA, NIELS O.; FESTUCCIA, WILLIAM T. mTORC1 inhibition with rapamycin exacerbates adipose tissue inflammation in obese mice and dissociates macrophage phenotype from function. Immunobiology, v. 222, n. 2, p. 261-271, FEB 2017. Web of Science Citations: 18.

LABBE, SEBASTIEN M.; MOUCHIROUD, MATHILDE; CARON, ALEXANDRE; SECCO, BLANDINE; FREINKMAN, ELIZAVETA; LAMOUREUX, GUILLAUME; GELINAS, YVES; LECOMTE, ROGER; BOSSE, YOHAN; CHIMIN, PATRICIA; FESTUCCIA, WILLIAM T.; RICHARD, DENIS; LAPLANTE, MATHIEU. mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold. SCIENTIFIC REPORTS, v. 6, NOV 23 2016. Web of Science Citations: 11.

CHAAR, LAIALI J.; COELHO, ALINE; SILVA, NATALIA M.; FESTUCCIA, WILLIAM L.; ANTUNES, VAGNER R. High-fat diet-induced hypertension and autonomic imbalance are associated with an upregulation of CART in the dorsomedial hypothalamus of mice. PHYSIOLOGICAL REPORTS, v. 4, n. 11 JUN 2016. Web of Science Citations: 11.

MAGDALON, JULIANA; CHIMIN, PATRICIA; BELCHIOR, THIAGO; NEVES, RODRIGO X.; VIEIRA-LARA, MARCEL A.; ANDRADE, MAYNARA L.; FARIAS, TALITA S.; BOLSONI-LOPES, ANDRESSA; PASCHOAL, VIVIAN A.; YAMASHITA, ALEX S.; KOWALTOWSKI, ALICIA J.; FESTUCCIA, WILLIAM T. Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1861, n. 5, p. 430-438, MAY 2016. Web of Science Citations: 14.