title: Dynamin-Related Protein 1-Dependent Mitochondrial Fission Changes in the Dorsal Vagal Complex Regulate Insulin Action.
abstract: Mitochondria undergo dynamic changes to maintain function in eukaryotic cells. Insulin action in parallel regulates glucose homeostasis, but whether specific changes in mitochondrial dynamics alter insulin action and glucose homeostasis remains elusive. Here, we report that high-fat feeding in rodents incurred adaptive dynamic changes in mitochondria through an increase in mitochondrial fission in parallel to an activation of dynamin-related protein 1 (Drp1) in the dorsal vagal complex (DVC) of the brain. Direct inhibition of Drp1 negated high-fat-feeding-induced mitochondrial fission, endoplasmic reticulum (ER) stress, and insulin resistance in the DVC and subsequently restored hepatic glucose production regulation. Conversely, molecular activation of DVC Drp1 in healthy rodents was sufficient to induce DVC mitochondrial fission, ER stress, and insulin resistance. Together, these data illustrate that Drp1-dependent mitochondrial fission changes in the DVC regulate insulin action and suggest that targeting the Drp1-mitochondrial-dependent pathway in the brain may have therapeutic potential in insulin resistance.
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Filippi
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Mona A
authors.initials: MA
authors.lastname: Abraham
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Pamuditha N
authors.initials: PN
authors.lastname: Silva
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada.
authors.forename: Mozhgan
authors.initials: M
authors.lastname: Rasti
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Mary P
authors.initials: MP
authors.lastname: LaPierre
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Paige V
authors.initials: PV
authors.lastname: Bauer
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Jonathan V
authors.initials: JV
authors.lastname: Rocheleau
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON M5G 2C4, Canada. Electronic address: tony.lam@uhnres.utoronto.ca.
authors.forename: Tony K T
authors.initials: TKT
authors.lastname: Lam
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D059305:Diet, High-Fat; D034281:Dynamins / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: dorsal vagal complex; dynamin-related protein 1; insulin resistance; mitochondrial fission