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Obesity, insulin resistance and type 2 diabetes mellitus are positively correlated with neurophysiological changes in brain regions including the hippocampus, a component directly involved in complex memory and learning processes. The incretins glucagon-like peptide-l (GLP-l) and glucose-dependent insulinotropic polypeptide (GIP) are multifunctional gut hormones that mediate cognitive- enhancing properties in the hippocampus. As such, this thesis evaluates the impact of diet and obesity-related diabetes on brain function and characterises effects of established and novel incretin therapeutics on cognitive function and metabolic control in animal models. High-fat diet induced insulin resistant mice were dosed twice-daily over a 3-4 week period with the established GLP-l mimetics Exendin-4 and Liraglutide or the GIP mimetic [D-Ala2]GIP(1-42). Effects on metabolic control, cognitive function and hippocampal synaptic plasticity were evaluated. Additionally, the effects of twice-daily Liraglutide were tested over 3 weeks in a more severe animal model of diabetes, obese diabetic (ob/ob) mice. Collectively, incretin therapeutics decreased non-fasting plasma glucose concentrations, increased plasma insulin and improved glucose tolerance. Furthermore, high-fat mice displayed impairment in recognition index (RI) during the object recognition task; whilst high- fat fed and ob/ob mice displayed severely compromised induction and maintenance of hippocampal LTP transmission. Importantly, Exendin-4, Liraglutide and [D- Ala2]GIP(1-42) treated high-fat mice displayed a marked increase in RI indicating enhanced memory, whilst LTP impairment was ameliorated. Other studies showed that chronic administration of Liraglutide rescued LTP and significantly enhanced Mashl expression in ob/ob mice. It was established that pharmacological doses of the incretin metabolites GLP-l(9-36)amide or GIP(3-42) did not influence cognitive function or hippocampal synaptic plasticity in high-fat mice. Collectively, the data in this thesis illustrate negative impact of high-fat diet, obesity and type 2 diabetes on cellular mechanisms involved in neuronal development, neurogenesis and memory formation. Furthermore, this thesis highlights the growing potential of GLP-l and GIP therapeutics in ameliorating these neuronal dysfunctions by enhancing synaptic transmission, neurogenesis and promoting neuroprotection.

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This thesis has investigated the first part of a two-stage therapeutic intervention against obesity in which adipose tissue lipolysis will be combined with increased energy expenditure: the approach is also designed to consider agents that will benefit glycaemic control in coexistent obesity and diabetes by improving insulin sensitivity. Rodent and human in vitro models of adipocyte biology and skeletal muscle have been developed, characterised and evaluated. They include isolated epididymal and parametrial adipocytes of lean and obese diabetic ob/ob mice, cultured 3T3-L1 preadipocytes, isolated human omental and subcutaneous adipocytes and rat L6 cultured muscle cells. Compounds investigated for anti-obesity and anti-diabetic properties include M2 (sibutramine metabolite), 3-guanidinopropionic acid and mazindol. In vivo studies were undertaken to investigate these compounds further in lean and ob/ob mice. In vivo studies indicated that M2 and 3-guanidinopropionic acid reduced body weight gain in ob/ob mice. The three compounds increased lipolysis in adipocytes isolated from lean and ob/ob mice and human adipose depots. The direct action of these compounds was mediated via a pathway involving the b adrenoceptors and components of the lipolytic signalling pathway, including protein kinase A and p38 MAP kinase. In addition, M2 and mazindol were capable of increasing glucose uptake into insulin sensitive tissues. M2 and mazindol can act directly on adipose tissue and skeletal muscle to increase glucose uptake via a pathway involving new protein synthesis and activation of the glucose transporters. The M2-stimulated pathway is activated by the conversion of phosphatidylinositol bisphosphate to phosphatidylinositol trisphosphate by phosphatidylinositol 3-kinase. Thus, M2 mazindol and 3-GPA showed pharmacodynamic properties which suggested they might be potential therapeutic treatments for obesity and diabetes.

This thesis reviews the literature on, and describes experimental work carried out with, the drug rimonabant, an antagonist at the cannabinoid CBI receptor. -, Rimonabant was licensed in Europe for the treatment of obesity in 2006, however it <- was withdrawn from the market in 2008, because of unacceptable psychiatric side effects, notably depression and anxiety. The mechanism( s) by which CB 1 antagonists produce such symptoms is unclear. The Introduction to this thesis reviews the literature on clinical depression, with special reference to endocannabinoids, and concludes that there are several plausible neurobiological mechanisms linking CB 1 antagonism to the symptoms of this disease. These include inhibition ofphasic dopamine firing elicited by reward, leading to anhedonia; disinhibition ofthe hypothalamo-pituitary stress axis; interference with the extinction of negative emotional memories; and interference with hippocampal neurogenesis. The remainder of the thesis describes the methods and results of four studies in which healthy volunteers were given rimonabant in double-blind, placebo- , controlled experiments. This work was intended to elucidate possible mechanisms by which rimonabant produces depression, with the twin goals of advancing the understanding ofthe endocannabinoid system, and contributing to our knowledge of the neurobiology of clinical depression. Two studies made use of cognitive psychological tasks in order to investigate the impact of rim on ab ant on responses to positive and negative emotional stimuli. The other two studies used functional magnetic resonance imaging (fMRI) to probe the neural effects of CBI antagonism on various functions ofthe brain. Taken together, the results of these four investigations suggest that rimonabant causes depression via interference with the brain's response to positive stimuli and enhancement ofthe response to negative ones. I conclude by discussing the key role of endocannabinoids in mood. The important implications for our understanding of the pathophysiology of clinical depression are explained.