Molecular basis of leptin resistance

• Grant number: 10/18086-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2012
• End date: January 31, 2016
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Jose Donato Junior
• Grantee: Jose Donato Junior
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Carol Fuzeti Elias ; Newton Sabino Canteras
• Associated research grant(s): 14/50140-6 - Clams comprehensive Lab animal monitoring system, AP.EMU
• Associated scholarship(s): 13/25032-2 - The role of SOCS3 in the control of hyperphagia, body weight regain and gluconeogenesis after a period of food restriction, BP.DR; 13/16374-7 - Crosstalk between leptin and prolactin in the brain: possible mechanism of metabolic changes during pregnancy, BP.IC; 12/15517-6 - Involvment of molecular factors in metabolic changes during pregnancy: role of SOCS3, BP.DR

Abstract

More than 40% of Brazilian adults are obese or overweight. The excessive accumulation of body fat is considered an important risk factor for developing cardiovascular disease, diabetes mellitus and cancer. Despite recent advances in understanding the physiological components that regulate energy balance, little is known about the molecular mechanisms that are involved in the predisposition to obesity. The resistance to the effects of the adipokine leptin is a condition frequently observed in various situations of increased adiposity. Furthermore, hypothalamic expression of proteins known as suppressors of cytokine signaling (SOCS) is increased in situations of leptin resistance. The leptin receptor is member of the class I cytokine receptors. Thus, increased SOCS inhibits the leptin-induced intracellular signaling. Experimental evidence has indicated that particularly SOCS3 is involved in the leptin resistance induced by diet-induced obesity. However, the possible involvement of SOCS3 in the etiology of other forms of leptin resistance has not yet been investigated. Thus, this project aims to generate and validate a genetically engineered mouse that carries inactivation of Socs3 gene exclusively in cells that express the leptin receptor. Subsequently, this animal model will be used in order to investigate the role of SOCS3 in the etiology of leptin resistance observed in three different metabolic situations: in the chronic exposure to a high-fat/caloric diet, during the aging process and in pregnancy. (AU)

Scientific publications

(24)

(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)

LIMA, LEANDRO B.; BUENO, DEBORA; LEITE, FERNANDA; SOUZA, STEFANI; GONCALVES, LUCIANO; FURIGO, ISADORA C.; DONATO, JR., JOSE; METZGER, MARTIN. Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei. JOURNAL OF COMPARATIVE NEUROLOGY, v. 525, n. 10, p. 2411-2442, JUL 1 2017. (13/21722-4, 10/18086-0, 12/02388-3)

PEDROSO, JOAO A. B.; BUONFIGLIO, DANIELLA C.; CARDINALI, LAIS I.; FURIGO, ISADORA C.; RAMOS-LOBO, ANGELA M.; TIRAPEGUI, JULIO; ELIAS, CAROL F.; DONATO, JR., JOSE. Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity. MOLECULAR METABOLISM, v. 3, n. 6, p. 608-618, SEP 2014. (10/18086-0, 13/21722-4)

BUONFIGLIO, DANIELLA C.; RAMOS-LOBO, ANGELA M.; FREITAS, VANESSA M.; ZAMPIERI, THAIS T.; NAGAISHI, VANESSA S.; MAGALHAES, MAGNA; CIPOLLA-NETO, JOSE; CELLA, NATHALIE; DONATO, JR., JOSE. Obesity impairs lactation performance in mice by inducing prolactin resistance. SCIENTIFIC REPORTS, v. 6, MAR 1 2016. (10/18086-0, 13/16374-7, 14/11752-6, 15/10992-6, 12/15517-6, 10/07699-1)

PEDROSO, JOAO A. B.; ZAMPIERI, THAIS T.; DONATO, JR., JOSE. Reviewing the Effects of l-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis. NUTRIENTS, v. 7, n. 5, p. 3914-3937, MAY 2015. (13/25032-2, 12/15517-6, 10/18086-0)

DA SILVA, REGINA P.; ZAMPIERI, THAIS T.; PEDROSO, JOAO A. B.; NAGAISHI, VANESSA S.; RAMOS-LOBO, ANGELA M.; FURIGO, ISADORA C.; CAMARA, NIELS O.; FRAZAO, RENATA; DONATO, JR., JOSE. Leptin Resistance Is Not the Primary Cause of Weight Gain Associated With Reduced Sex Hormone Levels in Female Mice. Endocrinology, v. 155, n. 11, p. 4226-4236, NOV 2014. (13/00801-3, 10/18086-0, 12/12202-4, 13/16374-7, 12/02270-2, 12/15517-6, 13/21722-4)

