The impact of metabolic stress induced by obesity on the bone marrow niche during melanoma growth and metastasis is largely unknown. Here we employed diet induced obese mouse models, where mice received high-fat (HFD) or normal diet (ND) for 6 weeks before challenge with B16F10 melanoma cells. Tumor size, bone loss and osteoclast numbers were assessed histologically in the tibial bones. For defining the molecular pathway, osteopontin (OPN) knock-out mice, interleukin (IL) 6 neutralizing antibody or Janus kinase (JAK) 2 inhibition was carried out in the same model. Mechanistic studies such as adipocyte-melanoma co-cultures for defining adipocyte induced changes of tumor cell proliferation and expression profiles were also performed. Moreover, bone marrow derived monocyte-melanoma co-cultures were set up to define circulating factors present in HFD mice induced activation of osteoclasts. In addition, the effects of systemic factors from HFD mice on B16F10 melanoma cells were also evaluated in vitro. As results, HFD enhanced melanoma burden in bone by increasing tumor area and osteoclast numbers. This process was associated with higher numbers of bone marrow adipocytes expressing IL-6 in direct vicinity to tumor cells. Inhibition of IL-6 or of its downstream signalling JAK2 blocked HFD-induced tumor progression. In addition, circulating factors present in HFD mice enhanced melanoma cell proliferation and migration, activated nuclear factor-κB (NF-κB) signalling, and upregulated its downstream targets, such as chemokine (C-X-C motif) ligands (CXCLs) and adhesion and angiogenesis molecules in melanoma cells in vitro. The phenotypic changes of melanoma cells triggered macrophage and osteoclast accumulations accompanied by increased osteopontin expression and CD31+ cells in the bone melanoma niche. In addition, melanoma cells pre-treated with HFD serum increased osteoclastogenesis in an OPN dependent manner in vitro. Furthermore, OPN triggered osteoclastogenesis and also exerted a positive feedback loop to tumor cells, which was abrogated in its absence in vivo and in vitro. Moreover, melanoma cells became more “aggressive” in the presence of bone marrow adipocytes, whereas the latter underwent a dedifferentiation process into preadipocytes with upregulation of CXCLs and pro-inflammatory genes. Therefore, the bone marrow adipocytes, macrophages/osteoclasts and CD31+ cells constitute a stroma rich environment for melanoma cells in the bone marrow by HFD. Metabolic stress by HFD promotes melanoma cell growth in the bone marrow niche by an increase in IL-6-JAK2-osteopontin mediated activation of tumor cells and osteoclast differentiation.