Investigating the Wnt/β-catenin Pathway in Conventional Dendritic cells in Obesity-Induced Tissue Inflammation and Insulin Resistance
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Chronic low-grade inflammation in visceral adipose tissue (VAT) is a key feature of obesity and crucial in the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). VAT harbours resident immune cells including conventional dendritic cells (cDC), that work in cooperation to regulate metabolic homeostasis. Modulation of the immune system has the potential to ameliorate disease progression. VAT-cDCs are characterised by the activation of the Wnt/β-catenin pathway, which is known to modulate cDC function and promote T cell immune tolerance. Impaired Wnt/β-catenin pathway activity in VAT-cDCs is observed during obesity. The aim of this thesis was to investigate the effect of sustained activation of Wnt/β-catenin signalling in cDCs in obese VAT, with the hypothesis that this could revert the development of VAT inflammation and IR. The immune and metabolic phenotype was characterised in mice with constitutively active β-catenin in cDCs, referred to as gain-of-function (GOF), in a model of diet-induced VAT inflammation. Increased tolerogenic responses of VAT-cDCs in the GOF mice was able to revert the development of VAT inflammation in part, altering T cell recruitment and inducing a more T cell immunosuppressive phenotype, but not sufficient to improve insulin sensitivity. Improvement of whole-body glucose homeostasis in the GOF mice was explained by increased insulin production from the islets. Reduced islet inflammation and expansion of islets, provided a greater insulin reserve in the GOF mice, improving β-cell insulin compensation in response to obesity-induced IR. Enhanced levels of adiponectin and reduced secretion of CCL17 in the GOF mice, prompted the investigation of atherogenic development in Ldlr-/- GOF chimera mice. Constitutive activation of β-catenin in cDCs was not sufficient to decrease aortic lesion density. Collectively these results indicate the significance of systemically modulating Wnt/β-catenin pathway in cDCs, with the potential to control the development of VAT inflammation and metabolic dysfunction in obesity.
AuthorsMacdougall, C; Queen Mary University of London
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