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Molecular basis of leptin resistance


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)

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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)
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, . (10/18086-0)
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, . (10/18086-0, 12/12202-4, 12/15517-6, 13/07908-8)
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, . (14/11752-6, 12/12202-4, 10/18086-0, 15/10992-6, 13/07908-8, 13/21722-4)
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, . (12/15517-6, 10/18086-0)
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, . (12/15517-6, 10/18086-0)
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, . (12/15517-6, 10/18086-0)
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, . (15/10992-6, 10/18086-0, 12/02388-3)
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, . (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, . (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, . (13/25032-2, 10/18086-0, 14/11752-6, 12/12202-4, 15/10992-6, 13/07908-8, 12/15517-6, 13/21722-4)
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, . (12/15517-6, 10/18086-0, 14/06372-0)
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., . (12/15517-6, 11/12893-4, 10/18086-0, 13/04703-6, 13/25032-2)
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, . (12/02388-3, 13/21722-4, 10/18086-0)
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, . (13/21722-4, 10/18086-0, 12/02388-3)
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, . (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, . (11/11792-0, 10/18086-0)
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, . (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, . (12/15517-6, 12/02388-3, 10/18086-0, 13/16374-7)
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, . (10/18086-0, 12/23535-4, 13/21722-4, 14/11752-6, 14/50140-6, 15/10992-6)
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, . (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, . (10/18086-0, 13/16374-7, 14/11752-6, 15/10992-6, 12/15517-6, 10/07699-1)
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, . (13/00801-3, 10/18086-0, 12/12202-4, 13/16374-7, 12/02270-2, 12/15517-6, 13/21722-4)
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, . (13/25032-2, 12/15517-6, 10/18086-0)

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