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

• Grant number: 15/19530-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: November 01, 2015
• End date: 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
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Alex Shimura Yamashita ; Fernanda Janku Cabral ; Patricia Chimin
• Associated research 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): 20/10215-8 - mTORC1 is a major regulator of adipose tissue BCAA metabolism and lipolysis in visceral, subcutaneous and brown adipose tissue of mice through a mechanism that involves PPARgamma activation, BP.MS; 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; + associated scholarships 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; 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 involvement 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

(32)

(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)

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. (16/23169-9, 16/07062-0, 15/19530-5)

FESTUCCIA, WILLIAM T.. Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases. MOLECULAR NUTRITION & FOOD RESEARCH, v. 65, n. 1, SI, MAR 2020. (15/19530-5)

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; et al. 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. (15/19530-5, 12/02270-2, 11/10783-7, 09/15354-7)

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.; et al. 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. (10/51906-1, 11/03972-8, 12/25317-4, 15/19530-5, 13/14203-0, 09/15354-7)

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. (13/06206-0, 11/13563-8, 09/15354-7, 10/19018-9, 15/19530-5)

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; et al. 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. (15/19530-5, 12/02270-2, 11/10783-7, 09/15354-7)

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.; et al. Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects. MOLECULAR METABOLISM, v. 29, p. 124-135, NOV 2019. (15/03292-8, 17/22057-5, 10/52557-0, 16/02207-0, 17/01184-9, 15/01316-7, 15/19530-5, 12/07259-7, 17/07975-8)

SOUZA, CAMILA O.; TEIXEIRA, ALEXANDRE A. S.; BIONDO, LUANA AMORIM; SILVEIRA, LOREANA SANCHES; DE SOUZA BREDA, CRISTIANE N.; BRAGA, TARCIO T.; CAMARA, NIELS O. S.; BELCHIOR, THIAGO; FESTUCCIA, WILLIAM T.; DINIZ, TIEGO A.; et al. Palmitoleic acid reduces high fat diet-induced liver inflammation by promoting PPAR-gamma-independent M2a polarization of myeloid cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1865, n. 10, OCT 2020. (13/04765-1, 19/06172-4, 19/24112-9, 15/19530-5, 16/01409-8)

CASTRO, ERIQUE; VIEIRA, THAYNA S.; OLIVEIRA, TIAGO E.; ORTIZ-SILVA, MILENE; ANDRADE, MAYNARA L.; TOMAZELLI, CAROLINE A.; PEIXOTO, ALBERT S.; SOBRINHO, CLEYTON R.; MORENO, MAYARA F.; GILIO, GUSTAVO R.; et al. Adipocyte-specific mTORC2 deficiency impairs BAT and iWAT thermogenic capacity without affecting glucose uptake and energy expenditure in cold-acclimated mice. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 321, n. 5, p. E592-E605, NOV 2021. (16/23169-9, 19/25943-1, 17/23040-9, 15/13508-8, 17/17582-3, 18/03418-0, 17/17403-1, 17/12260-8, 19/01763-4, 19/17660-0, 15/19530-5, 20/09399-7, 19/04271-5, 12/25317-4)

CHAVES-FILHO, ADRIANO B.; PEIXOTO, ALBERT S.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; PERANDINI, LUIZ A.; MOREIRA, RAFAEL J.; DA SILVA, RAILMARA P.; DA SILVA, BEATRIZ P.; MORETTI, EDUARDO H.; STEINER, ALEXANDRE A.; et al. Futile cycle of beta-oxidation and de novo lipogenesis are associated with essential fatty acids depletion in lipoatrophy. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1868, n. 3, p. 14-pg., 2022-12-20. (16/23169-9, 17/23040-9, 20/04159-8, 18/03418-0, 20/09399-7, 20/12969-0, 19/26473-9, 13/07937-8, 15/19530-5, 18/11156-5, 19/17660-0)

