Hypothalamic ΔFosB prevents age-related metabolic decline and functions via SNS
| Autor: | Anna Idelevich, Francesca Gori, Kenichi Nagano, Glenn C. Rowe, Kazusa Sato, Roland Baron |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Blood Glucose medicine.medical_specialty Aging Sympathetic Nervous System Hypothalamus 030209 endocrinology & metabolism Carbohydrate metabolism SNS 03 medical and health sciences Mice 0302 clinical medicine Internal medicine Diabetes mellitus Glucose Intolerance medicine Glucose homeostasis Animals Homeostasis glucose Transcription factor Adiposity Chemistry Cell Biology medicine.disease Blockade AP-1 transcription factor 030104 developmental biology Endocrinology ΔFosB Insulin Resistance Energy Metabolism Proto-Oncogene Proteins c-fos FOSB Research Paper |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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