Appetite suppression and weight reduction by a centrally active aminosterol.
The rise in obesity and its complications has generated enormous interest in the regulation of feeding and body weight. We show that a spermine metabolite of cholesterol (MSI-1436) decreases body weight, specifically fat, by suppressing feeding and preventing the reduction in energy expenditure, hormonal changes, and patterns of neuropeptide expression normally associated with weight loss. MSI-1436 enters the brain after peripheral injection and is more potent when injected into the cerebral ventricle (intracerebroventricular [ICV]). Systemic or ICV MSI-1436 administration induced similar patterns of Fos immunoreactivity in the brain, especially the paraventricular hypothalamic nucleus (PVN). This brain region integrates neural signals from hypothalamic and brain stem nuclei and regulates feeding behavior, autonomic function, and neuroendocrine function. Microinjection of MSI-1436 into the PVN potently suppressed feeding and reduced body weight for several days. Unlike caloric restriction, MSI-1436 decreased mRNA levels of agouti-related peptide and neuropeptide Y in the hypothalamus. These findings indicate that MSI-1436 acts in the brain to regulate food intake and energy expenditure, likely through suppression of orexigenic hypothalamic pathways.
Ahima
Rexford S
RS
Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania School of Medicine, 764 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA. ahima@mail.med.upenn.edu
Patel
Hiralben R
HR
Takahashi
Nobuhiko
N
Qi
Yong
Y
Hileman
Stanley M
SM
Zasloff
Michael A
MA
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D002776:Cholestanes / Q000008:administration & dosage / Q000494:pharmacology*; D002777:Cholestanols / Q000008:administration & dosage / Q000494:pharmacology; D002149:Energy Intake / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects*
C441128:3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate; D016588:Anticarcinogenic Agents; D001067:Appetite Depressants; D002776:Cholestanes; D002777:Cholestanols; D016760:Proto-Oncogene Proteins c-fos; D013096:Spermine; C079655:squalamine