title: Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress.
abstract: The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vernia
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Caroline
authors.initials: C
authors.lastname: Morel
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States.|Harvard Medical School, Boston, United States.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Madara
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Cavanagh-Kyros
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Tamera
authors.initials: T
authors.lastname: Barrett
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chase
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Kennedy
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, United States.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States.
authors.forename: Richard A
authors.identifier: http://orcid.org/0000-0003-4461-0778
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States.|Harvard Medical School, Boston, United States.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Roger J
authors.identifier: http://orcid.org/0000-0002-0130-1652
authors.initials: RJ
authors.lastname: Davis
mesh_terms: D054369:Agouti-Related Protein / Q000032:analysis; D000818:Animals; D059305:Diet, High-Fat; D006963:Hyperphagia; D051379:Mice; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10 / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D013312:Stress, Physiological
chemical_list: D054369:Agouti-Related Protein; D048057:Mitogen-Activated Protein Kinase 10
keywords: JNK; cell biology; leptin; mouse; neuroscience; satiety; signal transduction