ABSTRACT
BACKGROUND AND PURPOSE: Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti-obesity effects of MCH1 receptor antagonists. EXPERIMENTAL APPROACH: To examine the mechanisms of action of the anti-obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair-feeding study in mice with diet-induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions. KEY RESULTS: Treatment with the MCH1 receptor antagonist at 30 mg.kg(-1) for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair-feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair-fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis. CONCLUSIONS AND IMPLICATIONS: Our results indicate that an MCH1 receptor antagonist caused anti-obesity effects im mice by acting on both energy intake and energy expenditure.
Subject(s)
Anti-Obesity Agents/pharmacology , Pyridones/pharmacology , Pyrrolidines/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Anti-Obesity Agents/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Eating/drug effects , Energy Metabolism/drug effects , Humans , Liver/drug effects , Liver/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Pyridones/pharmacokinetics , Pyrrolidines/pharmacokinetics , RNA, Messenger/biosynthesis , Radioligand Assay , Rats , Receptors, Somatostatin/biosynthesis , Receptors, Somatostatin/genetics , Thermogenesis/drug effectsABSTRACT
BACKGROUND AND PURPOSE: Melanin-concentrating hormone (MCH) is a cyclic orexigenic neuropeptide predominantly expressed in the lateral hypothalamus. We investigated the roles of MCH1 receptor signalling in ovariectomy (OVX)-induced obesity in female C57BL/6J mice, an animal model of postmenopausal obesity. EXPERIMENTAL APPROACH: The effects of blocking signalling via the MCH1 receptor on OVX-induced obesity was investigated by using Mch1r deficient (KO) mice and chronic treatment with a selective MCH1 receptor antagonist. KEY RESULTS: OVX induced body weight gain and increases in the weight of visceral fat and of liver; these effects were attenuated following OVX in Mch1r KO mice. OVX-induced triglyceride (TG) accumulation and elevated expression of lipogenic genes were significantly ameliorated in the liver of Mch1r KO mice. In agreement with these results, chronic i.c.v. infusion of a selective MCH1 receptor antagonist significantly reduced body weight gain, visceral fat and liver weights in OVX mice, and hepatic TG contents and lipogenic gene expression levels were normalized. CONCLUSION AND IMPLICATIONS: Our results indicate that MCH1 receptor signalling is involved in the development of fatty liver, as well as obesity, in OVX mice, and suggest a therapeutic potential for MCH1 receptor antagonists in the treatment of obesity and fatty liver.
Subject(s)
Fatty Liver/drug therapy , Obesity/drug therapy , Receptors, Somatostatin/genetics , Animals , Disease Models, Animal , Drug Design , Fatty Liver/physiopathology , Female , Gene Expression Regulation/drug effects , Lipogenesis/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Obesity/physiopathology , Ovariectomy , Postmenopause , Random Allocation , Receptors, Somatostatin/antagonists & inhibitors , Signal Transduction/drug effects , Signal Transduction/physiology , Triglycerides/metabolism , Weight Gain/drug effectsABSTRACT
Glossopharyngeal neuralgia is an uncommon craniofacial pain syndrome. An association with syncope is even less common. We report a case illustrating that the glossopharyngeal neuralgia-syncope syndrome can occur without pain in the sensory distribution of the glossopharyngeal nerve and that it can have similar consequences. We suggest that permanent cardiac pacing alone may be a viable option in the initial management of such cases.
Subject(s)
Glossopharyngeal Nerve/pathology , Neuralgia/complications , Syncope/complications , Aged , Cerebral Angiography , Electroencephalography , Female , Glossopharyngeal Nerve/physiopathology , Humans , Neuralgia/physiopathology , Pacemaker, Artificial , Syncope/physiopathology , Syncope/therapyABSTRACT
A 41-year-old man presented with bilateral posterior cerebral artery infarcts. He had visual object agnosia and prosopagnosia with preservation of reading abilities. There was also defective visual memory, topographic orientation, and color perception, as well as simultanagnosia. From the clinical facts and CT findings, it was postulated that bilateral visual-limbic disconnection accounted for the patient's visual agnosia and related disturbances.
Subject(s)
Agnosia/complications , Dyslexia, Acquired/complications , Vision Disorders/complications , Adult , Agnosia/psychology , Dyslexia, Acquired/psychology , Humans , Male , Psychological Tests , Vision Disorders/psychologyABSTRACT
We report a 59 year old woman who presented with double vision, nuchal pain and mild dementia. On neurological examination she demonstrated third, sixth and seventh nerve palsies and ataxia. Following intravenous ACTH and oral prednisone therapy she showed a remarkable recovery which left her with only a left facial weakness. She remained well for two years. She then developed bulbar palsy and profound dementia. Pathological examination revealed progressive supranuclear palsy (PSP). This patient demonstrated a greater variability in the course of PSP than has previously been recognized.
Subject(s)
Bulbar Palsy, Progressive/pathology , Adrenocorticotropic Hormone/therapeutic use , Brain/pathology , Brain/ultrastructure , Bulbar Palsy, Progressive/drug therapy , Bulbar Palsy, Progressive/physiopathology , Female , Humans , Middle Aged , Prednisone/therapeutic useABSTRACT
The serum 25-OHD3 concentrations were measured in 16 normal subjects and in 12 haemodialysed patients with chronic renal failure. The mean values found in the two groups were 27.8 +/- 17.8 ng/ml and 23.9 +/- 12 ng/ml, respectively. The difference between the two values is not significant.
