Mechanism of action of bromocriptine and prolactin antagonists in the treatment of Diabetes and Obesity

• Grant number: 13/21722-4
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): March 01, 2014
• Effective date (End): October 31, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Jose Donato Junior
• Grantee: Isadora Clivatti Furigo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by dysfunctions in the metabolism of glucose, amino acids and free fat acids. Although most therapies to treat diabetes have peripheral effects, a growing number of studies show that the brain plays a critical role in the control of glucose homeostasis. The quick release bromocriptine mesylate (Cycloset®) was the first FDA approved drug to treat T2DM that has its primary actions on central nervous system. Several studies have shown beneficial effects of bromocriptine, a dopaminergic agonist, to reduce hyperglycemia and hyperlipidemia in obese animals. Therefore, a possible mechanism of action of this drug can be by blocking prolactin secretion. High serum prolactin levels in patients with prolactinomas or during the usage of antipsychotics cause abnormalities in the metabolism of carbohydrates and lipids, resembling the features of the metabolic syndrome. At the present study, we hypothesized that at least part of the beneficial effects of bromocriptine is mediated by inhibiting prolactin secretion. In this context, we believe that administration of prolactin antagonist (anti-PrlR) may be a promising approach for the treatment of diabetes and obesity. Based on this hypothesis, we will carry out experiments in four groups of genetically obese and diabetic mice (ob/ob): 1) control group, 2) group treated with prolactin, 3) group treated with bromocriptine, and 4) group treated with bromocriptine and prolactin. Another group of animals will receive Anti-PrlR and their results will be compared with those observed in control animals and in a group that will be treated with bromocriptine. We will assess whether Anti-PrlR improve the diabetes and obesity phenotype of ob/ob mice. Thus, if we confirm our hypothesis, the anti-PrlR may become a new class of drugs for the treatment of metabolic diseases such as obesity and T2DM.

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)

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)

SILVEIRA, MARINA AUGUSTO; FURIGO, ISADORA C.; ZAMPIERI, THAIS T.; BOHLEN, TABATA M.; DE PAULA, DANIELLA G.; FRANCI, CELSO RODRIGUES; DONATO, JR., JOSE; FRAZAO, RENATA. STAT5 signaling in kisspeptin cells regulates the timing of puberty. Molecular and Cellular Endocrinology, v. 448, n. C, p. 55-65, JUN 15 2017. (15/20198-5, 12/12202-4, 15/10992-6, 13/07908-8, 13/21722-4, 15/14588-5)

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)

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)

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)

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)

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)

BUONFIGLIO, DANIELLA C.; RAMOS-LOBO, ANGELA M.; SILVEIRA, MARINA A.; FURIGO, ISADORA C.; HENNIGHAUSEN, LOTHAR; FRAZAO, RENATA; DONATO, JR., JOSE. Neuronal STAT5 signaling is required for maintaining lactation but not for postpartum maternal behaviors in mice. Hormones and Behavior, v. 71, p. 60-68, MAY 2015. (12/12202-4, 13/21722-4, 14/11752-6)

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)

FURIGO, ISADORA C.; SUZUKI, MIRIAM F.; OLIVEIRA, JOAO E.; RAMOS-LOBO, ANGELA M.; TEIXEIRA, PRYSCILA D. S.; PEDROSO, JOAO A.; DE ALENCAR, AMANDA; ZAMPIERI, THAIS T.; BUONFIGLIO, DANIELLA C.; QUARESMA, PAULA G. F.; et al. Suppression of Prolactin Secretion Partially Explains the Antidiabetic Effect of Bromocriptine in ob/ob Mice. Endocrinology, v. 160, n. 1, p. 193-204, JAN 2019. (13/25032-2, 14/11752-6, 15/10992-6, 12/15517-6, 13/21722-4, 17/25281-3, 12/24345-4)

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)

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)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FURIGO, Isadora Clivatti. The study of the mechanisms of action of bromocriptine and prolactin antagonists to treat Type 2 Diabetes Mellitus and Obesity.. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.