SEGO, CHEMUTAI; GONCALVES, LUCIANO; LIMA, LEANDRO; FURIGO, ISADORA C.; DONATO, JR., JOSE; METZGER, MARTIN. Lateral Habenula and the Rostromedial Tegmental Nucleus Innervate Neurochemically Distinct Subdivisions of the Dorsal Raphe Nucleus in the Rat. JOURNAL OF COMPARATIVE NEUROLOGY, v. 522, n. 7, p. 1454-1484, MAY 1 2014. (11/03292-7, 10/18086-0, 12/02388-3)

NAGAISHI, V. S.; CARDINALI, L. I.; ZAMPIERI, T. T.; FURIGO, I. C.; METZGER, M.; DONATO, JR., J.. POSSIBLE CROSSTALK BETWEEN LEPTIN AND PROLACTIN DURING PREGNANCY. Neuroscience, v. 259, p. 71-83, FEB 14 2014. (12/15517-6, 12/02388-3, 10/18086-0, 13/16374-7)

FURIGO, ISADORA C.; KIM, KI WOO; NAGAISHI, VANESSA S.; RAMOS-LOBO, ANGELA M.; DE ALENCAR, AMANDA; PEDROSO, JOAO A. B.; METZGER, MARTIN; DONATO, JR., JOSE. Prolactin-sensitive neurons express estrogen receptor-alpha and depend on sex hormones for normal responsiveness to prolactin. Brain Research, v. 1566, p. 47-59, MAY 30 2014. (13/21722-4, 12/02388-3, 10/18086-0, 13/16374-7)

PEDROSO, JOAO ALFREDO B.; NISHIMURA, LUCIANA SIGUETA; DE MATOS-NETO, EMIDIO MARQUES; DONATO, JR., JOSE; TIRAPEGUI, JULIO. Leucine improves protein nutritional status and regulates hepatic lipid metabolism in calorie-restricted rats. Cell Biochemistry and Function, v. 32, n. 4, p. 326-332, JUN 2014. (11/11792-0, 10/18086-0)

PEDROSO, JOAO A. B.; DE MENDONCA, PEDRO O. R.; FORTES, MARCO A. S.; TOMAZ, IGOR; PECORALI, VITOR L.; AURICINO, THAIS B.; COSTA, ISMAEL C.; LIMA, LEANDRO B.; FURIGO, ISADORA C.; BUENO, DEBORA N.; et al. SOCS3 expression in SF1 cells regulates adrenal differentiation and exercise performance. Journal of Endocrinology, v. 235, n. 3, p. 207-222, DEC 2017. (10/18086-0, 12/23535-4, 13/21722-4, 14/11752-6, 14/50140-6, 15/10992-6)

DA SILVA, EDUARDO SIMAO; FLORES, RAFAEL APPEL; RIBAS, ANDERSON SAVARIS; TASCHETTO, ANA PAULA; FARIA, MOACIR SERRALVO; LIMA, LEANDRO BUENO; METZGER, MARTIN; DONATO, JR., JOSE; PASCHOALINI, MARTA APARECIDA. Injections of the of the alpha(1)-adrenoceptor antagonist prazosin into the median raphe nucleus increase food intake and Fos expression in orexin neurons of free-feeding rats. Behavioural Brain Research, v. 324, p. 87-95, MAY 1 2017. (12/02388-3, 13/21722-4, 10/18086-0)

ZAMPIERI, THAIS TESSARI; OLIVEIRA DA SILVA, TIAGO EUGENIO; ROMEU, DEBORAH DE PAULA; TORRAO, ANDREA DA SILVA; DONATO, JR., JOSE. SOCS3 expression within leptin receptor-expressing cells regulates food intake and leptin sensitivity but does not affect weight gain in pregnant mice consuming a high-fat diet. Physiology & Behavior, v. 157, p. 109-115, APR 1 2016. (12/15517-6, 10/18086-0, 14/06372-0)

RAMOS-LOBO, ANGELA M.; TEIXEIRA, PRYSCILA D. S.; FURIGO, ISADORA C.; DONATO, JR., JOSE. SOCS3 ABLATION IN SF1 CELLS CAUSES MODEST METABOLIC EFFECTS DURING PREGNANCY AND LACTATION. Neuroscience, v. 365, p. 114-124, DEC 4 2017. (10/18086-0, 15/10992-6, 14/11752-6, 13/21722-4)

PEDROSO, JOAO A. B.; DA SILVA, IVSON B.; ZAMPIERI, THAIS T.; TOTOLA, LEONARDO T.; MOREIRA, THIAGO S.; TANIGUTI, ANA P. T.; DINIZ, GABRIELA P.; BARRETO-CHAVES, MARIA LUIZA M.; DONATO, JOSE, JR.. SOCS3 Ablation in Leptin Receptor-Expressing Cells Causes Autonomic and Cardiac Dysfunctions in Middle-Aged Mice despite Improving Energy and Glucose Metabolism. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 12, p. 19-pg., 2022-06-01. (12/15517-6, 11/12893-4, 10/18086-0, 13/04703-6, 13/25032-2)

