Low bone strength in overweight individuals is a significant medical problem. One important determinant of mesenchymal stem cell fate into osteoblasts or adipocytes is the Wnt signaling pathway. We recently showed that Dickkopf-1 (DKK1), a potent Wnt inhibitor, is upregulated in obese mice. In this study, we investigated the role of DKK1 in the pathogenesis of obesity-induced bone loss using global and tissue-specific KO mice. Obesity was induced in 8-week-old male mice with an inducible global (Rosa26-CreERT2) or osteoprogenitor- (Osx-Cre-) specific deletion of Dkk1 with a high-fat diet (HFD) containing 60% fat. After 12 weeks, body weight, bone volume, bone fat mass, and bone turnover were assessed. Dkk1 fl/fl ;Rosa26-CreERT2 mice experienced a similar increase in body weight and white fat pads as control mice. A HFD significantly reduced trabecular bone mass and the bone formation rate in Cre- mice and Dkk1 fl/fl ;Rosa26-CreERT2 mice. Interestingly, Dkk1 fl/fl ;Rosa26-CreERT2 mice were protected from HFD-induced cortical bone loss. Furthermore, a HFD was associated with increased bone marrow fat in the femur, which was less pronounced in Dkk1 fl/fl ;Rosa26-CreERT2 mice. Mice with an osteoprogenitor-specific Dkk1 deletion showed similar results as the global knockout, showing a protection against HFD-induced cortical bone loss and an accumulation of bone marrow fat, but a similar decrease in trabecular bone volume. In summary, DKK1 appears to contribute distinctly to cortical, but not trabecular bone loss in obesity. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.