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

Authors

  • Glenn C Rowe,

    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Current affiliation:
    1. Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
    Search for more papers by this author
  • Vincent Vialou,

    1. Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA
    Search for more papers by this author
  • Kazusa Sato,

    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Search for more papers by this author
  • Hiroaki Saito,

    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Search for more papers by this author
  • Min Yin,

    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Search for more papers by this author
  • Thomas A Green,

    1. Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA
    Current affiliation:
    1. Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX, USA.
    Search for more papers by this author
  • Sutada Lotinun,

    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Search for more papers by this author
  • Marie Kveiborg,

    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Current affiliation:
    1. Department of Biomedical Sciences and Biotech Research & Innovation Center, University of Copenhagen, Copenhagen, Denmark.
    Search for more papers by this author
  • William C Horne,

    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    Search for more papers by this author
  • Eric J Nestler,

    1. Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, USA
    Search for more papers by this author
  • Roland Baron

    Corresponding author
    1. Department of Medicine, Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, and Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA
    • Department of Oral Medicine, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
    Search for more papers by this author

Abstract

The regulation of bone and fat homeostasis and its relationship to energy expenditure has recently been the focus of increased attention because of 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 ΔFosB, a splice variant of the AP-1 transcription factor FosB with mixed agonist-antagonistic properties, have increased energy expenditure and bone mass. Because these mice express ΔFosB in bone, fat, and hypothalamus, we sought to determine 1) whether overexpression of ΔFosB within the hypothalamus was sufficient to regulate energy expenditure and whether it would also regulate bone mass, and 2) whether these effects were the result of antagonism to AP-1. Our results show that stereotactic injection of an adeno-associated virus vector to restrict overexpression of ΔFosB to the ventral hypothalamus of wild-type 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 overexpression of a dominant-negative DNJunD, a pure AP-1 antagonist. Taken together, these results suggest that downregulation of AP-1 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 because ΔFosB is expressed and regulated in the hypothalamus. © 2012 American Society for Bone and Mineral Research.

Ancillary