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Title: Adipose tissue derived factors in obesity, inflammation & energy homeostasis
Author: Kusminski, C. M.
ISNI:       0000 0004 2709 8327
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2006
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Obesity is the foremost contributory factor in the progression to type 2 diabetes mellitus (T2DM). Moreover, chronic inflammation, through activation of innate immunity is proposed to link obesity, insulin resistance and T2DM. Adipose tissue, traditionally considered a storage compartment for triglycerides, also functions as an active endocrine organ. Adipocyte-secreted products, termed adipokines, may link obesity-associated inflammation and insulin resistance. Adipokines exert multiple effects on insulin sensitisation, glucose homeostasis, inflammatory processes or central systems mediating energy expenditure. This thesis principally examined two adipokines; resistin and adiponectin. Resistin and components of innate immunity were assessed in human obesity. In-vitro analysis established that resistin was expressed and secreted by human adipocytes. Furthermore, key factors in the innate immune pathway were highly expressed in obese and T2DM adipose tissue. This thesis further explored the pro-inflammatory actions of resistin in adipocytes. Resistin stimulated the secretion of inflammatory cytokines from adipocytes and, the expression of key intermediates of the innate immune and insulin signalling pathways. Clinical studies entailed examination of resistin as a marker of inflammation in childhood obesity. Serum analysis revealed gender-differences in resistin levels in obese children. Furthermore, bacterial endotoxin correlated with several markers of inflammation and cardiovascular disease; suggesting endotoxin as a contributor to inflammation in childhood obesity. This thesis subsequently examined another adipokine, adiponectin; considered to have a `ying-and-yang' relationship with resistin. Studies explored a central role for adiponectin in energy homeostasis. Gelfiltration liquid chromatography established that the adiponectin trimer was predominant in human cerebrospinal fluid. Such identification of trimeric adiponectin in vivo implicates the pharmacologically generated globular adiponectin in central regulation of energy expenditure. In conclusion, resistin may serve as a pathogenic pro-inflammatory factor, exacerbating inflammation within adipose tissue; potentially contributing to the progression of obesity-driven T2DM. Alternatively, adiponectin may have favourable central actions, influencing energy expenditure through its basic trimeric form. Collectively, this thesis suggests that resistin and adiponectin, with a range of opposing properties, may substantially affect whole-body metabolism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology ; RC Internal medicine