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The Importance of Gastrointestinal Hormones in the Development of Obesity- Related Hypertension

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The Importance of Gastrointestinal Hormones in the Development of Obesity- Related Hypertension The importance of gastrointestinal hormones in the development of obesity- related hypertension Jackie M.Y. How B. Sc., Hons. (Melb.) A thesis submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy The University of Melbourne Clinical Pharmacology and Therapeutics Unit Department of Medicine Austin Health Heidelberg, Victoria, Australia January 2015 Produced on archival quality paper "Once we accept our limits, we go beyond them" Albert Einstein Abstract In recent years, obesity has reached pandemic proportions and leading risk factor for the development of cardiovascular diseases. Obese individuals have been shown to have 3.5 times greater risk of developing hypertension than individuals with normal body weight. According to the Framingham Study, up to 75% newly-diagnosed cases of hypertension may be attributable to obesity. While sympathoactivation had been established as one of the main contributors to obesity-related hypertension, recent evidence suggests that attenuated sympathoinhibitory mechanisms may be just as important. Disruption to the delicate balance of sympathoinhibitory and sympathoexcitatory mechanisms may cause a disturbance to vasoconstrictor and vasodilator mechanisms, thus impacting cardiovascular homeostasis. The hormone leptin has received considerable attention in the aetiology of obesity-related hypertension. This peptide is primarily derived from adipose tissue and acts centrally to reduce appetite and increase energy expenditure. However obesity is associated with leptin resistance as many obese individuals have abnormally elevated circulating levels of leptin (hyperleptinaemia). This phenomenon is known as selective leptin resistance, in which the beneficial metabolic effects of leptin on energy expenditure are abolished but the sympathoexcitatory effects are sustained. This prolonged sympathoactivation is thought to contribute to the development of hypertension in obesity. Leptin is not only found in adipose tissue but also the stomach. This gastric- derived leptin is involved in the short-term regulation of food intake and satiety signalling, unlike adipose leptin that is involved on long-term regulatory mechanisms via transcriptional changes occurring in forebrain regions. The gut peptide, cholecystokinin (CCK), is involved in regulating satiety and many other digestive processes. Studies have shown that feeding and CCK administration induce the release of gastric leptin. Our laboratory was the first to demonstrate that the gut peptides, CCK and leptin, play a role in cardiovascular control via a centrally-mediated tri-synaptic reflex. CCK and gastric leptin have an interactive relationship in cardiovascular regulation, and the effects of gastric leptin are due to CCK release within the gut. CCK elicits a centrally-mediated bimodal sympathetic reflex dependent on the activation of i CCK1 receptors located on subdiaphragmatic vagal afferents. Our laboratory has found that CCK inhibits a subpopulation of presympathetic vasomotor neurons in the rostral ventrolateral medulla (RVLM) that are critical to blood pressure regulation. Furthermore, this subset of neurons is proposed to modulate sympathetic vasomotor outflow specifically to the gastrointestinal and renal vascular beds, inhibition of which results in withdrawal of sympathetic vasomotor tone to promote vasodilation. The gastrointestinal and renal circulations receive up to 50% of total blood volume postprandially. Since the satiety effects of gastric leptin and CCK are affected in obesity, we hypothesised that disruption to the sympathoinhibitory and vasodilator effects of gut hormones may impact on cardiovascular homeostasis, thus contributing to hypertension in obesity. Specifically, this thesis has focussed on the cardiovascular role of gastrointestinal hormones in the aetiology of obesity-related hypertension. In order to address this hypothesis, we first established a diet induced obesity (DIO) model using polygenic out-bred male Sprague-Dawley rats fed a moderately high-fat diet (MHFD; 32% kcal from fat). After a 13-15 week feeding period, MHFD fed animals were segregated according to weight gain, with the upper tertile weight- gainers being assigned to the obesity-prone (OP) group and the lower tertile to the obesity-resistant (OR) group. Control animals were fed a low-fat diet (LFD; 9% kcal from fat). Initial weights of the animals were not significantly different between the groups. OP animals typically developed elevated resting arterial pressure (AP), increased weight gain, adiposity index and plasma leptin levels when compared with OR or control animals. However the plasma