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Leptin modulates feeding related hypothalamic and peripheral neuronal activity in the normal and obese rats
LEPTIN MODULATES FEEDING RELATED HYPOTHALAMIC AND PERIPHERAL NEURONAL ACTIVITY IN THE NORMAL AND OBESE RATS T. Shiraishi’), K. Sasak?), A. Niijima3’ and Y .00mura4)
INSIGHT INTO ANOREXIA: A KEY ROLE OF HYPOTHALAMIC NEURONAL HISTAMINE Toshiie Sakata
Department of Internal Medicine I, School of Medicine, Oita Medical University, Oita, Japan
‘)Dept.ofNe ur op hy siol. Tokai Univ. Sch. of Med., Isehara, "Dept. of Bio-Inform. Eng. Fac.of Eng. Toyama Univ., Toyama “Dept. of Phys’101 Niigata Univ. Fat. of Med., Niigata and ‘)Bio-Act. Inst. Nippon Zohki Pharmaceut. Co., Yashiro, Japan
In a series of studies on histaminergic functions in the brain, anorexia was found to be induced by either activation of HI-receptor or inhibition of H3-receptor in the ventromedial hypothalamic nucleus (VMH) or the paraventricular nucleus, each of which is a satiety center. Starvation activated neuronal histamine (HA) in the hypothalamus. Such energy deficit in turn accelerated glycogenolysis in the astrocytes to prevent brain functions from glucoprivation. Thus, intraneuronal glucoprivation in the brain increases satiety signals to produce anorexia through activation of hypothalamic HA neurons. The activation of HA system, on the other hand, accelerated and lipolysis peripherally through hyperglycemia activation of sympathetic nerve system, along with decrease in body temperature. Expressions of acyl CoA synthetase in the adipocytes and glucose transporter IV in the muscles were concomitantly suppressed. Central administration of corticotropin releasing hormone (CRH), a potent anorectic peptide, activated hypothalamic HA neurons, and activation of HA neurons ehhanced hypothalamic CRH expression. These findings imply one of the rationales for efficacy of a low-calorie diet as a therapeutic tool for weight reduction, and in addition, why patients with anorexia nervosa or malignant diseases hardly improve their emaciation.
Using Wistar SPFNAF male (350-450g) and Zucker obese (SOO-8OOg)rats , we investigated effects of leptin on the neuronal activity on the hypothalamus, the vagal hepatic afferent and sympathetic efferent from the both brown and white adipose tissues (BAT/WAT) under urethane anesthetized and brain-slice preparations. Low doses (l-10 pg) of leptin inhibited glucose-sensitive vagal hepatic afferent discharges, and sympathetic efferent discharges of BAT/WAT were facilitated. Indicate that the peripheral information might be sent ascending to the hypothalamus. Most of the neurons in the arcuate nucleus were significantly inhibited their neuronal activity by leptin (100 nmol-0.1 pmol). Electrophoretic applications of leptin to the feeding center (LHA), glucose-sensitive neurons (GSN) and non-GSNs were significantly inhibited. To the satiety center (VMH) neurons, most of the glucorecetor neurons were significantly excited. This deoolarization caused bv Na+/K+channel onening that co&irmed by whole ckll patch-clamp m&hod: The paraventricular nucleus neurons showed enhancement of neuronal activity by leptin. However, effects of leptin on these neuronal activity showed slightly or almost none in the Zucker obese rats. Results showed that leptin ascend lipotic information to the feeding related hypothalamic neurons, and mediated by signal transduction, through both the central and the peripheral nervous systems.
