Identifying novel mediators of adipose tissue and skeletal muscle crosstalk and their role in mediating muscle metabolic phenotype and insulin sensitivity

Nicholson, Thomas Andrew (2020). Identifying novel mediators of adipose tissue and skeletal muscle crosstalk and their role in mediating muscle metabolic phenotype and insulin sensitivity. University of Birmingham. Ph.D.

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Abstract

Type II diabetes is a chronic metabolic disorder that carries a significant and increasing economic burden. Unfortunately, there is no cure for type II diabetes and treatments are limited. Adipose tissue cross talk with skeletal muscle and adipose-secreted cytokines (adipokines) have been implicated in driving skeletal muscle insulin resistance typical of type II diabetes; although this is largely based on evidence from animal models and rodent cell lines.

The aim of this thesis was to investigate the role of novel adipose/skeletal muscle cross talk mechanisms in mediating human skeletal muscle insulin signalling. This thesis demonstrates that the novel adipokine vaspin is secreted from human subcutaneous adipose tissue, and is more highly expressed in obese older individuals compared to lean older individuals. Furthermore, using primary human myotubes derived from lean and obese donors, vaspin was demonstrated to induce activation of the PI3K/AKT axis, promote both GLUT4 expression and translocation, and sensitise older obese human skeletal muscle to insulin-mediated glucose uptake.

This thesis also presents the first evidence of differential secretion of extracellular vesicles from lean and obese subcutaneous adipose tissue. Such vesicles were capable of increasing skeletal muscle inflammation, in addition to upregulating both atrophic and metabolic skeletal muscle gene expression, supporting the notion that extracellular vesicles are novel mediators of adipose tissue and skeletal muscle crosstalk in humans.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):