| Summary: | Obesity is a major growing cause of death with no effective long-term treatment apart from surgical procedures such as Roux-en-Y gastric bypass (RYGB). The sustained weight loss following surgery is thought to be due in part to the increased levels of circulating anorexigenic gut hormones such as peptide YY3-36 (PYY3-36). Peripheral administration of PYY3-36 suppresses appetite in rodents and man and represents a potential therapy for obesity however its effects on feeding are transient. Here I have characterized a long-lasting PYY3-36 analogue; PYY3-36 latrotoxin (PYY3-36 (LT)) which demonstrated greater longevity than PYY3-36 in acute feeding studies and that produced a 10% reduction in bodyweight following once daily peripheral administration in a one month chronic feeding study performed on diet induced obese mice. Manganese enhanced MRI (MEMRI) has been used previously to assess the effects of nutritional status and gut hormones on brainstem and hypothalamic neuronal activity in vivo. I revealed through the MEMRI technique that the anorexigenic hormone pancreatic polypeptide (PP) modulates hypothalamic neuronal activity in fasted mice. Following this work, I performed more in-depth MEMRI experiments that revealed differential temporal effects of PYY3-36 and PYY3-36 (LT) on hypothalamic neuronal activity in fasted mice after treatment that corresponded to the effects seen with these peptides in feeding stuides. I also performed pharmacological MEMRI studies with the food additive monosodium glutamate (MSG) and confirmed its excitatory effect on neurons of the arcuate nucleus of the hypothalamus (ARC) following peripheral administration to mice. Roux-en-Y gastric bypass has been shown to increase energy expenditure possibly via a brown adipose tissue (BAT) mediated mechanism. I performed positron emission tomography-computed tomography (PET-CT) experiments on a rodent model of RYGB. I observed no differences in the activity of BAT of RYGB animals compared to shamoperated controls, indicating means other than increased BAT activity account for the weight loss seen in this bariatric model. The work in this thesis demonstrates that long-lasting PYY3-36 analogues represent a viable obesity therapy. Furthermore, I have further developed both MEMRI and PET-CT techniques for the study of energy balance.
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