title: Leptin gene transfer in the hypothalamus enhances longevity in adult monogenic mutant mice in the absence of circulating leptin.
abstract: Leptin, a product of the ob gene, is a pleiotropic signal implicated in regulation of multiple physiological functions in the periphery and centrally, including hypothalamic integration of energy homeostasis. Recessive mutations of ob gene result in early onset of hyperphagia, morbid obesity, metabolic disorders, early mortality and shortened life-span. Intracerebroventricular injection of recombinant adeno-associated virus vector (rAAV) encoding the leptin gene in adult obese ob/ob mice enhanced leptin transgene expression only in the hypothalamus, normalized food intake, body weight and more than doubled the life-span as compared to control cohorts and extended it to near that of normal wild type mice. These life-extending benefits were associated with drastic reductions in visceral fat, and blood glucose and insulin levels, but elevated ghrelin levels, the anti-aging biomarkers. Thus, bioavailability of leptin transduced by ectopic gene in the hypothalamus alone is both necessary and sufficient to normalize life-span. Evidently, site-specific ectopic gene expression with rAAV is durable and safe for alleviating neural disorders that stem from missing or functional disruption of a single gene.
authors.affiliation: Department of Neuroscience, University of Florida McKnight Brain Institute, Gainesville, FL, USA.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Boghossian
authors.forename: Naohiko
authors.initials: N
authors.lastname: Ueno
authors.forename: Michael G
authors.initials: MG
authors.lastname: Dube
authors.forename: Pushpa
authors.initials: P
authors.lastname: Kalra
authors.forename: Satya
authors.initials: S
authors.lastname: Kalra
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001069:Appetite Regulation / Q000235:genetics; D001786:Blood Glucose / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D054439:Ghrelin; D006963:Hyperphagia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D007031:Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D036361:Peptide Hormones / Q000097:blood
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D020738:Leptin; D036361:Peptide Hormones