The Expression of Inflammatory Genes in 3T3-L1 Adipocytes Exhibits a Memory to Stimulation by Macrophage Secretions

Abstract

ABSTRACTObesity is characterized by increased output of inflammatory compounds from adipose tissue. Whilst the relative contribution of adipocytes and resident macrophages to this phenomenon is debated, there is no doubt that the secretions of each cell type can stimulate the expression of inflammatory genes in the other. We hypothesized that mechanisms must exist to prevent an escalating positive feedback loop between the two cell types, so that after an initial exposure to macrophage secretions, adipocytes would become desensitized to subsequent inflammatory stimulation.We used microarrays to investigate the response of 3T3-L1 adipocytes to macrophage secretions (macrophage conditioned medium, MCM). MCM caused a rapid (<4 hours) and high amplitude (over 100-fold) rise in the expression of several inflammatory genes. For some genes, generally cytokines, expression returned to basal levels within 24 h following removal of the MCM, but other transcripts, notably those for acute phase proteins and extracellular matrix remodeling proteins, remained highly expressed even during the washout period.Unexpectedly, some cytokine genes (e.g., iNOS, IL-6) showed an enhanced expression to a second exposure of MCM, illustrating that the transcriptome response of 3T3-L1 adipocytes retains a memory to the first stimulus. We characterized the parameters that give rise to the memory phenomenon, finding that additional stimuli do not augment or abrogate the effect. The memory is preserved for several days after the initial exposure and it is not due to a change in sensitivity to the MCM but, rather, a change in the capacity of the signal-target system. The possible mechanisms of the memory are discussed, along with the physiological ramifications should the phenomenon be replicated in vivo.