title: Oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics: Immunofluorescent localization in the mouse hypothalamus.
abstract: This study describes the localization of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics, in the hypothalamus of Swiss Webster and C57BL/6J wild-type mice, leptin-deficient ob/ob mice, and leptin-resistant diet-induced obese (DIO) mice. The mice were given [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in 0.3% dodecyl maltoside by oral gavage. Once peak serum concentrations were reached, the mice received a lethal dose of pentobarbital and were subjected to intracardiac perfusion fixation. The brains were excised, post-fixed in paraformaldehyde, and cryo-protected in sucrose. Free-floating frozen coronal sections were cut at 25-µm and processed for imaging by immunofluorescence microscopy. In all four strains of mice, dense staining was concentrated in the area of the median eminence, at the base and/or along the inner wall of the third ventricle, and in the brain parenchyma at the level of the arcuate nucleus. These results indicate that [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 cross the blood-brain barrier and concentrate in an area of the hypothalamus known to regulate energy balance and glucose homeostasis. Most noteworthy is the localization of [D-Leu-4]-OB3 immunoreactivity within the hypothalamus of DIO mice via a conduit that is closed to leptin in this rodent model, and in most cases of human obesity. Together with our previous studies describing the effects of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on energy balance, glucose regulation, and signal transduction pathway activation, these findings are consistent with a central mechanism of action for these synthetic peptide leptin mimetics, and suggest their potential usefulness in the management of leptin-resistant obesity and type 2 diabetes in humans.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Albany Medical College, Albany, NY 12208, USA; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Anderson
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Jacobson
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Novakovic
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Albany Medical College, Albany, NY 12208, USA; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA. Electronic address: grassop@mail.amc.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Grasso
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001812:Blood-Brain Barrier / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007031:Hypothalamus / Q000737:chemistry* / Q000276:immunology; D020738:Leptin / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics*; D008297:Male; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics*
chemical_list: D000906:Antibodies; D020738:Leptin; D010446:Peptide Fragments; C410793:leptin (116-130)
keywords: Blood-brain barrier; Diabetes; Diet-induced obesity; Leptin mimetics; Leptin resistance