The gut hormone oxyntomodulin is an attractive potential treatment for obesity as it reduces food intake and increases energy expenditure in rats and in man. However, the mechanisms by which OXM increases energy expenditure are not known.
Oxyntomodulin has a short half-life in vivo, so long-acting analogues are being developed for both obesity pharmacotherapy and to help us understand the physiology of OXM. This thesis uses the novel oxyntomodulin analogue, OX2, to investigate the energy expenditure effects of oxyntomodulin.
The first part of this thesis shows that OX2 increases energy expenditure acutely, as directly measured in CLAMS metabolic cages. Metabolic cage and pair-feeding studies show this increase in energy expenditure is sustained with prolonged administration of the oxyntomodulin analogue. The increase in energy expenditure occurs via activation of the glucagon receptor, as shown in studies using the GLP-1 antagonist Ex9-39, and comparing OX2 to the GLP-1 specific analogue OX2-Glu3.
Metabolic cage data shows that oxyntomodulin increases energy expenditure via altering metabolic processes rather than physical activity. The second part of this thesis investigates which pathways are affected by OXM. Using 6-hydroxydopamine to cause a chemical sympathectomy, this thesis demonstrates that the sympathetic nervous system is important in controlling the energy expenditure effects of OXM. Chronic administration of OX2 suppressed many metabolic pathways, including brown adipose tissue thermogenesis and organ growth. However, protein metabolisms and lipolysis were both increased, leading to a reduction in both body fat and body protein. The final part of this thesis then shows OX2 has acute, as well as chronic, effects on protein metabolism.
The findings in this thesis provide a basis for further investigations into the metabolic effects of oxyntomodulin. The thesis also underlines the importance of understanding these processes before oxyntomodulin analogues can be used in the treatment of obesity.