Individuals with type 2 diabetes are at higher risk of osteoporosis and major bone fractures independent of their body mass index (BMI). Bone marrow derived mesenchymal stem/ stromal cells (BMSC) that are obtained from these patients show reduced osteogenic potential and increased cell death. Currently, it is not known how high fat/glucose levels can suppress BMSC osteogenic differentiation potential however we envisage that diet impacts epigenetic regulators in BMSC. The present project examined the epigenetic mechanisms regulating BMSC dysfunction in response to high fat/glucose to identify targets for reversing high fat-mediated bone loss, aging and diseases. We hypothesize that high fat/glucose levels lead to changes in epigenetic gene expression patterns in BMSC that leads to compromised bone formation, which increases the likely hood of osteoporosis. Ten-eleven translocation (Tet) family is a group of DNA demethylases, able to convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), an epigenetic marker in osteogenesis. Our studies have shown that Tet2 is essential in driving the differentiation of bone forming osteoblasts and high glucose level inhibits the expression of Tet2. Furthermore, human BMSC grown in high glucose conditions were found to increase cell death, senescence and oxidative stress while decreasing cellular proliferation potential compared to regular growth media. High glucose levels also were shown to drive the differentiation of BMSC towards lipid forming adipocytes at the expense of mineral forming osteoblasts which was confirmed by differentiation gene expression analysis. Understanding the role of epigenetic regulators in hyperglycaemic conditions will help to identify solutions to battle bone loss seen in diseases such as diabetes and osteoporosis. Given that epigenetic marks can be reversed by pharmacological inhibitors and altered via changes in diet and lifestyle, these targets are of unique therapeutic importance.