title: Hypothalamic ΔFosB prevents age-related metabolic decline and functions via SNS.
abstract: The ventral hypothalamus (VHT) integrates several physiological cues to maintain glucose homeostasis and energy balance. Aging is associated with increased glucose intolerance but the underlying mechanisms responsible for age-related metabolic decline, including neuronal signaling in the VHT, remain elusive. We have shown that mice with VHT-targeted overexpression of ∆FosB, a splice variant of the AP1 transcription factor FosB, exhibit increased energy expenditure, leading to decreased adiposity. Here, we show that VHT-targeted overexpression of ∆FosB also improves glucose tolerance, increases insulin sensitivity in target organs and thereby suppresses insulin secretion. These effects are also observed by the overexpression of dominant negative JunD, demonstrating that they occur via AP1 antagonism within the VHT. Furthermore, the improved glucose tolerance and insulin sensitivity persisted in aged animals overexpressing ∆FosB in the VHT. These beneficial effects on glucose metabolism were abolished by peripheral sympathectomy and α-adrenergic, but not β-adrenergic, blockade. Taken together, our results show that antagonizing AP1 transcription activity in the VHT leads to a marked improvement in whole body glucose homeostasis via activation of the SNS, conferring protection against age-related impairment in glucose metabolism. These findings may open novel avenues for therapeutic intervention in diabetes and age-related glucose intolerance.
authors.affiliation: Department of Medicine, Harvard Medical School and Endocrine Unit MGH, and Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Kazusa
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Medicine, Harvard Medical School and Endocrine Unit MGH, and Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Idelevich
authors.affiliation: Department of Medicine, Harvard Medical School and Endocrine Unit MGH, and Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagano
authors.affiliation: Department of Medicine, Harvard Medical School and Endocrine Unit MGH, and Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: Department of Medicine, Harvard Medical School and Endocrine Unit MGH, and Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gori
authors.affiliation: Department of Medicine, Harvard Medical School and Endocrine Unit MGH, and Division of Bone and Mineral Metabolism, Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
mesh_terms: D050154:Adiposity / Q000502:physiology; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D018149:Glucose Intolerance / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos
keywords: SNS; aging; glucose; hypothalamus; ΔFosB