FLORES, RAFAEL APPEL; DA SILVA, EDUARDO SIMAO; RIBAS, ANDERSON SAVARIS; DAMBROS TASCHETTO, ANA PAULA; ZAMPIERI, THAIS TESSARI; DONATO, JR., JOSE; PASCHOALINI, MARTA APARECIDA. Evaluation of food intake and Fos expression in serotonergic neurons of raphe nuclei after intracerebroventricular injection of adrenaline in free-feeding rats. Brain Research, v. 1678, p. 153-163, JAN 1 2018. (12/15517-6, 10/18086-0)

FURIGO, ISADORA C.; METZGER, MARTIN; TEIXEIRA, PRYSCILA D. S.; SOARES, CARLOS R. J.; DONATO, JR., JOSE. Distribution of growth hormone-responsive cells in the mouse brain. Brain Structure & Function, v. 222, n. 1, p. 341-363, JAN 2017. (12/24345-4, 10/18086-0, 13/21722-4, 12/02388-3)

PEDROSO, JOAO A. B.; SILVEIRA, MARINA A.; LIMA, LEANDRO B.; FURIGO, ISADORA C.; ZAMPIERI, THAIS T.; RAMOS-LOBO, ANGELA M.; BUONFIGLIO, DANIELLA C.; TEIXEIRA, PRYSCILA D. S.; FRAZAO, RENATA; DONATO, JR., JOSE. Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice. Endocrinology, v. 157, n. 10, p. 3901-3914, OCT 2016. (13/25032-2, 10/18086-0, 14/11752-6, 12/12202-4, 15/10992-6, 13/07908-8, 12/15517-6, 13/21722-4)

LIMA, LEANDRO B.; METZGER, MARTIN; FURIGO, ISADORA C.; DONATO, JR., J.. Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures. Brain Research, v. 1646, p. 366-376, SEP 1 2016. (15/10992-6, 10/18086-0, 12/02388-3)

ZAMPIERI, THAIS T.; TORRES-LEAL, FRANCISCO L.; CAMPANA, AMANDA B.; LIMA, FABIO B.; DONATO, JR., JOSE. L-Leucine Supplementation Worsens the Adiposity of Already Obese Rats by Promoting a Hypothalamic Pattern of Gene Expression that Favors Fat Accumulation. NUTRIENTS, v. 6, n. 4, p. 1364-1373, APR 2014. (12/15517-6, 10/18086-0)

FURIGO, ISADORA C.; RAMOS-LOBO, ANGELA M.; FRAZAO, RENATA; DONATO, JR., J.. Brain STAT5 signaling and behavioral control. Molecular and Cellular Endocrinology, v. 438, n. C, p. 70-76, DEC 15 2016. (14/11752-6, 12/12202-4, 10/18086-0, 15/10992-6, 13/07908-8, 13/21722-4)

BOHLEN, TABATA M.; SILVEIRA, MARINA A.; ZAMPIERI, THAIS T.; FRAZAO, RENATA; DONATO, JR., JOSE. Fatness rather than leptin sensitivity determines the timing of puberty in female mice. Molecular and Cellular Endocrinology, v. 423, n. C, p. 11-21, MAR 5 2016. (10/18086-0, 12/12202-4, 12/15517-6, 13/07908-8)

ZAMPIERI, THAIS T.; PEDROSO, JOAO A. B.; FURIGO, ISADORA C.; TIRAPEGUI, JULIO; DONATO, JR., JOSE. Oral Leucine Supplementation Is Sensed by the Brain but neither Reduces Food Intake nor Induces an Anorectic Pattern of Gene Expression in the Hypothalamus. PLoS One, v. 8, n. 12, DEC 13 2013. (12/15517-6, 10/18086-0)

PEDROSA, ROGERIO G.; DONATO, JR., JOSE; PIRES, IVANIR S.; TIRAPEGUI, JULIO. Leucine supplementation increases serum insulin-like growth factor 1 concentration and liver protein/RNA ratio in rats after a period of nutritional recovery. APPLIED PHYSIOLOGY NUTRITION AND METABOLISM, v. 38, n. 6, p. 694-697, JUN 2013. (10/18086-0)

DONATO, JR., JOSE. The Central Nervous System as a Promising Target to Treat Diabetes Mellitus. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 12, n. 19, p. 2070-2081, OCT 2012. (10/18086-0)