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Regulation of activins and follistatin in Inflammatory and metabolic disorders

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posted on 2017-05-19, 02:30 authored by Wu, Hui
Activin A, a member of the transforming growth factor-β superfamily (TGF-β), increases in the circulation within one hour after administration of bacterial lipopolysaccharide. The source and regulation of activin A and follistatin, activin binding protein, during inflammation are poorly understood. This thesis examined the major tissue sources and regulation of activin A and follistatin following lipopolysaccharide in adult male mice (Chapter II). All tissues examined contained activin A protein in untreated mice, but mRNA expression varied more than 100-fold across the tissues. The results indicated that the rapid increase in circulating activin A during lipopolysaccharide-induced inflammation was regulated at the post-mRNA level, apparently from newly-translated and stored protein. The bone marrow was implicated as the most significant source of pre-formed activin A protein, although the liver expressed the highest levels of activin βA mRNA. Neutrophil precursors were the major cells containing significant activin A protein in the bone marrow. The lung was the only tissue with increased activin A protein, one hour post-lipopolysaccharide. Follistatin mRNA and protein were present in all tissues, with highest expression in the vas deferens. Inflammation has increasingly been implicated in the development of type 2 diabetes (T2D), a metabolic disorder characterized by insulin resistance and hyperglycaemia. Both activin A and activin B, another member of the TGF-β superfamily, play important roles in glucose metabolism. In order to evaluate the potential roles of activin A, B and follistatin in T2D, this thesis examined circulating levels of these proteins (Chapter III). Serum activin A, B and follistatin levels were not different between subjects with a normal oral glucose tolerance test, impaired glucose tolerance and/or impaired fasting glucose, or T2D. However, elevated levels of activin A and/or B were positively correlated with functional parameters of insulin resistance and T2D, specifically fasting glucose, fasting insulin, glycated haemoglobin and homeostasis model assessment of insulin resistance. These results suggested that serum activin A, B or follistatin were not independent risk indicators for T2D, but serum activin A and B levels were increased in parallel with increasing severity of disease in T2D patients. Finally, as the bone marrow and the neutrophils, in particular, had been identified as a significant source of activin A protein during inflammation following lipopolysaccharide, neutrophils extracted from mouse bone marrow were examined to investigate the regulation of the release of activin A (Chapter IV). The findings showed that activin A protein levels in untreated neutrophil precursors was at least 7-fold higher than that in mononuclear cells. Lipopolysaccharide was not able to stimulate the release of activin A protein from cultured neutrophil precursors, but tumour necrosis factor-α (TNF-α), induced release of activin A within one hour. Pre-treatment of the neutrophil precursors with insulin ablated the response to TNF-α. However, TNF-α does not appear to be the only stimulator of activin A during inflammation, since lipopolysaccharide induced activin A release into the circulation of TNF-α null mice. These data clarify the major sources of activin A release and the regulation of activin A release during inflammation. The discovery of the neutrophils’ role in activin A release and the role of activins and follistatin in T2D provide new insight on the potential for follistatin to act as a specific therapeutic agent or neutrophils as a specific target cells for controlling activins’ actions in various inflammatory diseases, and their consequences.

History

Principal supervisor

Mark P. Hedger

Year of Award

2013

Department, School or Centre

Hudson Institute of Medical Research

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences

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    Faculty of Medicine, Nursing and Health Sciences Theses

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