Combined inhibition of PI3Kβ and PI3Kγ reduces fat mass by enhancing α-MSH-dependent sympathetic drive
| Autor: | Daniela Carnevale, Giuseppe Lembo, Laura Braccini, Alessandra Ghigo, Michael Bauer, Reinhard Wetzker, Alessandro Vercelli, Dario Livio Longo, Alessia Perino, Emilio Hirsch, Marco Mongillo, Alexander Pfeifer, Ana Kilić, Martina Beretta, Ivan Enrico Repetto, Tania Zaglia, Silvio Aime, Roberta Iacobucci, Michaela Liebig-Gonglach |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Sympathetic nervous system
Sympathetic Nervous System Adipocytes White Adipose tissue Fluorescent Antibody Technique Stimulation White White adipose tissue Biochemistry Mice Phosphatidylinositol 3-Kinases Adipocytes Cyclic AMP Gene Knock-In Techniques In Situ Hybridization Phosphoinositide-3 Kinase Inhibitors media_common Feedback Physiological Blotting Statistics 3T3 Cells Immunohistochemistry Melanocortin 4 receptor medicine.anatomical_structure Adipose Tissue Animals Blotting Western Energy Metabolism Hypothalamus Immunoprecipitation Lipolysis Obesity Real-Time Polymerase Chain Reaction Statistics Nonparametric alpha-MSH Western medicine.drug medicine.medical_specialty media_common.quotation_subject Physiological Biology Feedback Norepinephrine Internal medicine medicine Nonparametric Molecular Biology Appetite Cell Biology Endocrinology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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