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 ΔFosB, 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 ΔFosB 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 ΔFosB 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.
Highlights
For the past few decades, obesity and its closely associated co-morbidities, such as type II diabetes mellitus have shown a steady rise among all age groups, from the adolescents to elderly
We have shown that restricted expression of ΔFosB in the ventral hypothalamus (VHT), which comprises, among others, Arcuate Nucleus (ARC) and Paraventricular Nucleus (PVN) nuclei, exerts beneficial effects on bone [17,18,19,20], and on metabolic homeostasis, both in terms of glucose metabolism and adiposity, which persist with aging
One of the most striking effects of ΔFosB expression in the VHT is the extreme reduction in the size of pancreatic islets, which occurs in parallel with the marked decrease in insulin secretion in response to glucose
Summary
For the past few decades, obesity and its closely associated co-morbidities, such as type II diabetes mellitus have shown a steady rise among all age groups, from the adolescents to elderly. While many peripheral metabolism regulating sites, such as pancreas and liver have been well studied, the central pathways, sensing glucose and affecting insulin production, feeding and energy expenditure, remain discordantly less explored. Neurons and astroglia express high levels of GLUT2 and low affinity www.aging‐us.com hexokinase, which allows them to sense glucose and the ATP/AMP ratio [10,11]. This sensing leads to a rapid cessation of feeding following intraventricular injection of glucose, via excitation or inhibition of neuronal activity [12]
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