MOLECULAR REGULATION OF THE BRAIN INTERLEUKIN-1-BETA SYSTEM IN OBESE (FA FA) AND LEAN (FA/FA) ZUCKER RATS/

Interleukin-1 beta (IL-1 beta) induces anorexia when administered acut ely or chronically into the cerebrospinal fluid (CSF) at doses that yi eld estimated pathophysiological concentrations. Enhanced sensitivity to IL-1 beta-induced anorexia has been observed in animal models of ob esity, including the obese (fa/fa) Zucker rat. Obesity is also associa ted with increased tumor necrosis factor-alpha mRNA expression in adip ose tissue. This suggests that obese individuals may have dissimilar s ensitivity to cytokine action and differential regulation of cytokine production. In this study, we investigated the regulation of the IL-1 beta system (IL-1 beta, IL-1 receptor type I (IL-1RI) and IL-1 recepto r antagonist (IL-1Ra)) in the central nervous system (CNS) in response to the chronic intracerebroventricular (i.c.v.) microinfusion (via os motic minipumps) of 8 ng IL-1 beta/24 h/72 h-a dose that yields estima ted pathophysiological concentrations in the CSF. IL-1 beta, IL-1RI an d IL-1Ra mRNAs were determined by sensitive RNase protection assays in brain target regions for IL-I beta (cerebellum, parieto-frontal corte x, hippocampus, hypothalamus and midbrain). The results show that chro nic i.c.v. microinfusion of IL-I beta increased the IL-1 beta mRNA, IL -IRI mRNA and IL-1Ra mRNA levels in the hypothalamus > cerebellum in b oth obese (fa/fa) and lean (Fa/Fa) Zucker rats. IL-1 beta mRNA levels also increased in the cortex, hippocampus and midbrain of obese (fa/fa ) rats. The profiles of IL-1 beta mRNA, IL-1RI mRNA and IL-1Ra mRNA in the same hypothalamic samples obtained from obese or lean rats were h ighly intercorrelated. However, no significant differences in the leve l of IL-1 beta system mRNAs induction were observed in any brain regio n between obese and lean rats. On the other hand, levels of rat glycer aldehyde 3-phosphate dehydrogenase mRNA were fairly constant, and heat -inactivated IL-1 beta (8 ng/24 h/72 h) had no effect on IL-1 beta, IL -1RI and IL-1Ra mRNAs levels in any brain region. The data suggest: (1 ) the operation of an IL-1 beta feedback system (IL-1 beta/IL-1Ra/IL-1 RI) in brain regions; (2) that enhanced sensitivity of obese rats to I L-1 beta-induced anorexia is not dependent on changes in the brain IL- 1 beta system at the mRNA level; and (3) that the present novel approa ch can be used to investigate the molecular basis of cytokine action i n the CNS.