Inflammation and immune response in obesity

• Grant number: 09/50809-5
• Support Opportunities: Research Projects - Thematic Grants
• Start date: January 01, 2010
• End date: December 31, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Licio Augusto Velloso
• Grantee: Licio Augusto Velloso
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas
• Principal investigators: Alexandre Leite Rodrigues de Oliveira ; José Barreto Campello Carvalheira ; Marcio Alberto Torsoni ; Silvana Auxiliadora Bordin da Silva
• Associated research grant(s): 13/08975-0 - Program for the visiting professor Franco Battista Ennio Folli, AV.EXT
• Associated scholarship(s): 12/17769-2 - Analysis of the Nocturnin gene polymorphisms in the Brazilian population, BP.IC; 12/03369-2 - Evaluation of the involvement of ghrelin in the induction of thymic atrophy observed in diabetic mice, BP.IC; 11/01568-5 - Effect of dexamethasone on the expression of miRNA in the endocrine pancreas in pregnant rats, BP.DR; + associated scholarships 11/08935-3 - The role of Toll-like receptor 4 in metabolic pathways of mice C3H/HeJ and C3H/HePas with diet-induced obesity, BP.DR; 10/19558-3 - Studies in leptin effects in thymus atrophy and immune responses during experimental diabetes, BP.DR; 10/13210-5 - Evaluation of the involvement of A20 deubiquitinase in the inflamation control in obesy adipose tissue, BP.MS; 10/05370-2 - Role of glial reactivity and expression of MHC class I in the maintenance of neuronal circuits in vitro, BP.PD; 10/00729-2 - The use of a fibrin sealant combined with bonemarrow mononuclear stem cells to repair motor roots after avulsion in the interface of CNS/PNS, BP.DR - associated scholarships

Abstract

Obesity results from the progressive 1055 of the homeostatic control of food intake and energy expenditure. Genetic and environmental factors contribute for the complex pathogenesis of this disease. However, in spite of the considerable advance obtained in the understanding of the mechanisms involved in the control of hunger and thermogenesis, this has provided no major breakthrough in the profilaxix and therapeutics of obesity. Thus, the incidence and prevalence of the disease are still rising. In a recent series of studies we and others observed that fatty acids present in the typical western diet are capable of inducing an inflammatory response in the hypothalamus. This inflammation is triggered by the activation of TLR4 and is, at least in part mediated by the activation of endoplasmic reticulum stress (ER-stress). Both the activation of TLR4 and the induction of ER-stress induce the transcription of genes encoding inflammatory cytokines, which enhance and perpetuate the local inflammatory response. With time, the hypothalamic neurons involved in the production of neurotransmitters that control energy homeostasis become dysfunctional favoring the loss of the homeostatic control of body adiposity. One of the characteristics of this phenomenon is the installation of resistance to the main adipostatic hormones, lepin and insulin. The magnitude of this hypothalamic dysfunction depends on a combination of environmental and genetic factors and only the identification of the factors and the mechanisms involved in the induction of a defective hypothalamic activity will allow the development of more specific and effective prophylactic and therapeutic methods. In the present project we plan to investigate several mechanisms potentially involved in the genesis of obesity, focusing on the inflammatory pathways. The first subproject will evaluate the mechanisms involved in the connection between TLR4 signaling and ER-stress induction the second subproject will determine how TLR4 participates in neuronal plasticity; the third subproject will evaluate the hypothesis that TLR4 activation modulates the signaling pathways of AMPK and mTOR which play central roles in the connection of nutrient- and hormone-dependent signaling pathways in the hypothalamus: the fourth subproject will search the genetic determinants of inflammatory response in obesity, using mouse strains with different predisposition for obesity, the fifth subproject will evaluate the roles played by microglia in the hypothalamic inflammation in obesity, the sixth subproject will use a model of neuronal damage for providing methodological advance for the understanding of inflammation in the central nervous system; the seventh subproject will study the mechanisms involved in TNF-alpha induced thermo genesis, by exploring the actions of this cytokine in the hypothalamus, the eighth subproject will develop a methodological tool for controlling the expression of neurotransmitters in the hypothalamus, and the nineth subproject will evaluate the roles of leptin in the control of the immune response. (AU)

Scientific publications

(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)

SEWAYBRICKER, LETICIA E.; SCHUR, ELLEN A.; MELHORN, SUSAN J.; CAMPOS, BRUNNO M.; ASKREN, MARY K.; NOGUEIRA, GUILHERME A. S.; ZAMBON, MARIANA P.; ANTONIO, MARIA ANGELA R. G. M.; CENDES, FERNANDO; VELLOSO, LICIO A.; et al. Initial evidence for hypothalamic gliosis in children with obesity by quantitative T2 MRI and implications for blood oxygen-level dependent response to glucose ingestion. PEDIATRIC OBESITY, v. 14, n. 2, SI, FEB 2019. (09/50809-5)

MELO, ARINE M.; BENATTI, RAFAELA O.; IGNACIO-SOUZA, LETICIA M.; OKINO, CAROLINE; TORSONI, ADRIANA S.; MILANSKI, MARCIANE; VELLOSO, LICIO A.; TORSONI, MARCIO ALBERTO. Hypothalamic endoplasmic reticulum stress and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy and lactation. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 63, n. 5, p. 682-692, MAY 2014. (11/17656-0, 09/50809-5)

SEWAYBRICKER, LETICIA E.; SCHUR, ELLEN A.; MELHORN, SUSAN J.; CAMPOS, BRUNNO M.; ASKREN, MARY K.; NOGUEIRA, GUILHERME A. S.; ZAMBON, MARIANA P.; ANTONIO, MARIA ANGELA R. G. M.; CENDES, FERNANDO; VELLOSO, LICIO A.; et al. Initial evidence for hypothalamic gliosis in children with obesity by quantitative T2 MRI and implications for blood oxygen-level dependent response to glucose ingestion. PEDIATRIC OBESITY, v. 14, n. 2, p. 10-pg., 2019-02-01. (09/50809-5)