Leptin resistance in microglia: the role of saturated fats and chaperones

• Grant number: 12/22198-4
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: March 01, 2013
• End date: February 28, 2014
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Licio Augusto Velloso
• Grantee: Andressa Coope dos Santos
• Supervisor: Martin G. Myers
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Michigan, United States

Abstract

Hypothalamic inflammation is a common feature of experimental obesity. The expression of inflammatory cytokines and activation of intracellular inflammatory signaling is involved in the induction of leptin and insulin resistance in the hypothalamus resulting in abnormal control of feeding and energy expenditure. Microglia, the macrophages of the central nervous system, can be activated by a number of pro-inflammatory factors, cytokines or metabolic hormones including leptin, that stimulate their production of inflammatory genes, which in turn, could exacerbate the inflammatory process. Microglial cells express high levels both isoforms of leptin receptors, Ob-Ra and Ob-Rb. To modulate and terminate the progression of inflammation, microglia express anti-inflammatory endogenous molecules, however the chronic insult induced by dietary signal in obesity leads to a chronic production of pro-inflammatory cytokines, suggesting impairment in this process. Because obesity itself is considered to be a state of chronic inflammation, we suspect that increased saturated fatty acids in the diet can trigger TLR4 activation in microglia cells, inducing inflammatory gene transcription and increasing cytokine release. This chronic inflammatory state could also trigger leptin resistance in microglia, disrupting the production of anti-inflammatory cytokines IL6 and IL10, which could counteract the inflammatory response. To test this hypothesis, we will chronically expose the murine microglial cell line, BV-2, to long chain saturated fatty acid and evaluate leptin signaling and cytokine production. In addition, we will evaluate if the modulation of the expression of the chaperone HSP70 can impact on the action of leptin in this cell line. (AU)