TY - JOUR

T1 - Energy expenditure and bone formation share a common sensitivity to AP-1 transcription in the hypothalamus

AU - Rowe, Glenn C

AU - Vialou, Vincent

AU - Sato, Kazusa

AU - Saito, Hiroaki

AU - Yin, Min

AU - Green, Thomas A

AU - Lotinun, Sutada

AU - Kveiborg, Marie

AU - Horne, William C

AU - Nestler, Eric J

AU - Baron, Roland

N1 - Copyright © 2012 American Society for Bone and Mineral Research.

PY - 2012

Y1 - 2012

N2 - The regulation of bone and fat homeostasis and its relationship to energy expenditure has recently been the focus of increased attention due to its potential relevance to osteoporosis, obesity and diabetes. Although central effectors within the hypothalamus have been shown to contribute to the regulation of both energy balance and bone homeostasis, little is known of the underlying mechanisms, including the possible involvement of transcriptional factors within the hypothalamus. Transgenic mice overexpressing ¿FosB, a splice variant of the AP1 transcription factor FosB with mixed agonist-antagonistic properties, have increased energy expenditure and bone mass. Since these mice express ¿FosB in bone, fat and hypothalamus, we sought to determine 1) whether overexpression of ¿FosB within the hypothalamus was sufficient to regulate energy expenditure and whether it would also regulate bone mass, and 2) whether these effects were due to antagonism to AP1. Our results show that stereotactic injection of an adeno-associated virus vector to restrict overexpression of ¿FosB to the ventral hypothalamus of wildtype mice induced a profound increase in both energy expenditure and bone formation and bone mass. This effect was phenocopied, at an even stronger level, by overexpressiong of a dominant-negative DNJunD, a pure AP1 antagonist. Taken together these results suggest that downregulation of AP1 activity in the hypothalamus profoundly increases energy expenditure and bone formation, leading to both a decrease in adipose mass and an increase in bone mass. These findings may have physiological implications since ¿FosB is expressed and regulated in the hypothalamus. © 2012 American Society for Bone and Mineral Research.

AB - The regulation of bone and fat homeostasis and its relationship to energy expenditure has recently been the focus of increased attention due to its potential relevance to osteoporosis, obesity and diabetes. Although central effectors within the hypothalamus have been shown to contribute to the regulation of both energy balance and bone homeostasis, little is known of the underlying mechanisms, including the possible involvement of transcriptional factors within the hypothalamus. Transgenic mice overexpressing ¿FosB, a splice variant of the AP1 transcription factor FosB with mixed agonist-antagonistic properties, have increased energy expenditure and bone mass. Since these mice express ¿FosB in bone, fat and hypothalamus, we sought to determine 1) whether overexpression of ¿FosB within the hypothalamus was sufficient to regulate energy expenditure and whether it would also regulate bone mass, and 2) whether these effects were due to antagonism to AP1. Our results show that stereotactic injection of an adeno-associated virus vector to restrict overexpression of ¿FosB to the ventral hypothalamus of wildtype mice induced a profound increase in both energy expenditure and bone formation and bone mass. This effect was phenocopied, at an even stronger level, by overexpressiong of a dominant-negative DNJunD, a pure AP1 antagonist. Taken together these results suggest that downregulation of AP1 activity in the hypothalamus profoundly increases energy expenditure and bone formation, leading to both a decrease in adipose mass and an increase in bone mass. These findings may have physiological implications since ¿FosB is expressed and regulated in the hypothalamus. © 2012 American Society for Bone and Mineral Research.

U2 - 10.1002/jbmr.1618

DO - 10.1002/jbmr.1618

M3 - Journal article

C2 - 22461201

VL - 27

SP - 1649

EP - 1658

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 8

ER -