THE ROLE OF HYPOTHALAMIC MELANOCORTINS IN MEDIATING THE CNS EFFECTS OF LEPTIN R. J. Seeley Department of Psychiatry and GraduateProgram in Neuroscience, University of Cincinnati, Cincinnati, OH 452670559 USA
POLYAMINES, SPERMINE AND SPERMIDINE, MAY MODULATE TIIE DRUG - INDUCED GINGIVAL OVERGROWTH M. Costuleanu’, N. Costuleanu’, L. Foia2, M. Pave12, A. Costuleanu”, V. Saila4, C. Bohotin’, R. lancu’, N. Foma’
Leptin is released from adipocytes and circulates in proportion to total adipose mass. As such, it is ideally suited to provide afferent information to the CNS concerning the status of peripheral energy balance. The signaling form of the leptin receptor is found in its highest density in the arcuate nucleus of the hypothalamus on two populations of neurons. One set of neurons are those that express neuropeptide Y (NPY) and the other is a set of neurons that express proopiomelanocortin (POMC). Both sets of neurons are regulated by leptin, NPY expression is inhibited while POMC is stimulated. In particular, a strong role can be made for involvement of these arcuate nucleus POMC neurons in leptin action. One post-translational product of POMC is a-melanocyte stimulating hormone (aMSH). a-MSH is a ligand for melanocortin (MC) receptors that are found in the hypothalamus such as MC4. Genetic deletion of the MC4 receptor results in obesity CNS administration of a-MSH decreases food intake as do more specific agonists of the MC4 receptor. Specific antagonists of the MC4 receptor increase food intake. Finally, pretreatment with a dose of an MC4 antagonist that has no effect on food intake or body weight can completely block the effect of leptin to suppress food intake. Additionally, increased expression of c-Fos in the paraventricular nucleus of leptin treated animals is also completely blocked by pretreatment with an MC4 antagonist. These data are consistent with the hypothesis that the POMC/aMSWMC4 system is one important component of the CNS system that mediates the actions of leptin.
‘Department of Pathophysloloa, ‘Department of Biochemisq, ‘Department of P~s~ologv, ‘Department of Prosthetics, University of Medicine and Pharmacy “Gr. T. Popa”, lasi, ‘Department of Prosthetics, IJniversiv “Apollonia”, RO - 6600,Romania The development of drug - induced gingival overgrowth may depend on a series of local factors, including the polyamines, spermine and spermidine. Since the polyamines have been found in high quantities in gingival crevicular fluid, we aimed the modulation of nifedipine - induced gingival overgrowth by spermine and spermidine. Thus, we worked on male Wistar rats of 20 days. All the series received nifedipine 150 mg / kg body weight p.o. for 7 days and then 250 mg I kg body weight p.o. for 13 days and a sucrose rich diet. In addition, one series received spermine 3 mg / kg body weight p.o_ for 20 days and one series spermidine 3 mg ! kg body weight p.o. for 20 days. At the end of experiment, the mandible condils were excised and the depth of gingival sulcus was measured. Our results show that spermine reduced and spermidine had no significant effects on gingival overgrowth induced by nifedipine
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INSIGHT INTO ANOREXIA: A KEY ROLE OF HYPOTHALAMIC NEURONAL HISTAMINE Toshiie Sakata
Department of Internal Medicine I, School of Medicine, Oita Medical University, Oita, Japan
‘)Dept.ofNe ur op hy siol. Tokai Univ. Sch. of Med., Isehara, "Dept. of Bio-Inform. Eng. Fac.of Eng. Toyama Univ., Toyama “Dept. of Phys’101 Niigata Univ. Fat. of Med., Niigata and ‘)Bio-Act. Inst. Nippon Zohki Pharmaceut. Co., Yashiro, Japan
In a series of studies on histaminergic functions in the brain, anorexia was found to be induced by either activation of HI-receptor or inhibition of H3-receptor in the ventromedial hypothalamic nucleus (VMH) or the paraventricular nucleus, each of which is a satiety center. Starvation activated neuronal histamine (HA) in the hypothalamus. Such energy deficit in turn accelerated glycogenolysis in the astrocytes to prevent brain functions from glucoprivation. Thus, intraneuronal glucoprivation in the brain increases satiety signals to produce anorexia through activation of hypothalamic HA neurons. The activation of HA system, on the other hand, accelerated and lipolysis peripherally through hyperglycemia activation of sympathetic nerve system, along with decrease in body temperature. Expressions of acyl CoA synthetase in the adipocytes and glucose transporter IV in the muscles were concomitantly suppressed. Central administration of corticotropin releasing hormone (CRH), a potent anorectic peptide, activated hypothalamic HA neurons, and activation of HA neurons ehhanced hypothalamic CRH expression. These findings imply one of the rationales for efficacy of a low-calorie diet as a therapeutic tool for weight reduction, and in addition, why patients with anorexia nervosa or malignant diseases hardly improve their emaciation.
