Differential effects of high-fat diet and exercise training on bone and energy metabolism

Abstract Bone microarchitectureand strength are impaired by obesity and physical inactivity, but the underlying molecular regulation of bone metabolism in response to these factors is not well understood. Therefore, we analyzed bone and energy metabolism in male mice fed a high-fat or standard chow diet for 12 weeks with or without free access to running wheels. High-fat diet (HFD) mimicked the human conditionof obesity and insulin resistance, including symptoms such as elevated serum glucose and insulin levels and reduced insulin-stimulated glucose uptakeinto muscle and adipose tissue. Interestingly, HFD also decreased (−44%) glucose uptakeinto bone marrow. Bone mass was reduced (−45%) by HFD due to a diminished (−45%) bone remodelingrate. Bone matrix quality aspects, such as biomechanical stability, were additionally decreased. Concurrently, the bone marrowadiposity increased (+63%) in response to a HFD. Further, we detected elevated expression of the Wnt signaling inhibitor dickkopf-1 (Dkk-1, +42%) in mice fed a HFD, but this was not reflected in serum samples obtained from obese humans. In mice, exercise attenuated the adverse effects of HFD by reversing the glucose uptakeinto bone marrow, improving the bone mass and bone matrix quality while decreasing the bone marrowadiposity. This data shows that exercise prevents some, but not all of the negative effects of HFD on bone healthand suggests that insulin signaling in bone marrowand Dkk-1 signaling may be involved in the pathogenesis of bone loss induced by HFD.