lipids, insulin and glucose were not significantly different between OP, OR or control animals, indicating that this model is independent of the metabolic syndrome. Using this DIO model, we examined the effects of CCK (2 µg/kg) and leptin (15 µg/kg) administered close to the coeliac artery and within the gastrointestinal circulation (termed "close arterial") on splanchnic sympathetic nerve discharge (SND), in artificially ventilated, isoflurane-anaesthetised animals. To determine whether any effects were attributable to obesity or the high-fat diet, animals were analysed according to weight gain (OP versus OR) or diet (all MHFD animals (including middle tertile) versus LFD animals). ii When analysed according to weight gain, the splanchnic sympathoinhibitory responses to CCK and leptin were significant attenuated or reversed respectively, in both the OP and OR animals when compared with control animals (P < 0.05). The splanchnic SND responses to these peptides were not significantly different between OP or OR animals (P > 0.05). Collectively, MHFD animals had significantly lower levels of CCK when compared to the LFD animals (P < 0.05) and this corresponded with attenuated or reversed splanchnic SND responses to CCK (P < 0.05) and leptin (P < 0.001), respectively. Since plasma CCK was only lower in MHFD animals, this suggested that diet alters the release of this peptide. The sympathoinhibitory effects of gastric leptin have been proposed to be due to CCK release. Therefore, in light of the attenuated sympathoinhibitory effects of CCK in MHFD rats, it is not surprising that the modest effects of close arterial leptin were reversed, possibly due to the unmasking of sympathoexcitatory mechanisms. These findings demonstrated that a high-fat diet is associated with blunted/reversed splanchnic sympathoinhibitory responses to CCK and gastric leptin, possibly impacting on sympathetic vasomotor mechanisms involved in circulatory control. Renal sympathetic nerve activity (SNA) has been implicated in the development of hypertension in obesity. Furthermore, hypertension has been associated with increased vascular resistance and impaired vasodilator mechanisms. To test whether renal SND and regional vasodilator responses to CCK were affected in obesity we recorded renal SNA and examined vasodilator responses in renal and superior mesenteric arteries using Doppler flowmetry techniques. We found that CCK (0.1 - 8 µg/kg) inhibited renal SND and increased renal vascular conductance (VC) in control and OR animals, however these responses were significantly attenuated in OP rats (P < 0.05 for all). While there was a tendency for the OP rats to have reduced mesenteric VC, this did not reach statistical significance. Resting AP was directly correlated with weight gain and was inversely correlated with CCK-induced vasodilatation in both the renal and mesenteric arteries (P < 0.05 for all). Animals with higher resting AP tended to have vasoconstrictor rather than vasodilator responses. These results suggest that in obese rats, disruption of CCK-induced sympathoinhibitory signals evoked by CCK reduces vasodilation in the splanchnic or renal regions. iii Our laboratory has proposed that the cardiovascular effects of gastric leptin are dependent on the release of CCK. We have shown that rats on a MHFD have lower circulating levels of CCK, suggesting that in these animals the release of this peptide is compromised. Since the splanchnic sympathoinhibitory effects of gastric leptin are abolished/reversed in MHFD animals, we therefore sought to investigate whether the renal sympathoinhibitory and regional vasodilator effects of gastric leptin are also altered. Close arterial leptin (15 µg/kg) inhibited renal SND in control animals, however this response was abolished in OP and OR rats (P < 0.01 for both). Renal VC was increased in control animals in response to leptin, but this response was significantly blunted only in the OP rats (P < 0.05). However the vasodilator response in the superior mesenteric artery was not significantly different between OP, OR or control rats (P > 0.05 for all). In agreement with our previous findings, renal sympathoinhibitory responses of gastric leptin were affected by diet. However the vasodilator response of this peptide in the renal vascular bed was only affected in OP animals, suggesting these responses are altered as a result of obesity. While we established that the typical sympathoinhibitory and vasodilatory effects of CCK and gastric leptin are attenuated or reversed in obese hypertensive animals, we did not identify the mechanisms for these changes. In the following study we sought to investigate whether these changes are due to aberrant central or peripheral mechanisms. The renal and splanchnic sympathoinhibitory effects of CCK are dependent on the activation of CCK1 receptors situated on subdiaphragmatic vagal
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