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The role of inflammation and the haematopoietic system in insulin resistance
thesisposted on 14.02.2017, 02:43 authored by Kowalski, Grzegorz (Greg) Michael
There is widespread acceptance in the literature that the accumulation of macrophages into expanding adipose tissue from excessive energy intake is a critical event that underlies the development of both local adipose tissue and whole body insulin resistance. Interleukin-10 (IL-10) is a potent immune cell derived anti-inflammatory Th2 cytokine. During adipose tissue expansion, a reduction in adipose tissue resident macrophage IL-10 secretion has been proposed to be an important event that leads to the shift in balance from a largely non-inflamed ‘healthy’ insulin sensitive adipose tissue, to an obese inflamed insulin resistant one. In the first part of this thesis it was hypothesized that a lack of immune cell (macrophage) derived IL-10 would exacerbate obesity induced adipose tissue inflammation, leading to insulin resistance and glucose intolerance. Using an adoptive bone marrow transplant (BMT) technique, mice that lack IL-10 in the haematopoietic compartment were created. These mice were fed a high fat diet to induce obesity and insulin resistance. Surprisingly, mice deficient in immune cell IL-10 did not develop heightened adipose tissue or hepatic inflammation, nor did they become more insulin resistant than wild type bone marrow transplant controls. The double stranded RNA-dependent protein kinase R (PKR) has been proposed to be a critical upstream lipid sensor linked to the activation of endoplasmic reticulum (ER) stress, inflammation and insulin resistance. It was hypothesised that immune cell (macrophage) PKR deletion in-vivo would protect mice from obesity induced adipose tissue inflammation and insulin resistance. Contrary to our hypothesis, mice lacking haematopoietic PKR, did not display protection from local adipose tissue or whole body insulin resistance, nor did they have altered adipose tissue or hepatic inflammation compared to wild type BMT controls. The last part of this thesis focused on characterising the temporal relationships between insulin resistance and inflammation. Molecular characterisation of adipose tissue and liver from previously performed mouse high fat feeding time course studies in our laboratory revealed a disassociation between the on-set of insulin resistance and the development of metabolic inflammation. Severe local adipose tissue, hepatic and whole body insulin resistance developed as early as after one week of high fat feeding, with this occurring in the absence of any classical markers of macrophage infiltration or inflammation. Collectively, these studies failed to show that modification of haematopoietic cell (macrophage) inflammatory potential in-vivo can alter the development of high fat diet induced insulin resistance and that the onset of insulin resistance does not coincide with metabolic tissue inflammation, suggesting inflammation is not a cause of insulin resistance, but rather a complication of obesity and/or the insulin resistant state.