Glucose-dependent insulinotropic peptide (GIP) is an intestinally secreted hormone the release of which is stimulated by nutrient ingestion. We previously reported that GIP receptors are present in osteoblastic cells and that GIP increases collagen type I synthesis and alkaline phosphatase activity in isolated osteoblasts. We have also shown that osteoclasts express GIP receptors and that GIP inhibits osteoclastic activity and differentiation. In addition, using GIP receptor knockout mice we demonstrated that absence of GIP receptor signaling resulted in a low bone mass phenotype. To further define GIP's role as an anabolic hormone in vivo, we utilized a genetically altered mouse model, a transgenic mouse overexpressing GIP under the control of the metallothionein promoter (Tg+). Tg+ mice had significantly higher mean GIP levels even in the absence of added dietary zinc. Tg+ animals also had a significant increase in markers of bone formation and a decrease in markers of bone resorption. Consistent with these biochemical data, GIP transgenic mice had a significant increase in bone mass as measured by densitometry and histomorphometry. These data support the conclusion that GIP inhibits bone resorption and stimulates bone formation and that excess signaling through the GIP receptor results in gain of bone mass. In view of GIP's role in nutrient absorption, our data suggest that this hormone may serve an important role in linking nutrient ingestion to bone formation.