Secreted by adipose tissue, leptin acts as a signal of energy reserve status, and acts in the brain as a negative feedback mechanism to suppress food intake and increase energy expenditure, the net effect of which is maintenance of energy homeostasis. In addition to its role as a satiety factor, leptin has widespread autonomic effects, increasing sympathetic tone to a variety of tissues, including those involved in arterial pressure regulation. Thus, leptin has been implicated as a critical link between obesity and hypertension. However, the specific mechanisms whereby leptin elicits its diverse effects are not fully understood. This is further complicated by the many sites of leptin action within the brain, as well as its diverse intracellular effects. Here, we investigate the possibility that distinct aspects of leptin function are controlled by different neuronal populations and/or molecular signaling cascades. Specifically, we identify unique roles for leptin action on POMC and AgRP neurons in differentially mediating the regional sympathetic effects of leptin. Furthermore, we show that leptin action via mTORC1 is required for the cardiovascular sympathetic but not the metabolic effects. Together, these findings point to complex neuroanatomical and molecular differences in the mechanisms underlying leptin’s effects on different physiological processes, with important implications for future research into obesity-associated hypertension.

Experiments were performed to test the postulate that exercise training (ExT) improves the blunted renal excretory response to acute volume expansion (VE), in part, by normalizing the neural component of the volume reflex typically observed in chronic heart failure (HF). Diuretic and natriuretic responses to acute VE were examined in sedentary and ExT groups of rats with either HF or sham-operated controls. Experiments were performed in anesthetized (Inactin) rats 6 wk after coronary ligation surgery. Histological data indicated that there was a 34.9 ± 3.0% outer and 42.5 ± 3.2% inner infarct of the myocardium in the HF group. Sham rats had no observable damage to the myocardium. In sedentary rats with HF, VE produced a blunted diuresis (46% of sham) and natriuresis (35% of sham) compared with sham-operated control rats. However, acute VE-induced diuresis and natriuresis in ExT rats with HF were comparable to sham rats and significantly higher than sedentary HF rats. Renal denervation abolished the salutary effects of ExT on renal excretory response to acute VE in HF. Since glomerular filtration rates were not significantly different between the groups, renal hemodynamic changes may not account for the blunted renal responses in rats with HF. Additional experiments confirmed that renal sympathetic nerve activity responses to acute VE were blunted in sedentary HF rats; however, ExT normalized the renal sympathoinhibition in HF rats. These results confirm an impairment of neurally mediated excretory responses to acute VE in rats with HF. ExT restored the blunted excretory responses as well as the renal sympathoinhibitory response to acute VE in HF rats. Thus the beneficial effects of ExT on cardiovascular regulation in HF may be partly due to improvement of the neural component of volume reflex. Copyright © 2006 the American Physiological Society.

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

Master of Science / Department of Anatomy and Physiology / Michael J. Kenney / Hyperthermia is an environmental stressor that produces marked increases in visceral sympathetic nerve discharge (SND) in young rats. The brainstem in rats contains the essential neural circuitry for mediating visceral sympathetic activation; however, specific brainstem sites involved remain virtually unknown. The rostral ventral lateral medulla (RVLM) is a key central nervous system region involved in the maintenance of basal SND and in mediating sympathetic nerve responses evoked from supraspinal sites. In the present study we tested the hypothesis that inhibition of RVLM synaptic activation at peak hyperthermia (internal body temperature, Tc, increased to 41.5°C) would affect heating-induced visceral sympathetic activation. Experiments were completed in chloralose-urethane anesthetized, baroreceptor-intact and sinoaortic-denervated, 3-6 month-old Sprague-Dawley rats. Bilateral inhibition of RVLM synaptic activation produced by muscimol microinjections (400 and 800 pmol) at 41.5°C resulted in immediate and significant reductions in peak heating-induced renal and splenic sympathoexcitation. Interruption of RVLM synaptic activation and axonal transmission by lidocaine microinjections (40 nmol) at 41.5°C produced significant reductions in hyperthermia-induced sympathetic activation to similar levels produced by RVLM muscimol microinjections. The total amount of SND inhibited by RVLM muscimol and lidocaine microinjections was significantly more during hyperthermia (41.5°C) than normothermia (38°C). These findings demonstrate that maintenance of sympathetic activation at peak hyperthermia is dependent on the integrity of RVLM neural circuits.

The mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved serine/threonine kinase regulating diverse cellular functions, including cell growth, protein synthesis and sensing nutrients and energy status. Prior studies have identified the involvement of hypothalamic mTORC1 in the control of energy balance, renal sympathetic activation and blood pressure regulation. Hypothalamic insulin receptor signaling through the phosphatidylinositol 3-kinase (PI3K) is known to regulate energy homeostasis and sympathetic nerve activity (SNA). We examined the role of hypothalamic mTORC1 in the anorectic and sympathetic effects of central insulin. mTORC1 inhibition by rapamycin or PI3K mutation resulted in blunted regional SNA responses to insulin. Rapamycin also blunted appetite-suppressing and body weight-reducing effects of insulin. Furthermore, biochemical analyses revealed PI3K-dependent activation of mTORC1 pathway by insulin in the arcuate nucleus of hypothalamus (ARC), where insulin initiates its central actions. These results indicate the significant contribution of mTORC1 pathway in the ARC to the central action of insulin on the regulation of energy homeostasis and SNA. Angiotensin II (Ang II) is a vasoconstrictive and anti-diuretic peptide produced in the renin-angiotensin system (RAS). Local brain RAS plays an important role in the control of blood pressure, electrolyte and fluid balance. Stimulation of Ang type 1 receptor (AT1R) by Ang II in the cardiovascular brain nuclei triggers drinking and pressor responses. Chronic Ang II action in CNS leads to transcriptional neuromodulation, which in turn, contributes to the development and maintenance of hypertension. Intracellular signaling cascades responsible for neuronal Ang II's actions include PI3K and extracellular signal-regulated kinase (ERK) pathways, which are known upstream effectors of mTORC1 in peripheral tissues. We investigated the involvement of mTORC1 signaling in the brain Ang II actions. Ang II was capable of activating mTORC1 in neuronal cell line and mouse brain, however mTORC1 inhibition had no influence on the drinking and pressor responses to Ang II. Moreover, we found an upregulated mTORC1 activity in the SFO of hypertensive transgenic mice with overactive brain RAS (sRA mice). Importantly, mTORC1 inhibition normalized systolic blood pressure in sRA mice. These results support a potential role of mTORC1 in the maintenance of neurogenic hypertension. Overall, data presented in this thesis provide a better understanding of neuronal mTORC1 function as a key effector component of insulin or Ang II-mediating regulation of physiological and pathophysiological processes.

No description available.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成8年3月8日 辻井洋一郎氏の博士論文として提出された

Modest recovery of somatic function after incomplete spinal cord injury (SCI) has been widely demonstrated. Recently we have shown that spontaneous recovery of baroreflex regulation of sympathetic activity also occurs in rats. Dietary restriction in the form of every other day fasting (EODF) has been shown to have beneficial effects on the recovery of motor function after SCI in rats. The goal of this study was to determine if EODF augments the improvement of baroreflex regulation of sympathetic activity after chronic left thoracic (T8) surgical spinal hemisection. To determine this, we performed baroreflex tests on ad-lib fed or EODF rats 1 week or 7 weeks after left T8 spinal hemisection. One week after T8 left hemisection baroreflex testing revealed that gain of baroreflex responsiveness, as well as the ability to increase renal sympathetic nerve activity (RSNA) at low arterial pressure, was significantly impaired in the ad-lib fed but not the EODF rats compared with sham lesioned control rats. However, baroreflex tests performed 7 weeks after T8 left hemisection revealed the inability of both ad-lib and EODF rats to decrease RSNA at elevated arterial pressures. While there is evidence to suggest that EODF has beneficial effects on the recovery of motor function in rats, EODF did not significantly improve the recovery of baroreflex regulation of sympathetic activity.