Using Wistar SPFNAF male (350-450g) and Zucker obese (SOO-8OOg)rats , we investigated effects of leptin on the neuronal activity on the hypothalamus, the vagal hepatic afferent and sympathetic efferent from the both brown and white adipose tissues (BAT/WAT) under urethane anesthetized and brain-slice preparations. Low doses (l-10 pg) of leptin inhibited glucose-sensitive vagal hepatic afferent discharges, and sympathetic efferent discharges of BAT/WAT were facilitated. Indicate that the peripheral information might be sent ascending to the hypothalamus. Most of the neurons in the arcuate nucleus were significantly inhibited their neuronal activity by leptin (100 nmol-0.1 pmol). Electrophoretic applications of leptin to the feeding center (LHA), glucose-sensitive neurons (GSN) and non-GSNs were significantly inhibited. To the satiety center (VMH) neurons, most of the glucorecetor neurons were significantly excited. This deoolarization caused bv Na+/K+channel onening that co&irmed by whole ckll patch-clamp m&hod: The paraventricular nucleus neurons showed enhancement of neuronal activity by leptin. However, effects of leptin on these neuronal activity showed slightly or almost none in the Zucker obese rats. Results showed that leptin ascend lipotic information to the feeding related hypothalamic neurons, and mediated by signal transduction, through both the central and the peripheral nervous systems.
THE ROLE OF HYPOTHALAMIC MELANOCORTINS IN MEDIATING THE CNS EFFECTS OF LEPTIN R. J. Seeley Department of Psychiatry and GraduateProgram in Neuroscience, University of Cincinnati, Cincinnati, OH 452670559 USA
POLYAMINES, SPERMINE AND SPERMIDINE, MAY MODULATE TIIE DRUG - INDUCED GINGIVAL OVERGROWTH M. Costuleanu’, N. Costuleanu’, L. Foia2, M. Pave12, A. Costuleanu”, V. Saila4, C. Bohotin’, R. lancu’, N. Foma’
Leptin is released from adipocytes and circulates in proportion to total adipose mass. As such, it is ideally suited to provide afferent information to the CNS concerning the status of peripheral energy balance. The signaling form of the leptin receptor is found in its highest density in the arcuate nucleus of the hypothalamus on two populations of neurons. One set of neurons are those that express neuropeptide Y (NPY) and the other is a set of neurons that express proopiomelanocortin (POMC). Both sets of neurons are regulated by leptin, NPY expression is inhibited while POMC is stimulated. In particular, a strong role can be made for involvement of these arcuate nucleus POMC neurons in leptin action. One post-translational product of POMC is a-melanocyte stimulating hormone (aMSH). a-MSH is a ligand for melanocortin (MC) receptors that are found in the hypothalamus such as MC4. Genetic deletion of the MC4 receptor results in obesity CNS administration of a-MSH decreases food intake as do more specific agonists of the MC4 receptor. Specific antagonists of the MC4 receptor increase food intake. Finally, pretreatment with a dose of an MC4 antagonist that has no effect on food intake or body weight can completely block the effect of leptin to suppress food intake. Additionally, increased expression of c-Fos in the paraventricular nucleus of leptin treated animals is also completely blocked by pretreatment with an MC4 antagonist. These data are consistent with the hypothesis that the POMC/aMSWMC4 system is one important component of the CNS system that mediates the actions of leptin.
‘Department of Pathophysloloa, ‘Department of Biochemisq, ‘Department of P~s~ologv, ‘Department of Prosthetics, University of Medicine and Pharmacy “Gr. T. Popa”, lasi, ‘Department of Prosthetics, IJniversiv “Apollonia”, RO - 6600,Romania The development of drug - induced gingival overgrowth may depend on a series of local factors, including the polyamines, spermine and spermidine. Since the polyamines have been found in high quantities in gingival crevicular fluid, we aimed the modulation of nifedipine - induced gingival overgrowth by spermine and spermidine. Thus, we worked on male Wistar rats of 20 days. All the series received nifedipine 150 mg / kg body weight p.o. for 7 days and then 250 mg I kg body weight p.o. for 13 days and a sucrose rich diet. In addition, one series received spermine 3 mg / kg body weight p.o_ for 20 days and one series spermidine 3 mg ! kg body weight p.o. for 20 days. At the end of experiment, the mandible condils were excised and the depth of gingival sulcus was measured. Our results show that spermine reduced and spermidine had no significant effects on gingival overgrowth induced by nifedipine
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