title: Lentivirus-mediated α-melanocyte-stimulating hormone overexpression in the hypothalamus decreases diet induced obesity in mice.
abstract: Melanocyte stimulating hormone (MSH) derived from the pro-hormone pro-opiomelanocortin (POMC) has potent effects on metabolism and feeding that lead to reduced body weight in the long-term. To determine the individual roles of POMC derived peptides and their sites of action, we created a method for the delivery of single MSH peptides using lentiviral vectors and studied the long-term anti-obesity effects of hypothalamic α-MSH overexpression in mice. An α-MSH lentivirus (LVi-α-MSH-EGFP) vector carrying the N'-terminal part of POMC and the α-MSH sequence was generated and shown to produce bioactive peptide in an in vitro melanin synthesis assay. Stereotaxis was used to deliver the LVi-α-MSH-EGFP or control LVi-EGFP vector to the arcuate nucleus (ARC) of the hypothalamus of male C57Bl/6N mice fed on a high-fat diet. The effects of 6-week-treatment on body weight, food intake, glucose tolerance and organ weights were determined. Additionally, a 14-day pairfeeding study was conducted to assess whether the weight decreasing effect of the LVi-α-MSH-EGFP treatment is dependent on decreased food intake. The 6-week LVi-α-MSH-EGFP treatment reduced weight gain (8.4 ± 0.4 g versus 12.3 ± 0.6 g; P < 0.05), which was statistically significant starting from 1 week after the injections. The weight of mesenteric fat was decreased and glucose tolerance was improved compared to LVi-EGFP treated mice. Food intake was decreased during the first week in the LVi-α-MSH-EGFP treated mice but subsequently increased to the level of LVi-EGFP treated mice. The LVi-EGFP injected control mice gained more weight even when pairfed to the level of food intake by LVi-α-MSH-EGFP treated mice. We demonstrate that gene transfer of α-MSH, a single peptide product of POMC, into the ARC of the hypothalamus, reduces obesity and improves glucose tolerance, and that factors other than decreased food intake also influence the weight decreasing effects of α-MSH overexpression in the ARC. Furthermore, viral MSH vectors delivered stereotaxically provide a novel tool for further exploration of chronic site-specific effects of POMC peptides.
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland.|Turku Centre for Biotechnology, University of Turku, Turku, Finland.|FinPharma Doctoral Program, Drug Discovery Section, Turku, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Eerola
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland.
authors.forename: W
authors.initials: W
authors.lastname: Nordlund
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland.|Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Virtanen
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland.|Turku PET Centre, Medicity/PET Preclinical Imaging, University of Turku, Turku, Finland.
authors.forename: A M
authors.initials: AM
authors.lastname: Dickens
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Mattila
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland.
authors.forename: S T
authors.initials: ST
authors.lastname: Ruohonen
authors.affiliation: Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Chua
authors.affiliation: Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Wardlaw
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.|Turku Heart Center, Turku University Hospital and University of Turku, Turku, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Savontaus
authors.affiliation: Department of Pharmacology, Drug Development and Therapeutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland.|Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Savontaus
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004032:Diet; D005951:Glucose Tolerance Test; D007031:Hypothalamus / Q000378:metabolism*; D016086:Lentivirus / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000517:prevention & control*; D000521:alpha-MSH / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D000521:alpha-MSH
keywords: POMC; mice; neuropeptides; obesity; α-MSH