ZU, YUJIAO; PAHLAVANI, MANDANA; RAMALINGAM, LATHA; JAYARATHNE, SHASIKA; ANDRADE, JOSE; SCOGGIN, SHANE; FESTUCCIA, WILLIAM T.; KALUPAHANA, NISHAN S.; MOUSTAID-MOUSSA, NAIMA. Temperature-Dependent Effects of Eicosapentaenoic Acid (EPA) on Browning of Subcutaneous Adipose Tissue in UCP1 Knockout Male Mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 10, p. 18-pg., 2023-05-13. (15/19530-5)

FESTUCCIA, WILLIAM; MOUSTAID-MOUSSA, NAIMA; MOREIRA, RAFAEL. Lipoatrophy-associated insulin resistance and hepatic steatosis are attenuated by intake of diet rich in omega 3 fatty acids. FASEB JOURNAL, v. 34, p. 1-pg., 2020-04-01. (15/19530-5)

FONSECA, MONIQUE T.; MORETTI, EDUARDO H.; MARQUES, LUCAS M. M.; MACHADO, BIANCA F.; BRITO, CAMILA F.; GUEDES, JADY T.; KOMEGAE, EVILIN N.; VIEIRA, THAYNA S.; FESTUCCIA, WILLIAM T.; LOPES, NORBERTO P.; et al. A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation. SCIENCE SIGNALING, v. 14, n. 679, p. 12-pg., 2021-04-20. (18/00849-0, 16/23540-9, 17/13350-0, 16/04921-1, 18/03418-0, 15/19530-5, 14/03719-9, 20/09399-7, 17/17403-1, 14/50265-3)

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, p. 9-pg., 2017-08-01. (15/19530-5, 16/23169-9, 16/07062-0)

FONSECA, MONIQUE T.; MORETTI, EDUARDO H.; MARQUES, LUCAS M. M.; MACHADO, BIANCA F.; BRITO, CAMILA F.; GUEDES, JADY T.; KOMEGAE, EVILIN N.; VIEIRA, THAYNA S.; FESTUCCIA, WILLIAM T.; LOPES, NORBERTO P.; et al. A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation. Science Signaling, v. 14, n. 679, APR 20 2021. (16/23540-9, 18/03418-0, 17/17403-1, 17/13350-0, 15/19530-5, 16/04921-1, 20/09399-7, 14/50265-3, 14/03719-9, 18/00849-0)

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. (15/22983-1, 15/19530-5, 13/15825-5)

ANDRADE, MAYNARA L.; GILIO, GUSTAVO R.; PERANDINI, LUIZ A.; PEIXOTO, ALBERT S.; MORENO, MAYARA F.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; VIEIRA, THAYNA S.; ORTIZ-SILVA, MILENE; THOMAZELLI, CAROLINE A.; et al. PAR gamma-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activit. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1866, n. 8, AUG 2021. (15/19530-5, 17/17582-3, 13/07937-8, 19/01763-4, 17/12260-8, 15/22983-1, 16/23169-9, 19/04271-5, 15/13508-8, 18/11156-5, 19/17660-0, 17/23040-9, 17/17403-1)

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; et al. 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. (13/07467-1, 16/04000-3, 17/17943-6, 15/19530-5, 14/06863-3, 18/15549-1, 13/07937-8)

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; et al. 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. (15/19530-5, 17/17582-3, 16/07062-0, 17/12260-8, 15/22983-1, 16/23169-9, 15/13508-8, 18/11156-5, 17/23040-9)

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. (15/19530-5)

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.; et al. 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. (12/25317-4, 15/19530-5, 12/02270-2, 15/13508-8, 09/15354-7)

LABBE, SEBASTIEN M.; MOUCHIROUD, MATHILDE; CARON, ALEXANDRE; SECCO, BLANDINE; FREINKMAN, ELIZAVETA; LAMOUREUX, GUILLAUME; GELINAS, YVES; LECOMTE, ROGER; BOSSE, YOHAN; CHIMIN, PATRICIA; et al. mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold. SCIENTIFIC REPORTS, v. 6, NOV 23 2016. (15/19530-5)

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; et al. 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. (15/19530-5, 16/07062-0, 17/12260-8, 16/23169-9, 15/13508-8)

