title: Combined inhibition of PI3Kβ and PI3Kγ reduces fat mass by enhancing α-MSH-dependent sympathetic drive.
abstract: Obesity is defined as an abnormal increase in white adipose tissue and has become a major medical burden worldwide. Signals from the brain control not only appetite but also energy expenditure, both of which contribute to body weight. We showed that genetic or pharmacological inhibition of two phosphatidylinositol 3-kinases (PI3Kβ and PI3Kγ) in mice reduced fat mass by promoting increased energy expenditure. This effect was accompanied by stimulation of lipolysis and the acquisition of the energy-burning characteristics of brown adipocytes by white adipocytes, a process referred to as "browning." The browning of the white adipocytes involved increased norepinephrine release from the sympathetic nervous system. We found that PI3Kβ and PI3Kγ together promoted a negative feedback loop downstream of the melanocortin 4 receptor in the central nervous system, which controls appetite and energy expenditure in the periphery. Analysis of mice with drug-induced sympathetic denervation suggested that these kinases controlled the sympathetic drive in the brain. Administration of inhibitors of both PI3Kβ and PI3Kγ to mice by intracerebroventricular delivery induced a 10% reduction in fat mass as quickly as 10 days. These results suggest that combined inhibition of PI3Kβ and PI3Kγ might represent a promising treatment for obesity.
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy. alessia.perino@epfl.ch alexander.pfeifer@uni-bonn.de emilio.hirsch@unito.it.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy. Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Beretta
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Kilić
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, 00161 Rome, Italy. Department of Angiocardioneurology and Translational Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077 Pozzilli (IS), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Carnevale
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Turin, 10043 Turin, Italy.
authors.forename: Ivan Enrico
authors.initials: IE
authors.lastname: Repetto
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Braccini
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Longo
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Liebig-Gonglach
authors.affiliation: Venetian Institute of Molecular Medicine, University of Padova, 35129 Padova, Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Zaglia
authors.affiliation: Department of Angiocardioneurology and Translational Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077 Pozzilli (IS), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Iacobucci
authors.affiliation: Department of Biomedical Sciences and Venetian Institute of Molecular Medicine, University of Padova, 35121 Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mongillo
authors.affiliation: Department of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, 07745 Jena, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wetzker
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, D-07747 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Aime
authors.affiliation: Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, University of Turin, 10043 Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vercelli
authors.affiliation: Department of Molecular Medicine, "Sapienza" University of Rome, 00161 Rome, Italy. Department of Angiocardioneurology and Translational Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077 Pozzilli (IS), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany. alessia.perino@epfl.ch alexander.pfeifer@uni-bonn.de emilio.hirsch@unito.it.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy. alessia.perino@epfl.ch alexander.pfeifer@uni-bonn.de emilio.hirsch@unito.it.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D016475:3T3 Cells; D052438:Adipocytes, White / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000254:growth & development; D000818:Animals; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D007031:Hypothalamus / Q000033:anatomy & histology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D009765:Obesity / Q000201:enzymology* / Q000503:physiopathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013564:Sympathetic Nervous System / Q000502:physiology*; D000521:alpha-MSH / Q000378:metabolism*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D000521:alpha-MSH; D000242:Cyclic AMP