Molecular regulation of the brain interleukin-1 β system in obese ( fa/ fa) and lean ( Fa/ Fa) Zucker rats

Abstract

Interleukin-1 β (IL-1 β) induces anorexia when administered acutely or chronically into the cerebrospinal fluid (CSF) at doses that yield estimated pathophysiological concentrations. Enhanced sensitivity to IL-1 β-induced anorexia has been observed in animal models of obesity, including the obese ( fa/ fa) Zucker rat. Obesity is also associated with increased tumor necrosis factor- α mRNA expression in adipose tissue. This suggests that obese individuals may have dissimilar sensitivity to cytokine action and differential regulation of cytokine production. In this study, we investigated the regulation of the IL-1 β system (IL-1 β, IL-1 receptor type I (IL-1RI) and IL-1 receptor antagonist (IL-1Ra)) in the central nervous system (CNS) in response to the chronic intracerebroventricular (i.c.v.) microinfusion (via osmotic minipumps) of 8 ng IL-1 β/24 h/72 h–a dose that yields estimated pathophysiological concentrations in the CSF. IL-1 β, IL-1RI and IL-1Ra mRNAs were determined by sensitive RNase protection assays in brain target regions for IL-1 β (cerebellum, parieto-frontal cortex, hippocampus, hypothalamus and midbrain). The results show that chronic i.c.v. microinfusion of IL-1 β increased the IL-1 β mRNA, IL-1RI mRNA and IL-1Ra mRNA levels in the hypothalamus>cerebellum in both obese ( fa/ fa) and lean ( Fa/ Fa) Zucker rats. IL-1 β mRNA levels also increased in the cortex, hippocampus and midbrain of obese ( fa/ fa) rats. The profiles of IL-1 β mRNA, IL-1RI mRNA and IL-1Ra mRNA in the same hypothalamic samples obtained from obese or lean rats were highly intercorrelated. However, no significant differences in the level of IL-1 β system mRNAs induction were observed in any brain region between obese and lean rats. On the other hand, levels of rat glyceraldehyde 3-phosphate dehydrogenase mRNA were fairly constant, and heat-inactivated IL-1 β (8 ng/24 h/72 h) had no effect on IL-1 β, IL-1RI and IL-1Ra mRNAs levels in any brain region. The data suggest: (1) the operation of an IL-1 β feedback system (IL-1 β/IL-1Ra/IL-1RI) in brain regions; (2) that enhanced sensitivity of obese rats to IL-1 β-induced anorexia is not dependent on changes in the brain IL-1 β system at the mRNA level; and (3) that the present novel approach can be used to investigate the molecular basis of cytokine action in the CNS.