Adipocytes, Macrophages and Inflammation

Abstract

While there is a very strong correlation between obesity and the development of insulin resistance and Type II diabetes, the molecular mechanisms involved are still unknown. However, one clue is that in both human subjects and animal models, obese adipose tissue is infiltrated with M1 macrophages and this creates a systemic low-grade, chronic inflammatory state that could be responsible for the negative consequences of obesity. A better understanding of the relationship between the adipocytes and macrophages under the inflammatory milieu may inform intervention strategies. In this study, the cross-talk between adipocytes and macrophages were investigated under inflammation at a transcriptional level. The gene expression of the adipocyte, 3T3-L1, was monitored in response to the pro-inflammatory secretions from an activated macrophage, RAW 264.7 cells. It was found that following exposure to this pro-inflammatory cocktail, adipocytes were able to respond to inflammatory stimuli in much the same way as immune cells, and displayed transient and drastic transcriptional regulation. Most excitingly, we showed that adipocytes exhibit a transcriptional memory effect, with the expression of many being quite different upon rechallenge with a second stimulus when compared to naïve cells. Microarray analysis revealed that this “memory” was demonstrated in a diverse group of sequences that were both up and down-regulated, including inflammatory and adipocyte-specific function associated sequences. Results suggested that the mechanism(s) behind this memory effect were both transcriptionally and post-transcriptionally regulated. Overall, this thesis shows that the inter-cellular communication between adipocytes and macrophages is strongly dependent on the environmental and temporal context of the adipocytes. This has far reaching implications for the study of the aetiology of the inflammatory state in obesity and, ultimately, the relationship between overweight and disease.