DONADO-PESTANA, CARLOS M.; PESSOA, ERIKA V. M.; RODRIGUES, LARISSA; ROSSI, RAFAELA; MOURA, MARCIO H. C.; DOS SANTOS-DONADO, PRISCILA R.; CASTRO, ERIQUE; FESTUCCIA, WILLIAM T.; GENOVESE, MARIA INES. Polyphenols of cambuci (Campomanesia phaea (O. Berg.)) fruit ameliorate insulin resistance and hepatic steatosis in obese mice. Food Chemistry, v. 340, MAR 15 2021. (15/19530-5, 18/24477-4)

ALBRACHT-SCHULTE, KEMBRA; WILSON, SAVANNA; JOHNSON, PAIGE; PAHLAVANI, MANDANA; RAMALINGAM, LATHA; GOONAPIENUWALA, BIMBA; KALUPAHANA, NISHAN S.; FESTUCCIA, WILLIAM T.; SCOGGIN, SHANE; KAHATHUDUWA, CHANAKA N.; et al. Sex-Dependent Effects of Eicosapentaenoic Acid on Hepatic Steatosis in UCP1 Knockout Mice. BIOMEDICINES, v. 9, n. 11, p. 18-pg., 2021-11-01. (15/19530-5)

CHAVES-FILHO, ADRIANO B.; DINIZ, LARISSA S.; SANTOS, ROSANGELA S.; LIMA, RODRIGO S.; ORELIANA, HECTOR; PINTO, ISABELLA F. D.; DANTAS, LUCAS S.; INAGUE, ALEX; FARIA, RODRIGO L.; MEDEIROS, MARISA H. G.; et al. Plasma oxylipin profiling by high resolution mass spectrometry reveal signatures of inflammation and hypermetabolism in amyotrophic lateral sclerosis. Free Radical Biology and Medicine, v. 208, p. 14-pg., 2023-08-25. (13/07937-8, 18/18633-3, 19/01763-4, 20/04159-8, 15/19530-5)

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)

ANDRADE, MAYNARA L.; GILIO, GUSTAVO R.; PERANDINI, LUIZ A.; PEIXOTO, ALBERT S.; MORENO, MAYARA F.; CASTRO, ERIQUE; OLIVEIRA, TIAGO E.; VIEIRA, THAYNA S.; ORTIZ-SILVA, MILENE; THOMAZELLI, CAROLINE A.; et al. PPAR gamma-induced upregulation of subcutaneous fat adiponectin secretion, glyceroneogenesis and BCAA oxidation requires mTORC1 activity. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, v. 1866, n. 8, p. 11-pg., 2021-05-19. (19/17660-0, 16/23169-9, 17/23040-9, 15/22983-1, 17/17403-1, 19/04271-5, 13/07937-8, 17/17582-3, 15/19530-5, 17/12260-8, 18/11156-5, 15/13508-8, 19/01763-4)

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, v. 2018, p. 18-pg., 2018-01-01. (15/22983-1, 13/15825-5, 15/19530-5)

FESTUCCIA, WILLIAM T.. Turning up the heat against metabolic syndrome and non-alcoholic fatty liver disease. Clinical Science, v. 131, n. 4, p. 2-pg., 2017-02-01. (15/19530-5)

FESTUCCIA, WILLIAM T.. Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases. MOLECULAR NUTRITION & FOOD RESEARCH, v. 65, n. 1, p. 9-pg., 2020-03-08. (15/19530-5)

PEIXOTO, ALBERT S.; MORENO, MAYARA F.; CASTRO, ERIQUE; PERANDINI, LUIZ A.; BELCHIOR, THIAGO; OLIVEIRA, TIAGO E.; VIEIRA, THAYNA S.; GILIO, GUSTAVO R.; TOMAZELLI, CAROLINE A.; LEONARDI, BIANCA F.; et al. Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning. JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY, v. N/A, p. 13-pg., 2023-07-05. (17/12260-8, 21/14419-0, 19/17660-0, 20/10215-8, 15/19530-5, 20/04159-8, 19/04271-5, 18/03418-0, 22/02123-1, 17/17582-3, 17/23040-9, 19/01763-4, 15/22983-1, 20/09399-7)