title: Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling.
abstract: Leptin regulates energy balance. However, knowledge of the critical intracellular transducers of leptin signaling remains incomplete. We found that Rho-kinase 1 (ROCK1) regulates leptin action on body weight homeostasis by activating JAK2, an initial trigger of leptin receptor signaling. Leptin promoted the physical interaction of JAK2 and ROCK1, thereby increasing phosphorylation of JAK2 and downstream activation of Stat3 and FOXO1. Mice lacking ROCK1 in either pro-opiomelanocortin (POMC) or agouti-related protein neurons, mediators of leptin action, displayed obesity and impaired leptin sensitivity. In addition, deletion of ROCK1 in the arcuate nucleus markedly enhanced food intake, resulting in severe obesity. Notably, ROCK1 was a specific mediator of leptin, but not insulin, regulation of POMC neuronal activity. Our data identify ROCK1 as a key regulator of leptin action on energy homeostasis.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Huang
authors.forename: Dong
authors.initials: D
authors.lastname: Kong
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Byun
authors.forename: Chianping
authors.initials: C
authors.lastname: Ye
authors.forename: Shuichi
authors.initials: S
authors.lastname: Koda
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Oh
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.forename: Bonghee
authors.initials: B
authors.lastname: Lee
authors.forename: Janice M
authors.initials: JM
authors.lastname: Zabolotny
authors.forename: Min Seon
authors.initials: MS
authors.lastname: Kim
authors.forename: Christian
authors.initials: C
authors.lastname: Bjørbæk
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D054369:Agouti-Related Protein / Q000502:physiology; D000818:Animals; D001069:Appetite Regulation / Q000235:genetics / Q000502:physiology; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D002478:Cells, Cultured; D004435:Eating; D004734:Energy Metabolism / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D054411:Receptors, Leptin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D054369:Agouti-Related Protein; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D011333:Pro-Opiomelanocortin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D054460:rho-Associated Kinases