title: Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers.
abstract: Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Hwan-Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Haeli
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Semple
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Insook
authors.initials: I
authors.lastname: Jang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Cazares
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Stuenkel
authors.affiliation: School of Computer Engineering, Nanyang Technological University, Singapore 639798, Singapore.
authors.forename: Jung-Jae
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: 1] Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul 140-743, Republic of Korea.
authors.forename: Jeong Sig
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004452:Echocardiography; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008247:Lysosomes / Q000378:metabolism*; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D009765:Obesity / Q000150:complications*; D010588:Phagosomes / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D014700:Verapamil; D002118:Calcium