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Increased Energy Expenditure and Insulin Sensitivity in the High Bone Mass FosB Transgenic Mice

Department of Orthopaedics (G.C.R., L.N., W.C.H., R.B.) and Internal Medicine and Cellular and Molecular Physiology (C.S.C., G.I.S.) and Howard Hughes Medical Institute (G.I.S.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Dr. Roland Baron, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, Massachusetts 02115. E-mail: roland_baron{at}hsdm.harvard.edu.

Obesity and osteoporosis are major health issues affecting millions of individuals. Transgenic mice overexpressing FosB, an activator protein-1 transcription factor, under the control of the enolase 2 (ENO2) promoter exhibit both an increase in bone density and a decrease in adipose mass. Here we demonstrate that FosB overexpression increases fatty-acid oxidation and energy expenditure, leading to a decrease in adipocyte size and adipose mass. In addition, the ENO2-FosB mice exhibit increased insulin sensitivity and glucose tolerance. Targeted overexpression of FosB in adipocytes using the adipocyte protein 2 promoter failed to induce changes in fat or in bone, showing that the effect on metabolic activity is not due to cell-autonomous effects of FosB within adipocytes. Detailed analysis of the ENO2-FosB mice demonstrated that energy expenditure was increased in muscle, independent of locomotor activity. These findings provide evidence that signaling downstream of FosB is a potential target for not only osteoporosis but also obesity and diabetes.